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Copyright copy 2014 American Scientific PublishersAll rights reservedPrinted in the United States of America
ReviewJournal of
Biomedical NanotechnologyVol 10 1751ndash1783 2014
wwwaspbscomjbn
Anticancer Use of Nanoparticles as Nucleic Acid Carriers
D Gozuacik1lowast H F Yagci-Acar3 Y Akkoc1 A Kosar2 A Isin Dogan-Ekici4 and Sinan Ekici51Faculty of Engineering and Natural Sciences Biological Sciences and Bioengineering Program Sabanci UniversityOrhanli-Tuzla 34956 Istanbul Turkey2Faculty of Engineering and Natural Sciences Mechatronics Engineering Program Sabanci University 34956 Istanbul Turkey3Department of Chemistry and Graduate School of Materials Science and Engineering Koc UniversityRumelifeneri Yolu Sarıyer 34450 Istanbul Turkey4Department of Pathology Yeditepe University School of Medicine Atasehir 34755 Istanbul Turkey5Department of Urology Maltepe University School of Medicine Maltepe 34843 Istanbul Turkey
Advances in nanotechnology opened up new horizons in the field of cancer research Nanoparticles made of variousorganic and inorganic materials and with different optical magnetic and physical characteristics have the potential torevolutionize the way we diagnose treat and follow-up cancers Importantly designs that might allow tumor-specifictargeting and lesser side effects may be produced Nanoparticles may be tailored to carry conventional chemotherapeuticsor new generation organic drugs Currently most of the drugs that are commonly used are small chemical moleculestargeting disease-related enzymes Recent progress in RNA interference technologies showed that even proteins thatare considered to be ldquoundruggablerdquo by small chemical molecules might be targeted by small RNAs for the purpose ofcuring diseases including cancer In fact small RNAs such as siRNAs shRNAs and miRNAs can drastically changecellular levels of almost any given disease-associated protein or protein group resulting in a therapeutic effect Genetherapy attempts were failing mainly due to delivery viral vector-related side effects Biocompatible non-toxic and efficientnanoparticle carriers raise new hopes for the gene therapy of cancer In this review article we discuss new advances innucleic acid and especially RNA carrier nanoparticles and summarize recent progress about their use in cancer therapy
KEYWORDS Cancer Drug Chemotherapy Nanomedicine Nanoparticles RNA Interference siRNA shRNA microRNA
Nanocarriers Targeted Therapy
CONTENTSIntroduction 1751Scope of the Review 1753RNA Interference 1754Small RNAS as Potent Drugs 1755RNADNA Nanocarriers for Cancer Therapy 1755
Liposomes 1758Lipidoids 1758Minicells 1758Polyplexes 1758PEI 1759PLGA 1759Dendrimers 1759Atelocollagen 1760Chitosan 1760Cyclodextrins 1760Aptamers 1760
lowastAuthor to whom correspondence should be addressedEmail dgozuaciksabanciuniveduReceived 10 February 2014Accepted 15 February 2014
Inorganic Particles 1760Carbon Nanotubes 1761Magnetic Nanoparticles 1761Quantum Dots 1761Gold Nanoparticles 1762Silica Nanoparticles 1762
Recent In Vivo Studies Using RNA Interference inCancer Therapy 1762
Tumor Types and RNAi Therapy 1762Combination Treatments 1773RNAi-Targeted Genes 1774miRNAs and Antagomirs 1774Targeted Delivery Strategies 1775Delivery Methods 1775
Conclusions 1775Acknowledgments 1776References 1776
INTRODUCTIONIn spite of the advances in medical sciences and technolo-gies cancer is still one of the leading causes of mortality
J Biomed Nanotechnol 2014 Vol 10 No 9 1550-70332014101751033 doi101166jbn20141935 1751
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and morbidity in developed and developing countries1
Classical treatment modalities namely chemotherapyradiotherapy and surgery have been used from the begin-ning of 20th century with limited treatment success ratesespecially for advanced stage disease In the last decades
D Gozuacik MD PhD is an Associate Professor in the Biological Sciences andBioengineering Program at Sabanci University Istanbul Turkey He received his Med-ical Doctor (MD) degree in 1995 from Hacettepe Medical Faculty Ankara Turkey hisDEA degree of biochemistry from Ecole Polytechnique Paris France and his PhDdegree on Molecular Cell Biology in 2001 from Paris XI University and Pasteur Insti-tute Paris Before joining Sabanci in 2006 he worked as a postdoctoral researcher inthe Weizmann Institute of Science (2001ndash2006) on cancer biology His current researchfocus is cellular death and stress responses including autophagy in health and diseaseRNA interference therapies and nano-drugs Dr Gozuacik is a board of directors mem-ber of the International Cell Death Society (ICDS) editor of the Autophagy journal(IF 12) and an ad hoc referee of various international journals and granting agen-
cies He received excellence awards from several institutions including European Molecular Biology Organization(EMBO) Roche Pharmaceuticals and Turkish Academy of Sciences
H F Yagci-Acar PhD is an Associate Professor in the Chemistry Department atKoccedil University Istanbul She received her BS and MS degrees in Chemistry fromBogazici University Istanbul Turkey in 1993 and 1995 respectively She received herPhD in Polymer Science and Engineering from University of Southern MississippiHattiesburg in 1999 She worked as a post-doctoral fellow at GE GRC-Niskayunabetween 2000 to 2002 and as a lead scientist until 2004 then she joined Koccedil Universityin 2004 Her research focuses on the development of novel polymers (living or conven-tional methods) magnetic nanoparticles luminescent semiconductor quantum dots andhybrid nanomaterials for biotechnology medicine and energy applications She receivedNational LlsquoOreal Women in Science Reward in Materials Science in 2005
Y Akkoc is a PhD student in the Biological Sciences and Bioengineering Program atSabanci University Istanbul He recieved his BSc degree from the Molecular Biologyand Genetics Department of Istanbul Kultur University in 2013 His research interestsinclude role of natural polyamines in cancer progression basic autophagy mechanismsand gene therapy of autophagy abnormalities
A Kosar PhD is an Associate Professor in the Mechatronics Program at Sabanci Uni-versity Istanbul He received the BSc degree in Mechanical Engineering from Bogazici(Bosphorus) University Istanbul He pursued his graduate studies in the Departmentof Mechanical Engineering at Rensselaer Polytechnic Institute where he completed hisMS and PhD degrees His research interests include micronano-scale heat transferand fluid flow cooling technologies magnetic manipulation of nanoparticles and mag-netic hyperthermia therapy Dr Kosar is a recipient of various national and internationalawards including Turkish Academy of Sciences Outstanding Young Investigator Award(GEBIP) and TUBITAK (The Scientific and Technological Research Council of Turkey)Incentive Award
chemotherapy and radiotherapy approaches evolved tominimize toxicity invasiveness and side effects while pre-serving effectiveness Yet the basic action mode of bothchemotherapy and radiotherapy is perturbation of the divi-sion and induction of the death of all rapidly proliferating
1752 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
A Isin Dogan-Ekici MD is an Associate Professor in the Pathology Department atthe Yeditepe University Hospital Istanbul She graduated from Hacettepe UniversitySchool of Medicine in 1997 Dr Dogan-Ekici obtained her pathology specialist degreefrom Hacettepe University School of Medicine Department of Pathology in 2003 Herresearch interests include surgical pathology nephropathology and urogenital systempathology and pathology of gene therapy models
Sinan Ekici MD is a Professor in the Department of Urology at the Maltepe Univer-sity School of Medicine He graduated from Hacettepe University School of Medicinein 1995 He obtained his urology specialist degree from Hacettepe University School ofMedicine Department of Urology in 2000 Dr Ekici worked as a clinical observer inMemorial Sloan Kettering Cancer Center New York and worked as research and clin-ical fellow in the Department of Urooncology Miami University School of MedicineUSA His research interests include urooncology endoscopic urology cancer biologygene therapy of urological cancers
cells in a non-selective way Consequently both of theseapproaches are accompanied with side effects ranging fromhair loss and gastrointestinal (GI) problems (hair folliclesand GI tract cells are amongst most rapidly proliferatingcells in the body) to secondary cancer development (egLeukemias) due to DNA damage Therefore developmentof targeted and cancer cell-selective therapies with minimalshort- and long-term side effects is an important challengeRecent progress in molecular biology genetics and
biotechnology allowed the development of small moleculedrugs targeting cancer-related proteins antibody-baseddrugs immunomodulatory approaches and cellular ther-apies ranging from improved bone marrow transplan-tation to stem cell treatments Some of these novelapproaches already entered clinical use alone or as partof an adjuvant or combinatory therapy with classical treat-ment modalities2 Parallel advances in diagnostic tech-niques cancer genetics and pathology led to a better andmore detailed classification of cancer subtypes allowingsubtype-specific even personalized treatment regimens3
In spite of all these innovations and efforts in the can-cer medicine field disease-free survival rates are lowand prognosis is still bad especially in advanced andormetastatic cases Therefore a better understanding ofcancer biology and development of novel and innovativetreatment approaches is still one of the most importantchallenges of modern science and medicineA great majority of small molecule drugs target disease-
related enzymes or receptors4 Yet we now understandthat complex processes and changes during cancer initia-tion progression and evolution leading to drug resistanceresult in the mutation andor dysregulation of enzyme
and non-enzyme proteins and even nucleic acids such asmicroRNAs and long non-coding RNAs5 In the post-genomic era with the advances in genomics and epigenet-ics of cancer gene therapy is one of the innovative cancertherapy fields gaining momentum in recent years Genetherapy approaches offer the possibility of up or downreg-ulation of dysregulated gene products and replacement ofmodifiedmutated transcripts with non-mutatedwild typeforms6 Experimental treatments using nucleic acids rangefrom DNAcDNA replacement therapies to RNA-basedregimens Although establishment of general concepts ofgene therapy date back to 1960s and 1970s issues relatedto the stability and half-life of the nucleic acid moleculesand most importantly lack of suitable delivery and target-ing systems limited the success of this promising technol-ogy Until recently viral systems were the major focus ofgene delivery studies and gene therapy protocols Modi-fied viruses including adenoviruses retroviruses herpesviruses and lentiviruses were examined and tested in detailas gene delivery agents In addition to severe immunereactions ranging from inflammation to shock insertionalmutagenesis caused by viral integration into the patientgenome constituted major side-effects and drawbacks rais-ing concerns and doubts about the future of gene therapy7
With recent advances in nanotechnology several non-viralgene delivery systems were developed as gene and drugcarriers reviving hopes about the use of nucleic acids aspotent drugs against cancer
SCOPE OF THE REVIEWIn this review we will summarize and discuss accumu-lating data about the use of nanoparticles as nucleic acid
J Biomed Nanotechnol 10 1751ndash1783 2014 1753
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
carriers We will limit ourselves to cancer gene ther-apy studies exploiting nanocarrier loaded small RNADNAmolecules ie RNA interference (RNAi) tools such assiRNAs shRNAs and microRNAs Merits and contribu-tions of antisense oligonucleotides in gene therapy experi-ence were discussed in detail elsewhere8
RNA INTERFERENCEDiscovery of RNA interference (RNAi) by Andrew Fireand Craig Mello was a breakthrough that was awarded bythe Nobel prize in Physiology or Medicine in 2006 SmallRNAs mediating RNA interference control gene expres-sion in organisms ranging from plants and C elegansto human Small interfering RNAs (siRNAs) short hair-pin RNAs (shRNAs) and microRNAs (miRNAs) are themost studied members of regulatory RNAs9 Non-codingsmall RNAs are not translated they mainly act at a post-transcriptional level determining the stability of messen-ger RNAs (mRNAs) and their translation into proteinsEndogenous siRNAs (endo-siRNAs) are coded not only
by transposons and other repeat elements but they mayalso originate from regions where both sense and antisensetranscripts are transcribed as well as from sequences giv-ing rise to potential hairpin structures inside pseudogenes
Scheme 1 RNA interference (RNAi) pathways (a) miRNA pathways (b) siRNA pathways See text for the pathway details RNAPol II RNA polymerase II Dicer Dicer enzyme complex into the siRNA RISC RNA-induced silencing complex (RISC) RdRPRNA-dependent RNA polymerase ORF open reading frame of the target gene AAAAA polyA tail of the mRNA
and even in protein-coding genes1011 On the other handmiRNAs may be intronic or intergenic Intronic miRNAsare transcribed from intron regions of some protein codingmRNAs while intergenic miRNAs are transcribed frommiRNA genes or gene clusters using their own promotersEndogenous siRNAs and miRNAs bear similarities to
each other from a structural and functional point of viewYet pathways leading to their maturation are rather spe-cific to the small RNA type (Scheme 1(a)) miRNAs aretranscribed by RNA polymerase II as primary-miRNAs(pri-miRNAs) and processed by a Drosha-DGCR8 com-plex in the nucleus to produce hairpin-shaped premature-miRNAs (pre-miRNA)12 Transport from nucleus isachieved with the help of the exportin-Ran GTPase com-plexes Further processing of the pre-miRNA hairpin bycytoplasmic DICER proteins produces sim 21ndash22 nt longmiRNAmiRNAlowast duplexes One of the mature miRNAstrands that originate from the duplex is then loaded ontoa complex called the RNA-induced silencing complex(RISC) including the Argonaute (eg AGO2) proteinsRISC then guides the mature miRNA strand towards tar-get messenger RNAs (mRNAs) It is believed that tar-get specificity of the miRNA and the fate of the targetmessenger RNA depends on the degree of complemen-tarity between matching sequences of these two types of
1754 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
RNAs While a partial complementarity may lead to theblockage of the translation machinery protein translationrepression andor sequestration of miRNA-mRNA com-plexes in compartments called P-bodies a perfect matchbetween these two RNAs may result in mRNA degradation(Scheme 1(a))Conversely endo-siRNAs complementary to template
mRNAs are synthesized by RNA-dependent RNA poly-merases (RdRP) and they are not transcribed from thegenomic DNA (Scheme 1(b)) It was long believed thatmammals did not have any RdRPs But this conceptis now changing For example human telomerase cat-alytic subunit (hTERT) was shown possess a mammalianRdRP activity required for double stranded RNA synthe-sis from the mitochondrial RNA processing endoribonu-clease noncoding RNA component1314 In the endogenoussiRNA pathway hairpin containing double-stranded RNAproducts of RdRP are further processed into functionalendogenous siRNAs in either a Dicer-dependent or aDicer-independent manner (Scheme 1(b)) In general thesense guide strand of the endo-siRNAs are loaded onto theRISC with AGO2 proteinsWhile in general mammalian miRNAs show partial
complementary to their mRNA target sequences and con-trol a wide number of functionally-related transcripts strictcomplementarity was thought to be necessary for siRNAfunction9 But even synthetic siRNAs or shRNAs that aredesigned to target one and only mRNA were shown toaffect so called ldquooff-target genesrdquo Therefore although agene with a dominant biological effect will be targeted bysiRNAshRNAs a spectrum of biological events might beaffected by the use of a small RNA Nevertheless in vitrocell culture and animal studies confirmed that the biolog-ical outcomes of siRNAshRNAs and even miRNAs wereusually determined by their effect on a dominant targetgene andor pathway1516
SMALL RNAS AS POTENT DRUGSUse of potent RNA interference strategies might give usnew opportunities for the treatment of diseases such ascancer17 Potential advantages of small RNAs over existingsmall molecule drugs and conventional therapies includeorganic composition natural metabolism lower drug tox-icity minimal immune reactions when designed optimallyand combined with appropriate carriers possibility ofmodulating targets that are considered as ldquoundruggablerdquo byconventional drugs possibility of targeting disease-relatedtissue-specific isoforms andor mutant transcripts and stan-dard chemical synthesis protocols Moreover RNA plat-forms are now widely used in high throughput formats fortarget validation and drug development processes reduc-ing the product development cycle and cost compared toconventional small molecules18
Modifications to the native RNA structure can cre-ate robust drug-like RNA molecules19 Synthetic 21-mer
RNA duplexes mimicking natural siRNAs and miRNAsare commonly used in RNA-based gene therapy protocolsAlternatively asymmetric 2527-mers or 2729-mers blunt25-mers blunt 27-mers and blunt 19-mers were tested fortheir stability and potency as RNA drugs with variablemerits20ndash23 These different synthetic RNAs might directlybe loaded onto the RISC complex or they might firstrequire processing by Dicer In fact even under in vitro con-ditions synthetic siRNAs were shown to directly load ontorecombinant human AGO2 proteins and form functionalcomplexes24 Therefore following delivery small RNAsmay rapidly form functional complexes and alter target pro-tein levels resulting in therapeutic changes in cellsNaked RNA molecules are highly susceptible to degra-
dation by nucleases that are abundant in tissues and in theblood circulation Therefore to stabilize RNA moleculesincrease their half-lives in biological environments andavoid immune reactions a number of chemical changesmight be introduced to the nucleic acid structures19
There are several commonly used RNA modifications2prime-O-methyl modifications into the sugar structure ofsome nucleotides may confer resistance to endonucle-ases decrease off-target effects when introduced into theseed region and minimize Toll-like receptor-mediatedimmune reactions25ndash27 Introduction of phosphorothioateboranophosphate or methylphosphonate backbone linkagesat the 3prime-end of the RNA strands may reduce their suscepti-bility to exonucleases Similarly alternative 2prime sugar mod-ifications such as 2prime-fluoro LNA (Locked nucleic acids)FANA (2prime-deoxy-2prime-Fluoro--d-arabinonucleic acid) and2primeMOE (2prime-O-methoxyethyl) modifications were reportedto increase endonuclease resistance of small RNAs28
While all these modifications result in more robust RNAmolecules they might affect the potency of the RNA inter-ference effects obtained during treatment Therefore evenif the changes were performed according to design criteriaor computer tools experimental testing is required in eachseparate case to confirm potency of modified small RNAmolecules on their mRNA targets2930
RNADNA NANOCARRIERS FORCANCER THERAPYUse of gene therapy and lately small RNAs for can-cer treatment was hindered by the lack of a suitabledelivery system Recent developments in nanotechnologyallowed the introduction of nanoparticles with very differ-ent physico-chemical properties Novel and sophisticatednanocarriers and their functionalized derivatives are beingtested as potent and in many cases targeted RNA drugdelivery agents Some formulations are already in clinicaltrials and a few of them were even approved by majoragencies such as the Food and Drug Agency (FDA) in theUSA31
Nanoparticles to be used as nucleic acid delivery agentsshould meet several criteria The particles should safely
J Biomed Nanotechnol 10 1751ndash1783 2014 1755
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and effectively deliver RNA molecules to cancer cells andtumors Therefore they have to be biocompatible notimmunogenic and they should not get modified or dis-solved into toxic substances under biological conditionsand before reaching the tumor target For effective deliv-ery and dosage nano conjugates have to be stable enoughin the blood circulation and resist shear forces proteasesand nucleases that they face with Complex formation withblood cells proteins and other blood components mightalso affect carrier size charge availability and efficacyClearance is also an important issue For nanocarriers
to reach therapeutic blood levels they should not be read-ily cleared through glomerular filtration in the kidneys ortrapped by the reticuloendothelial system For examplenaked siRNA molecules and nanoparticles less than 10 nmmay be filtrered and excreted through kidneys follow-ing systemic administration Carriers larger than 100 nmmight be phagocytosed and cleared by monocytes andmacrophages residing in the reticuloendothelial system(RES also called mononuclear phagocytic system) tissueswith high blood supply including pulmonary alveoli liversinusoids skin spleen etc32ndash36 In addition to the size of thenanoparticles their geometries surface charges hydropho-bicities and opsonization by serum proteins might affectclearance by monocytes and macrophages Additionallythe efficacy of nucleic acid drugs in specific tissues andorgans may depend on the ability of nanocarriers to pene-trate blood vessels and tissues and pass through biologicalbarriers such as the tight blood-brain-barrier of the centralnervous systemFor cancer treatment small RNA drugs should affect
genetic andor molecular changes specific to cancer cellsand that are rate-limiting for tumor growth The idealnanocarrier should be able to concentrate within the tumortissue and if possible target individual tumor cells in aselective way (eg through receptors or molecules thatare tumor-specific or that are enriched in the tumor tis-sue) and not penetrate normal cells Enhanced permeabilityand retention (EPR) effect offers an advantage for solid-tumor targeting The EPR effect is a result of neovascu-larisation new blood vessel formation to feed tumors withsizes beyond passive oxygen and nutrient diffusion lim-its (beyond 01ndash02 mm diameter)37 Blood vessels feed-ing tumor tissues are irregular and highly permeable Withthe lack of lymphatic drainage macromolecules are eas-ily retained in and around the tumor area3839 For exam-ple low molecular weight drugs may diffuse freely inand out of the tumor tissues but macromolecules (gt 40kDa) and nanoparticles of 100ndash200 nm accumulate inthe tumor tissue3840ndash43 EPR phenomenon was reported invarious human solid tumors as well as in inflammatorytissues44
Different types of nanoparticles were tested as drug car-riers and gene therapy tools (Scheme 2) The core structureof the particle may be a vesicle (liposomes) a polymer(eg PEI PLGA) a dendrimer carbon nanotubes silica or
metal nanoparticles (eg Gold) Porousvesiculate carrierssuch as liposomes polymeric micelles or some inorganicparticles (eg mesoporous silica) may encapsulate orabsorb RNADNA molecules Nanocarriers with a cationicnature including cationic liposomes cationic dendrimers(eg PAMAM) and polymers (eg PEI PDMAEMA) orcationic polymer coated inorganic particles (eg PEI cov-ered iron oxide) may form complexes through electro-static interactions with the negatively charged backboneof nucleic acids The nature and physico-chemical proper-ties of the nanoparticles may also influence their stabilityand half-life in blood criculation efficacy of their deliveryinto tissues and cells and their capacity to escape fromendosomes in the cell All these properties are determiningcriteria for nano drug efficacyTo improve stability RNADNA loading target speci-
ficity tracking cellular internalization endo-lysosomalescape and intracellular robustness additional functionalunits might be introduced to the basic structure ofthe nanocarriers (Scheme 3)45 Possible modificationsand changes include conjugation to proteins (antibodieslectins cytokines thrombin fibrinogen BSA transfer-rin) cellular or viral peptides (eg RGD LHRD TATPep-3 KALA) polysaccharides (eg lipopolysaccharideshyaluronic acid dextran chitosan) low molecular weightligands (eg folic acid anisamide) and polyunsaturatedfatty acids (eg palmitic acid and phospholipids) Thesestructures can be conjugated onto the nanocarrier surfacethough hydrolysable or non-hydrolysable chemical bondsand modifications such as amide ester silane hydrazoneor through the use of high avidity molecules such asavidin-biotin Fluorophores may also be added for par-ticle tracking purposes To improve the availability ofsuch groups and especially the targeting groups spacermolecules may be addedAn important modification relevant for biological func-
tion is ldquoPEGylationrdquo (Scheme 3)45 PEG coordinateswater molecules and forms an aqueous shell aroundnanoparticles shielding their charges PEGylation reducesinteraction with serum proteins decreases opsoniza-tion and clearance of nanoparticles by RES monocyte-macrophages sterically prevent nanocarrier aggregationand due to increased molecular weight above the thresholdfor glomerular filtration reduces elimination of the parti-cles through urinary excretion Hence PEG increases thestability improves biocompatibility prolongs blood circu-lation time and bioavailability of nanocarriers4647 Molec-ular weight and density of PEG chains on the nanocarriersurface may impact the function depending on the natureof the carried molecules ie siRNA47
On the other hand PEGylation significantly attenu-ates uptake of nanocarriers by target cells4849 More-over PEG chains were shown to block endosomal escapeand cytosolic release of chemical drugs and nucleicacids50 Blockage of cellular uptake and endosomal releasein the cell may severely attenuate drug efficacy and
1756 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 2 Major types of nanoparticles used as nucleic acid carriers
therapeutic RNA interference effects Various strategieswere adapted to overcome these negative effects of PEGwhile exploiting its circulatory advantages Cleavage ofPEG-chains upon delivery into the tumor environment wasachieved through addition of tumor-related matrix met-alloproteinase sensitive lipids or peptides51 pH-sensitivelinkers between the PEG moiety and nanocarriers canalso be used to release PEG from the particle in theacidic environment of the endosomes and allow cytosolic
Scheme 3 A representative nanoparticle with functional modifications Various molecules might be added to a nanoparticleto improve its physico-chemical properties and pharmacokinetics (eg PEG) to increase RNADNA binding (eg PEI) to allowbetter targeting (eg antibodies) or tracking (eg fluorophores)
release of small RNAs Modulation of the hydrophobic-ity of the PEGndashnanocarrier conjugate was also testedas a release strategy In lipid-based nanocarriers thelength of the alkyl chain of the PEG-lipid anchor wasshown to determine its affinity for the lipid deliveryvehicle and changing its length modified endosomalescape potential and drug effects52 Cholesterol-anchoredPEG was also shown to improve endosomal escapecapacities52
J Biomed Nanotechnol 10 1751ndash1783 2014 1757
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
LiposomesLiposomes have been tested extensively as gene deliv-ery agents Liposomes are artificial membrane-boundvesicles formed by bilayers of amphipathic lipids Theymight be unilamellar or multilamellar Their biocom-patibility low toxicity and low immunogenicity madethem popular agents for both in vitro and in vivo genedelivery5354 Liposomes are typically made of mix-tures of lipids found in biological membranes or theirderivatives including phosphatidylcholine (PC or DOPC12-Oleoyl-sn-Glycero-3-phosphatidylcholine) phosphatidyl-ethanolamine (PE or DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidylethanolamine) cholesterol and evenceramide53 Although liposomes made of neutral lipids aremore biocompatible than cationic lipids and have betterpharmacokinetics during preparation of gene deliveryvectors they bind less to negatively charged DNA orRNA molecules and have lower entrapment efficiencies55
Therefore despite their more toxic nature cationic lipidsare commonly used as liposome-based transfection agentsCationic lipids posses positively charged headgroupssuch as amines quaternary ammonium salts peptidesaminoacids or guanidiniums which electrostaticly attractand bind to negatively charged phosphate residues innucleic acid backbones The nature of cationic lipid head-groups determines the efficacy of gene delivery Thereforevarious mixtures of lipids with different headgroupsand properties were tested to achieve optimal liposomeformulations for drug andor gene delivery56ndash59
Although liposomes are excellent transfection agentsin vitro some side effects and problems were encoun-tered during in vivo studies56ndash59 These include intracellu-lar instability and failure to release small RNA contentsdose-dependent toxicity and pulmonary inflammation thatcorrelated with the production of reactive oxygen species(ROS) opsonization by serum proteins immunogenic-ity and uptake by the RES components60ndash63 Addition-ally cationic liposome-dependent gene expression changeswere observed during in vitro experiments with someformulations64
In order to minimize such undesired effects special-ized liposomes were produced through addition of vari-ous functional groups PEGylation and crosslinking withinthe bilayer of the liposomes was successfully utilized toimprove stability and decrease side effects65 PEGylationin general improved bioavailability and biocompatibilityas well For example to obtain improved pharmacokinet-ics PEGylated cationic liposomes called ldquosolid nucleicacid lipid particlesrdquo (SNALPs) were created and they weresuccessfully used for siRNA delivery In fact in SNALPsPEG coating neutralized net charge and increased theblood circulation time of the liposomes significantly66ndash72
Moreover fusogenic lipids added to liposome formula-tions improved cellular uptake and endosomal escape33
Most importantly SNALPs were relatively well toler-ated in vivo even in non-human primates3233 The list of
modifiedimproved liposomes performing well in in vivostudies also includes cationic solidndashlipid nanoparticles andcardiolipin-based liposomes3373ndash75 Currently improvedliposomes are one of the most promising tools for genedelivery and patented formulations produced by sev-eral companies were successful enough to reach clinicaltrials31
LipidoidsLipidoids are cationic lipids that are created by the conju-gation of primary or secondary amines to alkyl-acrylatesor alkyl-acrylamides76 They were introduced as novelalternatives to liposome formulations used in gene deliv-ery Changes in the composition lipidoids were shown toimprove their therapeutic properties For example changesin the alkyl chain length of the PEG lipid was reportedto affect PEG deshielding rate and dose kinetics of lipi-doids in the blood76 Moreover cholesterol incorporationwas shown to improve carrier stability Small sized lipi-doids (50ndash60 nm) were successfully used for the deliveryof siRNA into liver cells avoiding engulfment by Kuppfercells76 Lipidoids may also be used for coating inorganicnanoparticles in order to introduce cationic charges77 Lipi-doids have lower toxicity and increased efficacy thereforethey present an alternative to classical liposomes for genedelivery studies
MinicellsMinicells are bacteria-derived non-living anucleatednano-sized vesicles that were used as nano drug carriers78
Inactivation of min genes that control normal division inbacteria such as Salmonella typhimurium result in the for-mation of minicells min gene products ensure that celldivision septum is correctly located to the midpoint ofthe cell In case of min gene product mutations septa-tion defects result in the formation of minicells devoid ofthe chromosomal DNA Therapeutic RNAs may be loadedinto minicells by the introduction of shRNA of interestinto min mutant bacteria and eventually shRNAs segregateinto minicells78 Purified minicells prepared by this methodare pre-packaged with effective copy numbers of the plas-mid For targeting purposes tumor-specific antibodies maybe decorated onto minicells by the exploitation of bac-terial cell surface components such as O-polysaccharideof LPS Minicell-RNAi combinations proved to be effec-tive in experimental cancer treatment79 Other cell derived-vesicles that were tested as nanocarriers include bacterialghosts bacterial outer membranes or mammalian cell-derived exosomes80ndash82
PolyplexesMaterials that self-assemble with nucleic acids intonanocomplexes are called ldquopolyplexesrdquo These complexesgenerally form though the electrostatic interaction of the
1758 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
cationic units of the polymers with the anionic phos-phate groups of the nucleic acids Natural and biocompat-ible (eg chitosan Atelocollagen cyclodextrin) or morefrequently synthetic (eg Polyethylenimine PEI poly-L-lysine PLL poly-dl-lactide-co-glycolide PLGA) poly-mers are used for polyplex formation83ndash86 Flexibility of thesynthetic polymers in terms of chemical nature molecularweight and architecture (linear branched grafted blocky)provide opportunity to balance their toxicity improvenucleic acid binding protection and release efficienciesMoreover surface modifications may be introduced for tar-geting purposes and improved pharmacodynamics Poly-mers such as PLGA also benefit from a biodegradablenature which allows clearance of the nanocarriers in time
PEIPEI is the most widely and most successfully used polyca-tion for polyplexe formation It can be synthesized in lin-ear or branched forms and in variable molecular weights(from 1 kDa to gt 1000 kDa) Higher molecular weightpolymers (70 kDa and above) are very effective in nucleicacid binding but they are significantly toxic Low molec-ular weight forms (2 kDa or less) are less toxic but theyare less effective as transfection agents87 Therefore PEIsat and below 25 kDa with a branched or linear architec-ture are commonly used as gene delivery reagents88ndash91 Thegolden standard gene delivery polymer is branched PEIof 25 kDa which offers a balance between the toxicitynucleic acid bindingprotection and release Abundance ofpositive charges due to protonation under physiologicalconditions allows PEI to spontaneously form complexeswith negatively charged small RNAs and DNAs and pro-tect nucleic acid molecules from nuclease attacks84 More-over buried inside the polymer some off-target effects ofthe small RNAs were shown to be prevented92
The net positive charge of PEI-RNAi complexes alsoallow interactions with the negatively charged polysaccha-rides found on the cell surface93 These interactions arebelieved to be an important factor for the endocytosis ofthe complexes by target cells A key event for the successof gene delivery is the escape of the nucleic acids fromthe endosomal pathway in order to avoid accumulation anddegradation in the lysosomes of the cell93 The escape isthought to be the result of the lsquoproton spongersquo effect wherethe influx of protons and water lead to endosome swellingrupture and release of contents including nucleic acids tothe cytosolPEI-induced toxicity was proposed to be a result of
mitochondrial apoptosis induction by the polymer9495
Moreover PEI itself was shown to cause changes in geneexpression in vivo which might influence biological out-comes of treatment protocols59 PEGylation of the PEIreduces both cytotoxicity of PEI-polyplexes and increaseblood circulation half-life However a critical balanceneed to be achieved since PEGylation decreases the sur-face charge it impacts the binding capacity and cell
internalization of the polyplexes Alternatively short PEIchains attached together with hydrolysable links such asdisulfide and ester may provide initially a high molecu-lar weight PEI system for good nucleic acid condensationand protection but upon dissolution because of intracel-lular redox conditions they may act as a low molecularweight PEI polymers with lower toxicity87 Additionallypluronics that are block copolymers of ethylene glycol-propylene glycol-ethylene glycol can be used instead ofPEG Similar to PEG pluronics were shown to improvethe biocompatibility and bioavailability of the nanocarri-ers but they interact better with the cell membrane due tothe propylene glycol units and enhance cellular uptake ofthe particles87
PLGAPLGA is a biodegradable copolymer of glycolic acid andlactic acid96 It is widely used in biomedical research asan FDA-approved substance PLGA offers several advan-tages The polymer is highly stable biodegradable andallows sustained release During nucleic acid deliveryPLGA is easily taken up by cells through endocytosisand no serious toxicity problems were observed97 PLGAbinds nucleic acids weakly but it might encapsulate themfor drug delivery purposes Indeed PLGA nanoparticleswere used in several studies for delivery of drugs totumors through the EPR effects98 Yet following endocyto-sis PLGA particles do not effectively realease cargo fromendosomes8397 To overcome nucleic acid binding deliv-ery and endosomal release problems the surface of PLGAcan be decorated with various cationic nanoparticles suchas DOTAP PEI or polyamine and may be conjugated topeptides and antibodies99
DendrimersDendrimers are tree-like highly branched generally sym-metrical and three-dimensional macromolecules Theyhave uniform size and molecular weight which increaseswith each new branch (generation) Dendrimers possess ahighly functional outer surface allowing chemical modi-fications and interactions Therefore they may be used asflexible and modifiable gene delivery agents100 Besidesthe ability of dendrimers to encapsulate cargos add to theirpotential as drug carriers101 Dendrimers including poly-amidoamine dendrimers (PAMAM) poly-propylene imine(PPI) dendrimers poly-L-lysine dendrimers triazine den-drimers carbosilane dendrimers poly-glycerol-based den-drimers nanocarbon-based dendrimers and others weretested as RNAi delivery agents PAMAM and PPI den-drimers being the most commonly studied ones It wasshown that introduction of surface-modifications mini-mized toxicity-related problems increased RNAi-bindingand cellular uptake efficacies of the dendrimers102103
Of note in vivo gene expression changes were alsoobserved with drug-free dendrimers104 Therefore well
J Biomed Nanotechnol 10 1751ndash1783 2014 1759
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
controlled experiments are needed before drawing conclu-sions during RNA interference studies
AtelocollagenAtelocollagen is an organic protein-based moleculederived from type I collagen of calf dermis Sinceit is obtained following a pepsin treatment atelocolla-gen is devoid of telopeptides that are responsible forthe immunogenicity of collagen105 Moreover atelocol-lagen has low toxicity it was shown to stabilize RNAmolecules Increased cellular uptake and sustained deliv-ery was observed in in vivo making atelocollagen an idealagent for gene delivery106 Indeed several studies used ate-locollagen with success for the systemic or local deliveryof RNAi in tumor models107ndash109
ChitosanChitosan is obtained through alkaline deacetylation of thepolysaccharide chitin that forms the exoskeleton of crus-taceans some anthropods and insects Chitosan that is usedin biomedical research is a copolymer of N -acetyl-D-glucosamine and D-glucosamine having a positive chargeIn addition to being biodegradable and biocompatible chi-tosan has a low production cost Mucoadhesive propertiesof chitosan allow the penetration of the substance intoepithelial cell layers including the gastrointestinal barri-ers Nucleic acid encapsulation and sustained release wasproved to be possible using chitosan110ndash112 Moreover chi-tosan prolongs transient time in bowel improving par-enteral drug bioavailability113 Nanoparticles of chitosanare taken up into cells through endocytosis to a cer-tain extent To improve gene delivery efficacies PEG ordeoxycholic acid conjugates or modifications includingtrimethylation thiolation galactosylation may be intro-duced to chitosan111 Moreover chitosan-based carrierspossess functional groups that are suitable for conjugationto ligands relevant for targeted tumor delivery Althoughinefficient endosomal escape is a problem encounteredwith chitosan-based carriers some chemically modifiedforms showed improved escape properties114
CyclodextrinsCyclodextrins are natural polymers They are cyclicoligosaccharides of a glucopyranose generated during thebacterial digestion of cellulose Their central cavity ishydrophobic while the outer surface is a hydrophilicand they can create water-soluble molecular complexes115
Native cyclodextrins do not form stable complexeswith nucleic acids But the DNARNA complex for-mation capacities of the molecule can be modulatedand improved through molecular modifications includ-ing changes in functional groups hydrophilic-hydrophobicbalance charge density spacer length and conjugation toother carrier molecules115116 Cyclodextrins are not onlybiocompatible but they have the capacity to decrease
cytotoxicity of other molecules and carriers that are conju-gated to them117 Moreover cyclodextrins increase cellularadsorption and intake of molecules118 So in addition totheir use as a gene delivery agents cyclodextrins are usedas linking agents or structural modifiers in complex car-rier molecules For example conjugation of cyclodextrinto PEI resulted in lower toxicity and higher transfectionefficiencies119 In addition to the advantages cited abovea cyclodextrin polycation delivery system was reportedto block immune reactions raised against small RNAsthrough a masking effect120121 Importantly studies innon-human primates revealed that cyclodextrin-based car-riers were well tolerated and they do not stimulate signif-icant antibody responses120
AptamersAptamers are nucleic acid-based molecules selectedin vitro according to their capacity to bind target moleculesspecifically and with high affinity The immunogenicity ofaptamers is limited due to chemical modifications min-imizing adverse reactions Moreover nucleic acid natureand small size of aptamers result in improved transport andtissue penetration Since they can be specifically designedaccording to cell or tissue types (eg tumor cell com-ponents) side effects and off-target effects are minimalIn gene therapy applications the nucleic acid nature ofaptamers allows easy conjugation to RNADNA combin-ing targeting advantages with a therapeutic potential122
Alternatively non-covalent adapter linkages might be cre-ated between aptamers and RNA molecules Functionalgroups might be added to the 5prime- or 3prime-termini allowingcovalent or non-covalent conjugation of aptamers to carriernanoparticles123
Inorganic ParticlesInorganic nanoparticals such as carbon nanotubes mag-netic nanoparticles quantum dots and silica are the focusof recent efforts in drug and gene delivery Many of theseparticles actually offer the opportunity to combine imag-ing and therapeutic possibilities in the same particle ren-dering the nanocarrier a valuable ldquotheranosticrdquo device124
Increased surfacevolume ratio of inorganic particles pro-vides an opportunity for surface modifications includingconjugations to drugs oligonucleotides targeting peptidesor other molecules125126 Yet inorganic nanoparticles tendto aggregate and the size of the aggregate might have animpact on its function and biodistribution Such inorganicnanoparticles are hence coated with organic moleculeswhich provide colloid formation in aqueous and physiolog-ical media and stability Nature of the organic coatings hasto be designed for specific purposes but biocompatibilityof the organic molecules themselves andor their degra-dation products are critical for drug delivery purposes126
Chemistry of the coating might influence the half-life inblood and biodistribution as well as the toxicity of inor-ganic nanoparticles and their clearance mechanisms
1760 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Depending on the material they consist of inorganicnanoparticles may possess a number of different propertiessuch as high electron density and strong optical absorption(eg metal particles in particular Au) photoluminescenceor fluorescence (semiconductor quantum dots eg CdSeCdTe CdTeSeZnS) phosphorescence (doped oxide mate-rials eg Y2O3) or magnetic moment (eg iron oxide orcobalt nanoparticles) The shape of the nanoparticle is alsoan important factor influencing its interaction with cellsMany of the above mentioned nanoparticle are sphericalin shape except carbon nanotubes that are tubular
Carbon NanotubesCarbon nanotubes (CNTs) easily cross the plasma mem-brane and translocate directly into the cytoplasm of tar-get cells due to their nanoneedle structure and usingan endocytosis-independent mechanism yet they do notinduce cell death127ndash129 CNTs are classified as single-walled CNTs and multiwalled CNTs Single or multiplegraphine layer(s) might have a length ranging from 50 nmto 100 mm and a diameter of 1 nm to 100 nm Properfunctionalizing of CNTs by covalent or non-covalentstrategies (such as coating with PEG or Tween-20) mayprovide solubility in aqueous solutions and prevent non-specific interactions thus minimizing toxicity observedwith non-functionalized raw particles130131 Modificationsmight also increase biocompatibility and blood circulationhalf-life132133 CNTs have very strong absorption charac-teristics providing an opportunity for photothermal abla-tion therapy in addition to nanocarrier properties
Magnetic NanoparticlesMagnetic nanoparticles are composed of ferromagneticelements such as Ni Co Mn Fe Superparamagneticiron oxide nanoparticles (SPIONS) such as maghemite--Fe2O3 and magnetite-Fe3O4 are one of the most widelyused magnetic particles as nanocarriers due to relativelylow cost of production biocompatability and superpara-magnetic nature134135 SPIONS are approved by FDA forclinical trials They are commonly used as contrast agentsfor magnetic resonance imaging (MRI) SPION crystals(less than 10 nm in diameter) are coated for specificpurposes with organic molecules such as dextran aminodextran BSA PEI dendrimers lipids and trialkoxysi-lanes including aminopropyltriethoxy silane (APTES)Coating chemistry and preparation methods influence over-all hydrodynamic size pharmacokinetics and the contrasttype (dark-T 2 or bright-T 1 agent) Ability to track the fateof nucleic acid carrier magnetic nanoparticles in vivo usingMRI is highly desirable since it provides informationabout the location of the cargo and its biodistribution136
Attachment of ligands provides target specificity andPEGylation may improve biocompatibility and blood half-life These modifications are commonly introduced to SPI-ONs that are used for imaging and therapy purposes Due
to their magnetic nature drug or nucleic acid carrying SPI-ONs can be concentrated at desired diseased sites such astumors and they may be dragged magnetically towards thelesion area136137 Moreover magnetic nanoparticles offerthe possibility of hyperthermia treatment as a result ofmagnetic heating135 Under applied alternating magneticfield SPIONs cause local temperature increase (41ndash42 C)which may be exploited for alternative and efficient cancertherapy Therefore SPIONs are one of the most versatileand multifunctional nanoparticles Consequently SPIONswere used as popular gene delivery vehicles135
Magnetic nanoparticles may be engineered for oligonu-cleotide delivery purposes MRI visible PEI-PEG coatedSPIONs which are tagged with an antibody have beenshown to effectively carry siRNA to cancer cell lines andshowed low toxicity138 SPIONs coated with both thermoresponsive and cationic polymers such as poly[2-(2-methoxyethoxy)ethylmethacrylate]-b-poly-[2-(dimethyl-amino)ethyl methacrylate] were reported to have25ndash100 times better transfection efficiency than branchedPEI 25 kDa when coupled with magnetic targeting139
SPIONs coated with low molecular weight PEI(12ndash2 kDa) which is usually not effective as poly-plexes in transfection were shown succesful in deliveringsiRNA to mouse macrophages (H Yagci Acar WIPOPatent WO2006055447A3) Therefore magnetic nanpar-ticles are under heavy investigation for the developmentof multifunctional nanocarriers for cancer therapy anddiagnosis135
Quantum DotsSemiconductor quantum dots (QDs) are light-emittingnanoparticles of few nanometer in diameter and they havebeen increasingly used as biological imaging and labelingprobes140 Luminescencefluorescence properties of QDsdepend on the crystal size and type Chemical composi-tion of the crystalline semiconductor core determines theband gap of the material therefore the emission wave-length range Within possible spectral window size ofthe crystal determines the specific wavelength of lumines-cencefluorescence for each and every QD due to quan-tum confinement effect Broad absorption of QDs allowexcitation of multiple QDs at a single wavelength andminimal signal mixing due to the narrow emission bandIn addition they are much more resistant to photobleach-ing These two characteristics are the major advantages ofQDs compared to organic fluorophores as imaging probesUtilization of QDs in nucleic acid delivery aims bothimaging and therapy since in vivo localization of cargocan be observed using optical imaging systems141142 Forexample cationic CdTeZnS QDs conjugated with PEGwas demonstrated to form an effective nanoplex with sur-vivin siRNA and successfully transfeced human tonguecancer cells in vitro and provided real time tracking143
However well-established QDs harbour significant toxic-ity due to constituents such as Cd Se Te144 Therefore
J Biomed Nanotechnol 10 1751ndash1783 2014 1761
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
toxicity of these QDs is a drawback for their use in vivoAs an alternative silver (Ag) chalcogenites emerged assafer near-infra red-emitting QDs145146 Ag2S QDs did notinduce cytotoxicity ROS production apoptosis necrosisor DNA damage147 For example Ag2S QDs (coated with2-mercaptopropionic acid) emitting between 750ndash850 nmshowed no cytotoxicity in NIH3T3 cells at even highdoses (600 mgml) along with good cellular imagingpotential148
Gold NanoparticlesGold nanoparticles emerged as popular tools fornanocarrier-mediated gene therapy149 They are easily syn-thesized and biocompatible particles that allow addition offunctional molecules on their surface due to high surface-to-volume ratio114150 A variety of surface changes andfunctional additions were reported including cationic lipidcoating branched PEI addition or functionalization usingcationic quaternary ammonium or cystamine114151152
Indeed cystamine functionalized gold nanoparticles wereshown to effectively bind deliver and release 35 differ-ent miRNA in in vitro studies using neuroblastoma andovarian cancer cell lines153
Silica NanoparticlesSilica-based nanoparticles are inert stable biocompati-ble and biodegradable particles154 They can be renderedhydrophilic hydrophobic anionic or cationic using func-tional surface modifiers through electrostatic interactionsor by formation of any other type covalent bonds (egester amine) Common functionalization strategies to ren-der the molecule cationic and improve nucleic acid bind-ing include grafting of molecules such as PEI PEI-PEGand Poly-L-arginine155 Nucleic acids may also be loadedinside the mesoporous silica particles156 siRNA encapsu-lating mesoporous silica nanoparticles were successfullyused for in vitro and in vivo gene silencing in several stud-ies (For example Ref [156])
RECENT IN VIVO STUDIES USING RNAINTERFERENCE IN CANCER THERAPYThere is an exponential increase in the number of scientificpublications dedicated to gene therapy of diseases usingsmall RNAs and nanoparticles A literature search usingldquonanoparticlerdquo and ldquosiRNA shRNA or miRNArdquo revealedmore than 700 articles published in the last two yearsThis number is roughly equal to the number of all articlespublished in this field until two years ago So the field isexpanding and there seems to form a consensus aroundthe use of nanoparticles as next generation gene therapytools We believe that these high expectations are not onlya consequence of shifting trends in science and technol-ogy The exponential rise in interest in the field of smallRNA carrier nanoparticles is fueled by the advances inthe field of nano materials promising results obtained in
small RNA therapeutics by both academic laboratories andindustry and increasing number of successful clinical tri-als In this section we will summarize results of selectedrecent studies using RNA therapeutics for cancer treatmentin preclinical in vivo experimentsOverview of the works dealing with small RNA treat-
ment of experimental cancers and published within thelast two years were summarized in Table I Although sev-eral studies were performed using lipid-based nanopar-ticles (Liposomes micelles or lipidoids) other particlessuch as polymers organic or inorganic carriers and com-pounds mixtures with functional modifications of vari-able substances were also tested by many research teamswith reasonable success Scheme 4 summarizes the generalstrategy followed in most of these studies
Tumor Types and RNAi TherapyRecent studies in the literature showed that tumors of vari-ous tissue origins could be treated using RNA interferencestrategies (Table I) Fine tuning of nanoparticles throughaddition of functional moieties or modifications alloweddelivery of drugs into almost any kind of tumor tissue withaccompanied therapeutic effects Although several studiesused animal tumor models that resulted from the injectionof cell lines from most commonly seen human cancers(lung breast prostate cervix or ovarian cancer cell lines)animals with kidney urinary bladder head and neckgastric pancreatic melanomas neuroblastomas glioblas-tomas multiple myelomas or sarcomas were also treatedwith RNAinanocarrier strategy81156ndash170 These results givehope about the general use of RNA interference as astrategy to treat cancers of different origins Althoughit is difficult to compare the efficacies of different nucleicacid molecules and their interference effects at this pointsiRNA or microRNAs as well as shRNA vectors wereshown to achieve intratumoral in vivo target gene knock-down and anticancer effects leading to a decrease in tumorsize (For example Refs [156 171]) Since in most studiesin addition to RNAi loaded particles naked nanoparticlesor particles loaded with non-specific control nucleic acidswere also used antitumor effects obtained in these studiesare specific and they may be attributable to small RNAmolecules rather than the particles themselves underliningthe potential of RNA interference in cancer treatmentMajority of recent studies with in vivo models chose
to use human tumor cell line xenografts in immune com-promised mice nude or severe-combined immuno defi-cient SCID mice (Table I) (For example Refs [162 172])Syngeneic transplants and established genetically engi-neered mouse models of cancer were rarely studied in thiscontext167173ndash175 Therefore although antitumor effects andsome of the toxic effects (eg liver toxicity) might berevealed using immune compromised mice hematologicalimmunological and inflammatory side effects of the treat-ment strategies used in recent studies might need to berevisited using immunocompetent mice
1762 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IRec
entstudieswithRNAica
rryingnan
oparticles
forthetrea
tmen
tofex
perim
entalca
nce
rs(P
ublis
hed
within
thelast
twoye
ars)
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGF
Mag
netic
mes
oporou
ssilicana
nopa
rticles
PEIan
dfuso
genicpe
ptide
KALA
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[156
]
siRNA
Polo-likekina
se1(P
LK1)
pH-sen
sitiveca
tioniclip
idYSK05
-MEND
(YSK05
POPEcho
lesterol
=50
2525
)
PEG
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
PLK
1[51]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Bioen
gine
ered
bacterial
outermem
bran
eve
sicles
Hum
anep
idermal
grow
thfactor
rece
ptor
2(H
ER2)-spe
cific
affib
ody
targeting
HCC-195
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
KSP
Dec
reas
edtumor
volume
[81]
siRNA
Luciferase
Dioleoy
lpho
spha
tidic
acid-(DOPA
-)co
ated
nano
-sized
calcium
phos
phate(LCP-II)
DSPE-P
EG-an
dan
isam
idefortargeting
sigm
a-1rece
ptor
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
Xen
ograft
it
ND
Kno
ckdo
wnof
luciferase
[211
]
siRNA
mTERT
N-((2-hyd
roxy
-3-trim
ethy
l-am
mon
ium)propy
l)ch
itosa
nch
lorid
e(H
TCC)na
nopa
rticles
Partic
leload
edwith
paclita
xel
LCC
murinelung
canc
erce
llssy
ngen
eicsc
graft
oral
Noeffect
Kno
ckdo
wnof
mTERT
Dec
reas
edtumor
volume
Syn
ergize
dwith
paclita
xel
[159
]
siRNA
VEGF
Multilay
ered
polyion
complexes
Polyc
ationinterla
yeran
dade
tach
able
PEG
shell
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
[212
]
siRNA
Multid
rug
resistan
ceprotein1
(MRP1)
Nan
opartic
lesas
sembled
vialaye
r-by
laye
rde
positio
nof
siRNA
and
poly-L-arginine
Hya
lurona
n(H
A)co
ating
forHA-C
D44
targeting
MDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
it
Noeffect
Kno
ckdo
wnof
MRP1
Dec
reas
edtumor
volume
[183
]
siRNA
STA
T3-a
Nan
oporou
ssilicon
nano
particles
Argininean
dPEI
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicefat
padxe
nograft
iv
Noeffect
Kno
ckdo
wnof
STA
T3-a
[204
]
siRNA
Luciferase
Lipo
somal
nano
particle
Fou
rtand
emrepe
atsof
human
histon
eH2A
peptideinterven
edby
cathep
sinD
clea
vage
sites
PEG-A
nisa
mide
fortargeting
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
luciferase
[199
]
siRNA
Polo-likekina
se1(P
LK1)
Hya
luronicac
id(H
A)
base
dse
lfass
embling
HA-P
EIP
EG
nano
system
s
Hya
lurona
nforCD44
targeting
B16
F10
amurine
melan
omace
llsA54
9-luchu
man
lung
canc
erce
llsHep
3Bhu
man
liver
canc
erce
llsMDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
graftor
metas
tatic
lung
lesion
sby
IVinjection
it
ND
Kno
ckdo
wnof
PLK
1[160
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1763
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
P-glyco
protein
drug
expo
rter
(P-
gpM
DR1)
Mes
oporou
ssilica
nano
particles
Polye
thylen
eimine
polyethy
lene
glyc
ol(P
EI-PEG)co
polymer
MCF-7M
DR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gpMDR1
Dec
reas
edtumor
volume
Syn
ergy
with
doxo
rubicin
[179
]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Multifun
ctiona
lcarrie
rsy
stem
with
catio
nic
(olig
oethan
amino)am
ide
core
attach
edto
PEG
chain
Folic
acid
fortargeting
Inf7
(Infl
uenz
ape
ptide)
asen
doso
molytic
peptide
coup
ledto
the5prime-end
ofsiRNA
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
itor
iv
ND
Kno
ckdo
wnof
EG5
Dec
reas
edtumor
volume
[161
]
siRNA
Epide
rmal
Growth
Factor
Rec
eptor
(EGFR)
Poly-L-argininean
dde
xtransu
lfate-bas
edna
noco
mplex
FaDuhu
man
pharyn
xsq
uamou
sca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[172
]
siRNA
Cho
line
kina
se(C
hk)
Polye
thylen
imine-
polyethy
lene
glyc
ol(P
EI-PEG)co
grafted
polymer
Con
versionof
nontox
ic5-flu
oroc
ytos
ine(5-FC)to
cytotoxic5-flu
orou
racil
(5-FU)by
activating
bacterialc
ytos
ine
deam
inas
e(bCD)
PC3-PIP
andPC3-Flu
human
pros
tate
canc
erce
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
e[157
]
siRNA
Polo-like
kina
se1
(Plk1)
Cationiclip
idpo
lymer
hybrid
nano
particles
(cationiclip
id(N
N-
bis(2-hy
drox
yethyl)-N-
methy
l-N-(2-
choles
teryloxy
carbon
ylam
inoe
thyl)am
mon
ium
brom
ide
BHEM-C
hol)
andam
phiphilic
polymers(H
ydroph
obic
polylactideco
re)
PEG
shell
BT47
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Plk1
Dec
reas
edtumor
volume
[213
]
siRNA
hTERT
Single-walledca
rbon
nano
tube
s(S
WNTs)
Branc
hedPEIco
njug
ated
DSPE-P
EG20
00-M
aleimide
forco
njug
ationwith
NGR
(Cys
-Asn
-Gly-A
rg-C
ys-)
targetingpe
ptide(rec
ognize
tumor
neov
ascu
lature)
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
hTERT
Dec
reas
edtumor
volume
Syn
ergy
with
photothe
rmal
trea
tmen
t
[139
]
1764 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
REFERENCES1 R Siegel J Ma Z Zou and A Jemal Cancer statistics CA Can-
cer J Clin 64 9 (2014)2 M J Espiritu A C Collier and J P Bingham A 21st-century
approach to age-old problems The ascension of biologics in clini-cal therapeutics Drug Discov Today (2014)
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4 M N Patel M D Halling-Brown J E Tym P Workman andB Al-Lazikani Objective assessment of cancer genes for drug dis-covery Nat Rev Drug Discov 12 35 (2013)
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6 N F Sun Z A Liu W B Huang A L Tian and S Y Hu Theresearch of nanoparticles as gene vector for tumor gene therapyCrit Rev Oncol Hematol 89 352 (2013)
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
7 M Rothe U Modlich and A Schambach Biosafety challenges foruse of lentiviral vectors in gene therapy Curr Gene Ther 13 453(2013)
8 D R Corey RNA learns from antisense Nat Chem Biol 3 8(2007)
9 V N Kim MicroRNA biogenesis Coordinated cropping and dic-ing Nat Rev Mol Cell Biol 6 376 (2005)
10 D E Golden V R Gerbasi and E J Sontheimer An inside jobfor siRNAs Mol Cell 31 309 (2008)
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12 D H Kim M A Behlke S D Rose M S Chang S Choiand J J Rossi Synthetic dsRNA Dicer substrates enhance RNAipotency and efficacy Nat Biotechnol 23 222 (2005)
13 Y Maida M Yasukawa M Furuuchi T Lassmann R PossematoN Okamoto V Kasim Y Hayashizaki W C Hahn and K Masu-tomi An RNA-dependent RNA polymerase formed by TERT andthe RMRP RNA Nature 461 230 (2009)
14 N R Smalheiser The search for endogenous siRNAs in the mam-malian brain Exp Neurol 235 455 (2012)
15 K A Tekirdag G Korkmaz D G Ozturk R Agami andD Gozuacik MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5 Autophagy 9 374(2013)
16 G Korkmaz K A Tekirdag D G Ozturk A Kosar O USezerman and D Gozuacik MIR376A Is a Regulator ofStarvation-Induced Autophagy PLoS One 8 e82556 (2013)
17 D Castanotto and J J Rossi The promises and pitfalls of RNA-interference-based therapeutics Nature 457 426 (2009)
18 E Iorns C J Lord N Turner and A Ashworth Utilizing RNAinterference to enhance cancer drug discovery Nat Rev Drug Dis-cov 6 556 (2007)
19 M A Behlke Chemical modification of siRNAs for in vivo useOligonucleotides 18 305 (2008)
20 S D Rose D H Kim M Amarzguioui J D Heidel M ACollingwood M E Davis J J Rossi and M A Behlke Func-tional polarity is introduced by Dicer processing of short substrateRNAs Nucleic Acids Res 33 4140 (2005)
21 K Nishina T Unno Y Uno T Kubodera T KanouchiH Mizusawa and T Yokota Efficient in vivo delivery of siRNAto the liver by conjugation of alpha-tocopherol Mol Ther 16 734(2008)
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26 A D Judge G Bola A C Lee and I MacLachlan Design ofnoninflammatory synthetic siRNA mediating potent gene silencingin vivo Mol Ther 13 494 (2006)
27 A L Jackson J Burchard D Leake A Reynolds J SchelterJ Guo J M Johnson L Lim J Karpilow K NicholsW Marshall A Khvorova and P S Linsley Position-specificchemical modification of siRNAs reduces ldquooff-targetrdquo transcriptsilencing RNA 12 1197 (2006)
28 D Bumcrot M Manoharan V Koteliansky and D W Sah RNAitherapeutics A potential new class of pharmaceutical drugs NatChem Biol 2 711 (2006)
29 A S Peek and M A Behlke Design of active small interferingRNAs Curr Opin Mol Ther 9 110 (2007)
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33 D V Morrissey J A Lockridge L Shaw K Blanchard K JensenW Breen K Hartsough L Machemer S Radka V JadhavN Vaish S Zinnen C Vargeese K Bowman C S Shaffer L BJeffs A Judge I MacLachlan and B Polisky Potent and persis-tent in vivo anti-HBV activity of chemically modified siRNAs NatBiotechnol 23 1002 (2005)
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35 A Akinc A Zumbuehl M Goldberg E S Leshchiner V BusiniN Hossain S A Bacallado D N Nguyen J Fuller R AlvarezA Borodovsky T Borland R Constien A de Fougerolles J RDorkin K Narayanannair Jayaprakash M Jayaraman M JohnV Koteliansky M Manoharan L Nechev J Qin T RacieD Raitcheva K G Rajeev D W Sah J Soutschek I ToudjarskaH P Vornlocher T S Zimmermann R Langer and D G Ander-son A combinatorial library of lipid-like materials for delivery ofRNAi therapeutics Nat Biotechnol 26 561 (2008)
36 S C Semple A Akinc J Chen A P Sandhu B L Mui C KCho D W Sah D Stebbing E J Crosley E Yaworski I MHafez J R Dorkin J Qin K Lam K G Rajeev K F WongL B Jeffs L Nechev M L Eisenhardt M Jayaraman M KazemM A Maier M Srinivasulu M J Weinstein Q Chen R AlvarezS A Barros S De S K Klimuk T Borland V Kosovrasti W LCantley Y K Tam M Manoharan M A Ciufolini M A TracyA de Fougerolles I MacLachlan P R Cullis T D Madden andM J Hope Rational design of cationic lipids for siRNA deliveryNat Biotechnol 28 172 (2010)
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40 Y Matsumura and H Maeda A new concept for macromoleculartherapeutics in cancer chemotherapy Mechanism of tumoritropicaccumulation of proteins and the antitumor agent smancs CancerRes 46 6387 (1986)
41 T Ishimoto Y Takei Y Yuzawa K Hanai S Nagahara Y TarumiS Matsuo and K Kadomatsu Downregulation of monocytechemoattractant protein-1 involving short interfering RNA atten-uates hapten-induced contact hypersensitivity Mol Ther 16 387(2008)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
42 G J Villares M Zigler H Wang V O Melnikova H WuR Friedman M C Leslie P E Vivas-Mejia G Lopez-Berestein A K Sood and M Bar-Eli Targeting melanoma growthand metastasis with systemic delivery of liposome-incorporatedprotease-activated receptor-1 small interfering RNA Cancer Res68 9078 (2008)
43 E Kawata E Ashihara S Kimura K Takenaka K SatoR Tanaka A Yokota Y Kamitsuji M Takeuchi J KurodaF Tanaka T Yoshikawa and T Maekawa Administration of PLK-1 small interfering RNA with atelocollagen prevents the growth ofliver metastases of lung cancer Mol Cancer Ther 7 2904 (2008)
44 H Maeda J Wu T Sawa Y Matsumura and K Hori Tumorvascular permeability and the EPR effect in macromolecular thera-peutics A review J Control Release 65 271 (2000)
45 H Hatakeyama H Akita and H Harashima The polyethyleneg-lycol dilemma Advantage and disadvantage of PEGylation of lipo-somes for systemic genes and nucleic acids delivery to tumorsBiol Pharm Bull 36 892 (2013)
46 F Iversen C Yang F Dagnaes-Hansen D H Schaffert J Kjemsand S Gao Optimized siRNA-PEG conjugates for extended bloodcirculation and reduced urine excretion in mice Theranostics 3 201(2013)
47 A Malek O Merkel L Fink F Czubayko T Kissel andA Aigner In vivo pharmacokinetics tissue distribution and under-lying mechanisms of various PEI(-PEG)siRNA complexes Toxi-col Appl Pharmacol 236 97 (2009)
48 S D Li S Chono and L Huang Efficient gene silencingin metastatic tumor by siRNA formulated in surface-modifiednanoparticles J Control Release 126 77 (2008)
49 K Remaut B Lucas K Braeckmans J Demeester and S C DeSmedt Pegylation of liposomes favours the endosomal degradationof the delivered phosphodiester oligonucleotides J Control Release117 256 (2007)
50 G Adlakha-Hutcheon M B Bally C R Shew and T D MaddenControlled destabilization of a liposomal drug delivery systemenhances mitoxantrone antitumor activity Nat Biotechnol 17 775(1999)
51 Y Sato H Hatakeyama Y Sakurai M Hyodo H Akita andH Harashima A pH-sensitive cationic lipid facilitates the deliveryof liposomal siRNA and gene silencing activity in vitro and in vivoJ Control Release 163 267 (2012)
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53 H M Aliabadi B Landry C Sun T Tang and H UludagSupramolecular assemblies in functional siRNA delivery Where dowe stand Biomaterials 33 2546 (2012)
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55 S Y Wu and N A McMillan Lipidic systems for in vivo siRNAdelivery AAPS J 11 639 (2009)
56 H Tian S Liu J Zhang S Zhang L Cheng C Li X ZhangL Dai P Fan L Dai N Yan R Wang Y Wei and H DengEnhancement of Cisplatin sensitivity in lung cancer xenografts byliposome-mediated delivery of the plasmid expressing small hairpinRNA targeting survivin J Biomed Nanotechnol 8 633 (2012)
57 I R Gilmore S P Fox A J Hollins M Sohail andS Akhtar The design and exogenous delivery of siRNA for post-transcriptional gene silencing J Drug Target 12 315 (2004)
58 I R Gilmore S P Fox A J Hollins and S Akhtar Deliverystrategies for siRNA-mediated gene silencing Curr Drug Deliv3 147 (2006)
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silencing activity and specificity Adv Drug Deliv Rev 59 164(2007)
60 B Ozpolat A K Sood and G Lopez-Berestein Nanomedicinebased approaches for the delivery of siRNA in cancer J InternMed 267 44 (2010)
61 S Dokka D Toledo X Shi V Castranova and Y RojanasakulOxygen radical-mediated pulmonary toxicity induced by somecationic liposomes Pharm Res 17 521 (2000)
62 S Spagnou A D Miller and M Keller Lipidic carriers of siRNADifferences in the formulation cellular uptake and delivery withplasmid DNA Biochemistry (Mosc) 43 13348 (2004)
63 H Lv S Zhang B Wang S Cui and J Yan Toxicity of cationiclipids and cationic polymers in gene delivery J Control Release114 100 (2006)
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65 P Liu H Yu Y Sun M Zhu and Y Duan A mPEG-PLGA-b-PLLcopolymer carrier for adriamycin and siRNA delivery Biomaterials33 4403 (2012)
66 F Alexis E Pridgen L K Molnar and O C Farokhzad Factorsaffecting the clearance and biodistribution of polymeric nanoparti-cles Mol Pharm 5 505 (2008)
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68 J Heyes L Palmer K Bremner and I MacLachlan Cationic lipidsaturation influences intracellular delivery of encapsulated nucleicacids J Control Release 107 276 (2005)
69 O Meyer D Kirpotin K Hong B Sternberg J W Park M CWoodle and D Papahadjopoulos Cationic liposomes coated withpolyethylene glycol as carriers for oligonucleotides J Biol Chem273 15621 (1998)
70 M A Tran R J Watts and G P Robertson Use of liposomesas drug delivery vehicles for treatment of melanoma Pigment CellMelanoma Res 22 388 (2009)
71 C N Landen Jr A Chavez-Reyes C Bucana R Schmandt M TDeavers G Lopez-Berestein and A K Sood Therapeutic EphA2gene targeting in vivo using neutral liposomal small interferingRNA delivery Cancer Res 65 6910 (2005)
72 Z Ma J Li F He A Wilson B Pitt and S Li Cationic lipidsenhance siRNA-mediated interferon response in mice BiochemBiophys Res Commun 330 755 (2005)
73 J Jin K H Bae H Yang S J Lee H Kim Y Kim K M JooS W Seo T G Park and D H Nam In vivo specific delivery of c-Met siRNA to glioblastoma using cationic solid lipid nanoparticlesBioconjug Chem 22 2568 (2011)
74 P Y Chien J Wang D Carbonaro S Lei B Miller S SheikhS M Ali M U Ahmad and I Ahmad Novel cationic cardiolipinanalogue-based liposome for efficient DNA and small interferingRNA delivery in vitro and in vivo Cancer Gene Ther 12 321(2005)
75 A Pal A Ahmad S Khan I Sakabe C Zhang U N Kasidand I Ahmad Systemic delivery of RafsiRNA using cationic car-diolipin liposomes silences Raf-1 expression and inhibits tumorgrowth in xenograft model of human prostate cancer Int J Oncol26 1087 (2005)
76 A Akinc M Goldberg J Qin J R Dorkin C Gamba-VitaloM Maier K N Jayaprakash M Jayaraman K G RajeevM Manoharan V Koteliansky I Rohl E S Leshchiner R Langerand D G Anderson Development of lipidoid-siRNA formulationsfor systemic delivery to the liver Mol Ther 17 872 (2009)
77 S Jiang A A Eltoukhy K T Love R Langer and D GAnderson Lipidoid-coated iron oxide nanoparticles for efficientDNA and siRNA delivery Nano Lett 13 1059 (2013)
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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79 J A MacDiarmid N B Amaro-Mugridge J Madrid-WeissI Sedliarou S Wetzel K Kochar V N Brahmbhatt L PhillipsS T Pattison C Petti B Stillman R M Graham andH Brahmbhatt Sequential treatment of drug-resistant tumors withtargeted minicells containing siRNA or a cytotoxic drug NatBiotechnol 27 643 (2009)
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85 K A Howard Delivery of RNA interference therapeutics usingpolycation-based nanoparticles Adv Drug Deliv Rev 61 710(2009)
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Hartmann T Stoger and T H Kissel Polymer-related off-targeteffects in non-viral siRNA delivery Biomaterials 32 2388 (2011)
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95 A C Hunter and S M Moghimi Cationic carriers of genetic mate-rial and cell death A mitochondrial tale Biochim Biophys Acta1797 1203 (2010)
96 K A Woodrow Y Cu C J Booth J K Saucier-Sawyer M JWood and W M Saltzman Intravaginal gene silencing usingbiodegradable polymer nanoparticles densely loaded with small-interfering RNA Nat Mater 8 526 (2009)
97 K Singha R Namgung and W J Kim Polymers in small-interfering RNA delivery Nucleic Acid Ther 21 133 (2011)
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101 J Wu W Huang and Z He Dendrimers as carriers for siRNAdelivery and gene silencing A review Scientific World Journal2013 630654 (2013)
102 M L Patil M Zhang S Betigeri O Taratula H He andT Minko Surface-modified and internally cationic polyami-doamine dendrimers for efficient siRNA delivery Bioconjug Chem19 1396 (2008)
103 M L Patil M Zhang O Taratula O B Garbuzenko H He andT Minko Internally cationic polyamidoamine PAMAM-OH den-drimers for siRNA delivery Effect of the degree of quaternizationand cancer targeting Biomacromolecules 10 258 (2009)
104 A J Hollins Y Omidi I F Benter and S Akhtar Toxicoge-nomics of drug delivery systems Exploiting delivery system-induced changes in target gene expression to enhance siRNAactivity J Drug Target 15 83 (2007)
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106 T Ochiya K Honma F Takeshita and S NagaharaAtelocollagen-mediated drug discovery technology Expert OpinDrug Discov 2 159 (2007)
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108 T Koyanagi Y Suzuki Y Saga S Machida Y Takei H FujiwaraM Suzuki and Y Sato In vivo delivery of siRNA targetingvasohibin-2 decreases tumor angiogenesis and suppresses tumorgrowth in ovarian cancer Cancer Sci 104 1705 (2013)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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122 J Zhou and J J Rossi Aptamer-targeted cell-specific RNA inter-ference Silence 1 4 (2010)
123 J Zhou M L Bobbin J C Burnett and J J Rossi Currentprogress of RNA aptamer-based therapeutics Front Genet 3 234(2012)
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127 D Pantarotto R Singh D McCarthy M Erhardt J P BriandM Prato K Kostarelos and A Bianco Functionalized carbonnanotubes for plasmid DNA gene delivery Angew Chem Int EdEngl 43 5242 (2004)
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131 C P Firme 3rd and P R Bandaru Toxicity issues in the appli-cation of carbon nanotubes to biological systems Nanomedicine6 245 (2010)
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137 Y S Cho T J Yoon E S Jang K Soo Hong S YoungLee O Ran Kim C Park Y J Kim G C Yi and K ChangCetuximab-conjugated magneto-fluorescent silica nanoparticles for
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138 Y Chen W Wang G Lian C Qian L Wang L Zeng C LiaoB Liang B Huang K Huang and X Shuai Development of anMRI-visible nonviral vector for siRNA delivery targeting gastriccancer Int J Nanomedicine 7 359 (2012)
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142 S Li Z Liu F Ji Z Xiao M Wang Y Peng Y Zhang L LiuZ Liang and F Li Delivery of quantum Dot-siRNA nanoplexes inSK-N-SH cells for BACE1 gene silencing and intracellular imag-ing Mol Ther Nucleic Acids 1 e20 (2012)
143 J Zhao X Qiu Z Wang J Pan J Chen and J Han Applica-tion of quantum dots as vectors in targeted survivin gene siRNAdelivery Onco Targets Ther 6 303 (2013)
144 Y Su Y He H Lu L Sai Q Li W Li L Wang P ShenQ Huang and C Fan The cytotoxicity of cadmium based aqueousphasemdashsynthesized quantum dots and its modulation by surfacecoating Biomaterials 30 19 (2009)
145 H Y Yang Y W Zhao Z Y Zhang H M Xiong and S N YuOne-pot synthesis of water-dispersible Ag2S quantum dots withbright fluorescent emission in the second near-infrared windowNanotechnology 24 055706 (2013)
146 G Hong J T Robinson Y Zhang S Diao A L AntarisQ Wang and H Dai In vivo fluorescence imaging with Ag2Squantum dots in the second near-infrared region Angew Chem IntEd Engl 51 9818 (2012)
147 Y Zhang G Hong G Chen F Li H Dai and Q Wang Ag2Squantum dot A bright and biocompatible fluorescent nanoprobe inthe second near-infrared window ACS Nano 6 3695 (2012)
148 I Hocaoglu M N Ccedilizmeciyan R Erdem C Ozen A KurtA Sennaroglu and H Y Acar Development of highly luminescentand cytocompatible near-IR-emitting aqueous Ag2S quantum dotsJ Mater Chem 22 14674 (2012)
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1780 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
155 H Lee D Sung M Veerapandian K Yun and S W Seo PEGy-lated polyethyleneimine grafted silica nanoparticles Enhanced cel-lular uptake and efficient siRNA delivery Anal Bioanal Chem400 535 (2011)
156 X Li Y Chen M Wang Y Ma W Xia and H Gu A mesoporoussilica nanoparticlendashPEIndashfusogenic peptide system for siRNA deliv-ery in cancer therapy Biomaterials 34 1391 (2013)
157 Z Chen M F Penet S Nimmagadda C Li S R Banerjee P TWinnard Jr D Artemov K Glunde M G Pomper and Z MBhujwalla PSMA-targeted theranostic nanoplex for prostate cancertherapy ACS Nano 6 7752 (2012)
158 F Haque D Shu Y Shu L S Shlyakhtenko P G RychahouB M Evers and P Guo Ultrastable synergistic tetravalent RNAnanoparticles for targeting to cancers Nano Today 7 245 (2012)
159 W Wei P P Lv X M Chen Z G Yue Q Fu S Y Liu H Yueand G H Ma Codelivery of mTERT siRNA and paclitaxel bychitosan-based nanoparticles promoted synergistic tumor suppres-sion Biomaterials 34 3912 (2013)
160 S Ganesh A K Iyer D V Morrissey and M M AmijiHyaluronic acid based self-assembling nanosystems for CD44 tar-get mediated siRNA delivery to solid tumors Biomaterials 34 3489(2013)
161 C Dohmen D Edinger T Frohlich L Schreiner U LacheltC Troiber J Radler P Hadwiger H P Vornlocher and E WagnerNanosized multifunctional polyplexes for receptor-mediated siRNAdelivery ACS Nano 6 5198 (2012)
162 S A Jensen E S Day C H Ko L A Hurley J P LucianoF M Kouri T J Merkel A J Luthi P C Patel J I Cutler W LDaniel A W Scott M W Rotz T J Meade D A GiljohannC A Mirkin and A H Stegh Spherical nucleic acid nanoparticleconjugates as an RNAi-based therapy for glioblastoma Sci TranslMed 5 209ra152 (2013)
163 H Arima A Yoshimatsu H Ikeda A Ohyama K MotoyamaT Higashi A Tsuchiya T Niidome Y Katayama K Hattoriand T Takeuchi Folate-PEG-appended dendrimer conjugate withalpha-cyclodextrin as a novel cancer cell-selective siRNA deliverycarrier Mol Pharm 9 2591 (2012)
164 J Wei T Cheang B Tang H Xia Z Xing Z Chen Y FangW Chen A Xu S Wang and J Luo The inhibition of humanbladder cancer growth by calcium carbonateCaIP6 nanocompositeparticles delivering AIB1 siRNA Biomaterials 34 1246 (2013)
165 T Kanazawa K Sugawara K Tanaka S Horiuchi Y Takashimaand H Okada Suppression of tumor growth by systemic delivery ofanti-VEGF siRNA with cell-penetrating peptide-modified MPEG-PCL nanomicelles Eur J Pharm Biopharm 81 470 (2012)
166 M A Rahman A R Amin X Wang J E Zuckerman C HChoi B Zhou D Wang S Nannapaneni L Koenig Z ChenZ G Chen Y Yen M E Davis and D M Shin Systemic deliveryof siRNA nanoparticles targeting RRM2 suppresses head and necktumor growth J Control Release 159 384 (2012)
167 J Guo J R Ogier S Desgranges R Darcy and C OrsquoDriscollAnisamide-targeted cyclodextrin nanoparticles for siRNA deliveryto prostate tumours in mice Biomaterials 33 7775 (2012)
168 M Shen F Gong P Pang K Zhu X Meng C Wu J WangH Shan and X Shuai An MRI-visible non-viral vector for tar-geted Bcl-2 siRNA delivery to neuroblastoma Int J Nanomedicine7 3319 (2012)
169 D Lin Q Jiang Q Cheng Y Huang P Huang S Han S GuoZ Liang and A Dong Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and invivo siRNA delivery Acta Biomater 9 7746 (2013)
170 L Zou X Song T Yi S Li H Deng X Chen Z Li Y BaiQ Zhong Y Wei and X Zhao Administration of PLGA nanopar-ticles carrying shRNA against focal adhesion kinase and CD44results in enhanced antitumor effects against ovarian cancer CancerGene Ther 20 242 (2013)
171 T Yin P Wang J Li R Zheng B Zheng D Cheng R Li J Laiand X Shuai Ultrasound-sensitive siRNA-loaded nanobubblesformed by hetero-assembly of polymeric micelles and liposomesand their therapeutic effect in gliomas Biomaterials 34 4532(2013)
172 H J Cho S Chong S J Chung C K Shim and D D Kim Poly-L-arginine and dextran sulfate-based nanocomplex for epidermalgrowth factor receptor (EGFR) siRNA delivery Its application forhead and neck cancer treatment Pharm Res 29 1007 (2012)
173 F Abedini H Hosseinkhani M Ismail A J Domb A R OmarP P Chong P D Hong D S Yu and I Y Farber Cationizeddextran nanoparticle-encapsulated CXCR4-siRNA enhanced corre-lation between CXCR4 expression and serum alkaline phosphatasein a mouse model of colorectal cancer Int J Nanomedicine 7 4159(2012)
174 F Yang W Huang Y Li S Liu M Jin Y Wang L Jia andZ Gao Anti-tumor effects in mice induced by survivin-targetedsiRNA delivered through polysaccharide nanoparticles Biomateri-als 34 5689 (2013)
175 L Chen Y Ding Y Wang X Liu R Babu W Ravis and W YanCodelivery of zoledronic acid and doublestranded RNA from corendashshell nanoparticles Int J Nanomedicine 8 137 (2013)
176 H Jagani J V Rao V R Palanimuthu R C Hariharapura andS Gang A nanoformulation of siRNA and its role in cancer ther-apy In vitro and in vivo evaluation Cell Mol Biol Lett 18 120(2013)
177 L A Tobin Y Xie M Tsokos S I Chung A A Merz M AArnold G Li H L Malech and K F Kwong Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of can-cer cell internalization in vivo Biomaterials 34 2980 (2013)
178 J Shen H Sun P Xu Q Yin Z Zhang S Wang H Yu and Y LiSimultaneous inhibition of metastasis and growth of breast cancerby co-delivery of twist shRNA and paclitaxel using pluronic P85-PEITPGS complex nanoparticles Biomaterials 34 1581 (2013)
179 H Meng W X Mai H Zhang M Xue T Xia S Lin X WangY Zhao Z Ji J I Zink and A E Nel Codelivery of an optimaldrugsiRNA combination using mesoporous silica nanoparticles toovercome drug resistance in breast cancer in vitro and in vivo ACSNano 7 994 (2013)
180 C Zheng M Zheng P Gong J Deng H Yi P Zhang Y ZhangP Liu Y Ma and L Cai Polypeptide cationic micelles mediatedco-delivery of docetaxel and siRNA for synergistic tumor therapyBiomaterials 34 3431 (2013)
181 Q Hu W Li X Hu J Shen X Jin J Zhou G Tang and P KChu Synergistic treatment of ovarian cancer by co-delivery of sur-vivin shRNA and paclitaxel via supramolecular micellar assemblyBiomaterials 33 6580 (2012)
182 Y H Yu E Kim D E Park G Shim S Lee Y B KimC W Kim and Y K Oh Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA Eur J Pharm Biopharm 80 268(2012)
183 Z J Deng S W Morton E Ben-Akiva E C Dreaden K EShopsowitz and P T Hammond Layer-by-layer nanoparticles forsystemic codelivery of an anticancer drug and siRNA for potentialtriple-negative breast cancer treatment ACS Nano 7 9571 (2013)
184 X Q Liu M H Xiong X T Shu R Z Tang and J WangTherapeutic delivery of siRNA silencing HIF-1 alpha with micellarnanoparticles inhibits hypoxic tumor growth Mol Pharm 9 2863(2012)
185 J Xiao X Duan Q Yin Z Miao H Yu C Chen Z ZhangJ Wang and Y Li The inhibition of metastasis and growth ofbreast cancer by blocking the NF-kappaB signaling pathway usingbioreducible PEI-basedp65 shRNA complex nanoparticles Bioma-terials 34 5381 (2013)
186 R J Christie Y Matsumoto K Miyata T Nomoto S FukushimaK Osada J Halnaut F Pittella H J Kim N Nishiyama and
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
187 S Ganesh A K Iyer F Gattacceca D V Morrissey and M MAmiji In vivo biodistribution of siRNA and cisplatin adminis-tered using CD44-targeted hyaluronic acid nanoparticles J ControlRelease 172 699 (2013)
188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and morbidity in developed and developing countries1
Classical treatment modalities namely chemotherapyradiotherapy and surgery have been used from the begin-ning of 20th century with limited treatment success ratesespecially for advanced stage disease In the last decades
D Gozuacik MD PhD is an Associate Professor in the Biological Sciences andBioengineering Program at Sabanci University Istanbul Turkey He received his Med-ical Doctor (MD) degree in 1995 from Hacettepe Medical Faculty Ankara Turkey hisDEA degree of biochemistry from Ecole Polytechnique Paris France and his PhDdegree on Molecular Cell Biology in 2001 from Paris XI University and Pasteur Insti-tute Paris Before joining Sabanci in 2006 he worked as a postdoctoral researcher inthe Weizmann Institute of Science (2001ndash2006) on cancer biology His current researchfocus is cellular death and stress responses including autophagy in health and diseaseRNA interference therapies and nano-drugs Dr Gozuacik is a board of directors mem-ber of the International Cell Death Society (ICDS) editor of the Autophagy journal(IF 12) and an ad hoc referee of various international journals and granting agen-
cies He received excellence awards from several institutions including European Molecular Biology Organization(EMBO) Roche Pharmaceuticals and Turkish Academy of Sciences
H F Yagci-Acar PhD is an Associate Professor in the Chemistry Department atKoccedil University Istanbul She received her BS and MS degrees in Chemistry fromBogazici University Istanbul Turkey in 1993 and 1995 respectively She received herPhD in Polymer Science and Engineering from University of Southern MississippiHattiesburg in 1999 She worked as a post-doctoral fellow at GE GRC-Niskayunabetween 2000 to 2002 and as a lead scientist until 2004 then she joined Koccedil Universityin 2004 Her research focuses on the development of novel polymers (living or conven-tional methods) magnetic nanoparticles luminescent semiconductor quantum dots andhybrid nanomaterials for biotechnology medicine and energy applications She receivedNational LlsquoOreal Women in Science Reward in Materials Science in 2005
Y Akkoc is a PhD student in the Biological Sciences and Bioengineering Program atSabanci University Istanbul He recieved his BSc degree from the Molecular Biologyand Genetics Department of Istanbul Kultur University in 2013 His research interestsinclude role of natural polyamines in cancer progression basic autophagy mechanismsand gene therapy of autophagy abnormalities
A Kosar PhD is an Associate Professor in the Mechatronics Program at Sabanci Uni-versity Istanbul He received the BSc degree in Mechanical Engineering from Bogazici(Bosphorus) University Istanbul He pursued his graduate studies in the Departmentof Mechanical Engineering at Rensselaer Polytechnic Institute where he completed hisMS and PhD degrees His research interests include micronano-scale heat transferand fluid flow cooling technologies magnetic manipulation of nanoparticles and mag-netic hyperthermia therapy Dr Kosar is a recipient of various national and internationalawards including Turkish Academy of Sciences Outstanding Young Investigator Award(GEBIP) and TUBITAK (The Scientific and Technological Research Council of Turkey)Incentive Award
chemotherapy and radiotherapy approaches evolved tominimize toxicity invasiveness and side effects while pre-serving effectiveness Yet the basic action mode of bothchemotherapy and radiotherapy is perturbation of the divi-sion and induction of the death of all rapidly proliferating
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
A Isin Dogan-Ekici MD is an Associate Professor in the Pathology Department atthe Yeditepe University Hospital Istanbul She graduated from Hacettepe UniversitySchool of Medicine in 1997 Dr Dogan-Ekici obtained her pathology specialist degreefrom Hacettepe University School of Medicine Department of Pathology in 2003 Herresearch interests include surgical pathology nephropathology and urogenital systempathology and pathology of gene therapy models
Sinan Ekici MD is a Professor in the Department of Urology at the Maltepe Univer-sity School of Medicine He graduated from Hacettepe University School of Medicinein 1995 He obtained his urology specialist degree from Hacettepe University School ofMedicine Department of Urology in 2000 Dr Ekici worked as a clinical observer inMemorial Sloan Kettering Cancer Center New York and worked as research and clin-ical fellow in the Department of Urooncology Miami University School of MedicineUSA His research interests include urooncology endoscopic urology cancer biologygene therapy of urological cancers
cells in a non-selective way Consequently both of theseapproaches are accompanied with side effects ranging fromhair loss and gastrointestinal (GI) problems (hair folliclesand GI tract cells are amongst most rapidly proliferatingcells in the body) to secondary cancer development (egLeukemias) due to DNA damage Therefore developmentof targeted and cancer cell-selective therapies with minimalshort- and long-term side effects is an important challengeRecent progress in molecular biology genetics and
biotechnology allowed the development of small moleculedrugs targeting cancer-related proteins antibody-baseddrugs immunomodulatory approaches and cellular ther-apies ranging from improved bone marrow transplan-tation to stem cell treatments Some of these novelapproaches already entered clinical use alone or as partof an adjuvant or combinatory therapy with classical treat-ment modalities2 Parallel advances in diagnostic tech-niques cancer genetics and pathology led to a better andmore detailed classification of cancer subtypes allowingsubtype-specific even personalized treatment regimens3
In spite of all these innovations and efforts in the can-cer medicine field disease-free survival rates are lowand prognosis is still bad especially in advanced andormetastatic cases Therefore a better understanding ofcancer biology and development of novel and innovativetreatment approaches is still one of the most importantchallenges of modern science and medicineA great majority of small molecule drugs target disease-
related enzymes or receptors4 Yet we now understandthat complex processes and changes during cancer initia-tion progression and evolution leading to drug resistanceresult in the mutation andor dysregulation of enzyme
and non-enzyme proteins and even nucleic acids such asmicroRNAs and long non-coding RNAs5 In the post-genomic era with the advances in genomics and epigenet-ics of cancer gene therapy is one of the innovative cancertherapy fields gaining momentum in recent years Genetherapy approaches offer the possibility of up or downreg-ulation of dysregulated gene products and replacement ofmodifiedmutated transcripts with non-mutatedwild typeforms6 Experimental treatments using nucleic acids rangefrom DNAcDNA replacement therapies to RNA-basedregimens Although establishment of general concepts ofgene therapy date back to 1960s and 1970s issues relatedto the stability and half-life of the nucleic acid moleculesand most importantly lack of suitable delivery and target-ing systems limited the success of this promising technol-ogy Until recently viral systems were the major focus ofgene delivery studies and gene therapy protocols Modi-fied viruses including adenoviruses retroviruses herpesviruses and lentiviruses were examined and tested in detailas gene delivery agents In addition to severe immunereactions ranging from inflammation to shock insertionalmutagenesis caused by viral integration into the patientgenome constituted major side-effects and drawbacks rais-ing concerns and doubts about the future of gene therapy7
With recent advances in nanotechnology several non-viralgene delivery systems were developed as gene and drugcarriers reviving hopes about the use of nucleic acids aspotent drugs against cancer
SCOPE OF THE REVIEWIn this review we will summarize and discuss accumu-lating data about the use of nanoparticles as nucleic acid
J Biomed Nanotechnol 10 1751ndash1783 2014 1753
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
carriers We will limit ourselves to cancer gene ther-apy studies exploiting nanocarrier loaded small RNADNAmolecules ie RNA interference (RNAi) tools such assiRNAs shRNAs and microRNAs Merits and contribu-tions of antisense oligonucleotides in gene therapy experi-ence were discussed in detail elsewhere8
RNA INTERFERENCEDiscovery of RNA interference (RNAi) by Andrew Fireand Craig Mello was a breakthrough that was awarded bythe Nobel prize in Physiology or Medicine in 2006 SmallRNAs mediating RNA interference control gene expres-sion in organisms ranging from plants and C elegansto human Small interfering RNAs (siRNAs) short hair-pin RNAs (shRNAs) and microRNAs (miRNAs) are themost studied members of regulatory RNAs9 Non-codingsmall RNAs are not translated they mainly act at a post-transcriptional level determining the stability of messen-ger RNAs (mRNAs) and their translation into proteinsEndogenous siRNAs (endo-siRNAs) are coded not only
by transposons and other repeat elements but they mayalso originate from regions where both sense and antisensetranscripts are transcribed as well as from sequences giv-ing rise to potential hairpin structures inside pseudogenes
Scheme 1 RNA interference (RNAi) pathways (a) miRNA pathways (b) siRNA pathways See text for the pathway details RNAPol II RNA polymerase II Dicer Dicer enzyme complex into the siRNA RISC RNA-induced silencing complex (RISC) RdRPRNA-dependent RNA polymerase ORF open reading frame of the target gene AAAAA polyA tail of the mRNA
and even in protein-coding genes1011 On the other handmiRNAs may be intronic or intergenic Intronic miRNAsare transcribed from intron regions of some protein codingmRNAs while intergenic miRNAs are transcribed frommiRNA genes or gene clusters using their own promotersEndogenous siRNAs and miRNAs bear similarities to
each other from a structural and functional point of viewYet pathways leading to their maturation are rather spe-cific to the small RNA type (Scheme 1(a)) miRNAs aretranscribed by RNA polymerase II as primary-miRNAs(pri-miRNAs) and processed by a Drosha-DGCR8 com-plex in the nucleus to produce hairpin-shaped premature-miRNAs (pre-miRNA)12 Transport from nucleus isachieved with the help of the exportin-Ran GTPase com-plexes Further processing of the pre-miRNA hairpin bycytoplasmic DICER proteins produces sim 21ndash22 nt longmiRNAmiRNAlowast duplexes One of the mature miRNAstrands that originate from the duplex is then loaded ontoa complex called the RNA-induced silencing complex(RISC) including the Argonaute (eg AGO2) proteinsRISC then guides the mature miRNA strand towards tar-get messenger RNAs (mRNAs) It is believed that tar-get specificity of the miRNA and the fate of the targetmessenger RNA depends on the degree of complemen-tarity between matching sequences of these two types of
1754 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
RNAs While a partial complementarity may lead to theblockage of the translation machinery protein translationrepression andor sequestration of miRNA-mRNA com-plexes in compartments called P-bodies a perfect matchbetween these two RNAs may result in mRNA degradation(Scheme 1(a))Conversely endo-siRNAs complementary to template
mRNAs are synthesized by RNA-dependent RNA poly-merases (RdRP) and they are not transcribed from thegenomic DNA (Scheme 1(b)) It was long believed thatmammals did not have any RdRPs But this conceptis now changing For example human telomerase cat-alytic subunit (hTERT) was shown possess a mammalianRdRP activity required for double stranded RNA synthe-sis from the mitochondrial RNA processing endoribonu-clease noncoding RNA component1314 In the endogenoussiRNA pathway hairpin containing double-stranded RNAproducts of RdRP are further processed into functionalendogenous siRNAs in either a Dicer-dependent or aDicer-independent manner (Scheme 1(b)) In general thesense guide strand of the endo-siRNAs are loaded onto theRISC with AGO2 proteinsWhile in general mammalian miRNAs show partial
complementary to their mRNA target sequences and con-trol a wide number of functionally-related transcripts strictcomplementarity was thought to be necessary for siRNAfunction9 But even synthetic siRNAs or shRNAs that aredesigned to target one and only mRNA were shown toaffect so called ldquooff-target genesrdquo Therefore although agene with a dominant biological effect will be targeted bysiRNAshRNAs a spectrum of biological events might beaffected by the use of a small RNA Nevertheless in vitrocell culture and animal studies confirmed that the biolog-ical outcomes of siRNAshRNAs and even miRNAs wereusually determined by their effect on a dominant targetgene andor pathway1516
SMALL RNAS AS POTENT DRUGSUse of potent RNA interference strategies might give usnew opportunities for the treatment of diseases such ascancer17 Potential advantages of small RNAs over existingsmall molecule drugs and conventional therapies includeorganic composition natural metabolism lower drug tox-icity minimal immune reactions when designed optimallyand combined with appropriate carriers possibility ofmodulating targets that are considered as ldquoundruggablerdquo byconventional drugs possibility of targeting disease-relatedtissue-specific isoforms andor mutant transcripts and stan-dard chemical synthesis protocols Moreover RNA plat-forms are now widely used in high throughput formats fortarget validation and drug development processes reduc-ing the product development cycle and cost compared toconventional small molecules18
Modifications to the native RNA structure can cre-ate robust drug-like RNA molecules19 Synthetic 21-mer
RNA duplexes mimicking natural siRNAs and miRNAsare commonly used in RNA-based gene therapy protocolsAlternatively asymmetric 2527-mers or 2729-mers blunt25-mers blunt 27-mers and blunt 19-mers were tested fortheir stability and potency as RNA drugs with variablemerits20ndash23 These different synthetic RNAs might directlybe loaded onto the RISC complex or they might firstrequire processing by Dicer In fact even under in vitro con-ditions synthetic siRNAs were shown to directly load ontorecombinant human AGO2 proteins and form functionalcomplexes24 Therefore following delivery small RNAsmay rapidly form functional complexes and alter target pro-tein levels resulting in therapeutic changes in cellsNaked RNA molecules are highly susceptible to degra-
dation by nucleases that are abundant in tissues and in theblood circulation Therefore to stabilize RNA moleculesincrease their half-lives in biological environments andavoid immune reactions a number of chemical changesmight be introduced to the nucleic acid structures19
There are several commonly used RNA modifications2prime-O-methyl modifications into the sugar structure ofsome nucleotides may confer resistance to endonucle-ases decrease off-target effects when introduced into theseed region and minimize Toll-like receptor-mediatedimmune reactions25ndash27 Introduction of phosphorothioateboranophosphate or methylphosphonate backbone linkagesat the 3prime-end of the RNA strands may reduce their suscepti-bility to exonucleases Similarly alternative 2prime sugar mod-ifications such as 2prime-fluoro LNA (Locked nucleic acids)FANA (2prime-deoxy-2prime-Fluoro--d-arabinonucleic acid) and2primeMOE (2prime-O-methoxyethyl) modifications were reportedto increase endonuclease resistance of small RNAs28
While all these modifications result in more robust RNAmolecules they might affect the potency of the RNA inter-ference effects obtained during treatment Therefore evenif the changes were performed according to design criteriaor computer tools experimental testing is required in eachseparate case to confirm potency of modified small RNAmolecules on their mRNA targets2930
RNADNA NANOCARRIERS FORCANCER THERAPYUse of gene therapy and lately small RNAs for can-cer treatment was hindered by the lack of a suitabledelivery system Recent developments in nanotechnologyallowed the introduction of nanoparticles with very differ-ent physico-chemical properties Novel and sophisticatednanocarriers and their functionalized derivatives are beingtested as potent and in many cases targeted RNA drugdelivery agents Some formulations are already in clinicaltrials and a few of them were even approved by majoragencies such as the Food and Drug Agency (FDA) in theUSA31
Nanoparticles to be used as nucleic acid delivery agentsshould meet several criteria The particles should safely
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and effectively deliver RNA molecules to cancer cells andtumors Therefore they have to be biocompatible notimmunogenic and they should not get modified or dis-solved into toxic substances under biological conditionsand before reaching the tumor target For effective deliv-ery and dosage nano conjugates have to be stable enoughin the blood circulation and resist shear forces proteasesand nucleases that they face with Complex formation withblood cells proteins and other blood components mightalso affect carrier size charge availability and efficacyClearance is also an important issue For nanocarriers
to reach therapeutic blood levels they should not be read-ily cleared through glomerular filtration in the kidneys ortrapped by the reticuloendothelial system For examplenaked siRNA molecules and nanoparticles less than 10 nmmay be filtrered and excreted through kidneys follow-ing systemic administration Carriers larger than 100 nmmight be phagocytosed and cleared by monocytes andmacrophages residing in the reticuloendothelial system(RES also called mononuclear phagocytic system) tissueswith high blood supply including pulmonary alveoli liversinusoids skin spleen etc32ndash36 In addition to the size of thenanoparticles their geometries surface charges hydropho-bicities and opsonization by serum proteins might affectclearance by monocytes and macrophages Additionallythe efficacy of nucleic acid drugs in specific tissues andorgans may depend on the ability of nanocarriers to pene-trate blood vessels and tissues and pass through biologicalbarriers such as the tight blood-brain-barrier of the centralnervous systemFor cancer treatment small RNA drugs should affect
genetic andor molecular changes specific to cancer cellsand that are rate-limiting for tumor growth The idealnanocarrier should be able to concentrate within the tumortissue and if possible target individual tumor cells in aselective way (eg through receptors or molecules thatare tumor-specific or that are enriched in the tumor tis-sue) and not penetrate normal cells Enhanced permeabilityand retention (EPR) effect offers an advantage for solid-tumor targeting The EPR effect is a result of neovascu-larisation new blood vessel formation to feed tumors withsizes beyond passive oxygen and nutrient diffusion lim-its (beyond 01ndash02 mm diameter)37 Blood vessels feed-ing tumor tissues are irregular and highly permeable Withthe lack of lymphatic drainage macromolecules are eas-ily retained in and around the tumor area3839 For exam-ple low molecular weight drugs may diffuse freely inand out of the tumor tissues but macromolecules (gt 40kDa) and nanoparticles of 100ndash200 nm accumulate inthe tumor tissue3840ndash43 EPR phenomenon was reported invarious human solid tumors as well as in inflammatorytissues44
Different types of nanoparticles were tested as drug car-riers and gene therapy tools (Scheme 2) The core structureof the particle may be a vesicle (liposomes) a polymer(eg PEI PLGA) a dendrimer carbon nanotubes silica or
metal nanoparticles (eg Gold) Porousvesiculate carrierssuch as liposomes polymeric micelles or some inorganicparticles (eg mesoporous silica) may encapsulate orabsorb RNADNA molecules Nanocarriers with a cationicnature including cationic liposomes cationic dendrimers(eg PAMAM) and polymers (eg PEI PDMAEMA) orcationic polymer coated inorganic particles (eg PEI cov-ered iron oxide) may form complexes through electro-static interactions with the negatively charged backboneof nucleic acids The nature and physico-chemical proper-ties of the nanoparticles may also influence their stabilityand half-life in blood criculation efficacy of their deliveryinto tissues and cells and their capacity to escape fromendosomes in the cell All these properties are determiningcriteria for nano drug efficacyTo improve stability RNADNA loading target speci-
ficity tracking cellular internalization endo-lysosomalescape and intracellular robustness additional functionalunits might be introduced to the basic structure ofthe nanocarriers (Scheme 3)45 Possible modificationsand changes include conjugation to proteins (antibodieslectins cytokines thrombin fibrinogen BSA transfer-rin) cellular or viral peptides (eg RGD LHRD TATPep-3 KALA) polysaccharides (eg lipopolysaccharideshyaluronic acid dextran chitosan) low molecular weightligands (eg folic acid anisamide) and polyunsaturatedfatty acids (eg palmitic acid and phospholipids) Thesestructures can be conjugated onto the nanocarrier surfacethough hydrolysable or non-hydrolysable chemical bondsand modifications such as amide ester silane hydrazoneor through the use of high avidity molecules such asavidin-biotin Fluorophores may also be added for par-ticle tracking purposes To improve the availability ofsuch groups and especially the targeting groups spacermolecules may be addedAn important modification relevant for biological func-
tion is ldquoPEGylationrdquo (Scheme 3)45 PEG coordinateswater molecules and forms an aqueous shell aroundnanoparticles shielding their charges PEGylation reducesinteraction with serum proteins decreases opsoniza-tion and clearance of nanoparticles by RES monocyte-macrophages sterically prevent nanocarrier aggregationand due to increased molecular weight above the thresholdfor glomerular filtration reduces elimination of the parti-cles through urinary excretion Hence PEG increases thestability improves biocompatibility prolongs blood circu-lation time and bioavailability of nanocarriers4647 Molec-ular weight and density of PEG chains on the nanocarriersurface may impact the function depending on the natureof the carried molecules ie siRNA47
On the other hand PEGylation significantly attenu-ates uptake of nanocarriers by target cells4849 More-over PEG chains were shown to block endosomal escapeand cytosolic release of chemical drugs and nucleicacids50 Blockage of cellular uptake and endosomal releasein the cell may severely attenuate drug efficacy and
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 2 Major types of nanoparticles used as nucleic acid carriers
therapeutic RNA interference effects Various strategieswere adapted to overcome these negative effects of PEGwhile exploiting its circulatory advantages Cleavage ofPEG-chains upon delivery into the tumor environment wasachieved through addition of tumor-related matrix met-alloproteinase sensitive lipids or peptides51 pH-sensitivelinkers between the PEG moiety and nanocarriers canalso be used to release PEG from the particle in theacidic environment of the endosomes and allow cytosolic
Scheme 3 A representative nanoparticle with functional modifications Various molecules might be added to a nanoparticleto improve its physico-chemical properties and pharmacokinetics (eg PEG) to increase RNADNA binding (eg PEI) to allowbetter targeting (eg antibodies) or tracking (eg fluorophores)
release of small RNAs Modulation of the hydrophobic-ity of the PEGndashnanocarrier conjugate was also testedas a release strategy In lipid-based nanocarriers thelength of the alkyl chain of the PEG-lipid anchor wasshown to determine its affinity for the lipid deliveryvehicle and changing its length modified endosomalescape potential and drug effects52 Cholesterol-anchoredPEG was also shown to improve endosomal escapecapacities52
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
LiposomesLiposomes have been tested extensively as gene deliv-ery agents Liposomes are artificial membrane-boundvesicles formed by bilayers of amphipathic lipids Theymight be unilamellar or multilamellar Their biocom-patibility low toxicity and low immunogenicity madethem popular agents for both in vitro and in vivo genedelivery5354 Liposomes are typically made of mix-tures of lipids found in biological membranes or theirderivatives including phosphatidylcholine (PC or DOPC12-Oleoyl-sn-Glycero-3-phosphatidylcholine) phosphatidyl-ethanolamine (PE or DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidylethanolamine) cholesterol and evenceramide53 Although liposomes made of neutral lipids aremore biocompatible than cationic lipids and have betterpharmacokinetics during preparation of gene deliveryvectors they bind less to negatively charged DNA orRNA molecules and have lower entrapment efficiencies55
Therefore despite their more toxic nature cationic lipidsare commonly used as liposome-based transfection agentsCationic lipids posses positively charged headgroupssuch as amines quaternary ammonium salts peptidesaminoacids or guanidiniums which electrostaticly attractand bind to negatively charged phosphate residues innucleic acid backbones The nature of cationic lipid head-groups determines the efficacy of gene delivery Thereforevarious mixtures of lipids with different headgroupsand properties were tested to achieve optimal liposomeformulations for drug andor gene delivery56ndash59
Although liposomes are excellent transfection agentsin vitro some side effects and problems were encoun-tered during in vivo studies56ndash59 These include intracellu-lar instability and failure to release small RNA contentsdose-dependent toxicity and pulmonary inflammation thatcorrelated with the production of reactive oxygen species(ROS) opsonization by serum proteins immunogenic-ity and uptake by the RES components60ndash63 Addition-ally cationic liposome-dependent gene expression changeswere observed during in vitro experiments with someformulations64
In order to minimize such undesired effects special-ized liposomes were produced through addition of vari-ous functional groups PEGylation and crosslinking withinthe bilayer of the liposomes was successfully utilized toimprove stability and decrease side effects65 PEGylationin general improved bioavailability and biocompatibilityas well For example to obtain improved pharmacokinet-ics PEGylated cationic liposomes called ldquosolid nucleicacid lipid particlesrdquo (SNALPs) were created and they weresuccessfully used for siRNA delivery In fact in SNALPsPEG coating neutralized net charge and increased theblood circulation time of the liposomes significantly66ndash72
Moreover fusogenic lipids added to liposome formula-tions improved cellular uptake and endosomal escape33
Most importantly SNALPs were relatively well toler-ated in vivo even in non-human primates3233 The list of
modifiedimproved liposomes performing well in in vivostudies also includes cationic solidndashlipid nanoparticles andcardiolipin-based liposomes3373ndash75 Currently improvedliposomes are one of the most promising tools for genedelivery and patented formulations produced by sev-eral companies were successful enough to reach clinicaltrials31
LipidoidsLipidoids are cationic lipids that are created by the conju-gation of primary or secondary amines to alkyl-acrylatesor alkyl-acrylamides76 They were introduced as novelalternatives to liposome formulations used in gene deliv-ery Changes in the composition lipidoids were shown toimprove their therapeutic properties For example changesin the alkyl chain length of the PEG lipid was reportedto affect PEG deshielding rate and dose kinetics of lipi-doids in the blood76 Moreover cholesterol incorporationwas shown to improve carrier stability Small sized lipi-doids (50ndash60 nm) were successfully used for the deliveryof siRNA into liver cells avoiding engulfment by Kuppfercells76 Lipidoids may also be used for coating inorganicnanoparticles in order to introduce cationic charges77 Lipi-doids have lower toxicity and increased efficacy thereforethey present an alternative to classical liposomes for genedelivery studies
MinicellsMinicells are bacteria-derived non-living anucleatednano-sized vesicles that were used as nano drug carriers78
Inactivation of min genes that control normal division inbacteria such as Salmonella typhimurium result in the for-mation of minicells min gene products ensure that celldivision septum is correctly located to the midpoint ofthe cell In case of min gene product mutations septa-tion defects result in the formation of minicells devoid ofthe chromosomal DNA Therapeutic RNAs may be loadedinto minicells by the introduction of shRNA of interestinto min mutant bacteria and eventually shRNAs segregateinto minicells78 Purified minicells prepared by this methodare pre-packaged with effective copy numbers of the plas-mid For targeting purposes tumor-specific antibodies maybe decorated onto minicells by the exploitation of bac-terial cell surface components such as O-polysaccharideof LPS Minicell-RNAi combinations proved to be effec-tive in experimental cancer treatment79 Other cell derived-vesicles that were tested as nanocarriers include bacterialghosts bacterial outer membranes or mammalian cell-derived exosomes80ndash82
PolyplexesMaterials that self-assemble with nucleic acids intonanocomplexes are called ldquopolyplexesrdquo These complexesgenerally form though the electrostatic interaction of the
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
cationic units of the polymers with the anionic phos-phate groups of the nucleic acids Natural and biocompat-ible (eg chitosan Atelocollagen cyclodextrin) or morefrequently synthetic (eg Polyethylenimine PEI poly-L-lysine PLL poly-dl-lactide-co-glycolide PLGA) poly-mers are used for polyplex formation83ndash86 Flexibility of thesynthetic polymers in terms of chemical nature molecularweight and architecture (linear branched grafted blocky)provide opportunity to balance their toxicity improvenucleic acid binding protection and release efficienciesMoreover surface modifications may be introduced for tar-geting purposes and improved pharmacodynamics Poly-mers such as PLGA also benefit from a biodegradablenature which allows clearance of the nanocarriers in time
PEIPEI is the most widely and most successfully used polyca-tion for polyplexe formation It can be synthesized in lin-ear or branched forms and in variable molecular weights(from 1 kDa to gt 1000 kDa) Higher molecular weightpolymers (70 kDa and above) are very effective in nucleicacid binding but they are significantly toxic Low molec-ular weight forms (2 kDa or less) are less toxic but theyare less effective as transfection agents87 Therefore PEIsat and below 25 kDa with a branched or linear architec-ture are commonly used as gene delivery reagents88ndash91 Thegolden standard gene delivery polymer is branched PEIof 25 kDa which offers a balance between the toxicitynucleic acid bindingprotection and release Abundance ofpositive charges due to protonation under physiologicalconditions allows PEI to spontaneously form complexeswith negatively charged small RNAs and DNAs and pro-tect nucleic acid molecules from nuclease attacks84 More-over buried inside the polymer some off-target effects ofthe small RNAs were shown to be prevented92
The net positive charge of PEI-RNAi complexes alsoallow interactions with the negatively charged polysaccha-rides found on the cell surface93 These interactions arebelieved to be an important factor for the endocytosis ofthe complexes by target cells A key event for the successof gene delivery is the escape of the nucleic acids fromthe endosomal pathway in order to avoid accumulation anddegradation in the lysosomes of the cell93 The escape isthought to be the result of the lsquoproton spongersquo effect wherethe influx of protons and water lead to endosome swellingrupture and release of contents including nucleic acids tothe cytosolPEI-induced toxicity was proposed to be a result of
mitochondrial apoptosis induction by the polymer9495
Moreover PEI itself was shown to cause changes in geneexpression in vivo which might influence biological out-comes of treatment protocols59 PEGylation of the PEIreduces both cytotoxicity of PEI-polyplexes and increaseblood circulation half-life However a critical balanceneed to be achieved since PEGylation decreases the sur-face charge it impacts the binding capacity and cell
internalization of the polyplexes Alternatively short PEIchains attached together with hydrolysable links such asdisulfide and ester may provide initially a high molecu-lar weight PEI system for good nucleic acid condensationand protection but upon dissolution because of intracel-lular redox conditions they may act as a low molecularweight PEI polymers with lower toxicity87 Additionallypluronics that are block copolymers of ethylene glycol-propylene glycol-ethylene glycol can be used instead ofPEG Similar to PEG pluronics were shown to improvethe biocompatibility and bioavailability of the nanocarri-ers but they interact better with the cell membrane due tothe propylene glycol units and enhance cellular uptake ofthe particles87
PLGAPLGA is a biodegradable copolymer of glycolic acid andlactic acid96 It is widely used in biomedical research asan FDA-approved substance PLGA offers several advan-tages The polymer is highly stable biodegradable andallows sustained release During nucleic acid deliveryPLGA is easily taken up by cells through endocytosisand no serious toxicity problems were observed97 PLGAbinds nucleic acids weakly but it might encapsulate themfor drug delivery purposes Indeed PLGA nanoparticleswere used in several studies for delivery of drugs totumors through the EPR effects98 Yet following endocyto-sis PLGA particles do not effectively realease cargo fromendosomes8397 To overcome nucleic acid binding deliv-ery and endosomal release problems the surface of PLGAcan be decorated with various cationic nanoparticles suchas DOTAP PEI or polyamine and may be conjugated topeptides and antibodies99
DendrimersDendrimers are tree-like highly branched generally sym-metrical and three-dimensional macromolecules Theyhave uniform size and molecular weight which increaseswith each new branch (generation) Dendrimers possess ahighly functional outer surface allowing chemical modi-fications and interactions Therefore they may be used asflexible and modifiable gene delivery agents100 Besidesthe ability of dendrimers to encapsulate cargos add to theirpotential as drug carriers101 Dendrimers including poly-amidoamine dendrimers (PAMAM) poly-propylene imine(PPI) dendrimers poly-L-lysine dendrimers triazine den-drimers carbosilane dendrimers poly-glycerol-based den-drimers nanocarbon-based dendrimers and others weretested as RNAi delivery agents PAMAM and PPI den-drimers being the most commonly studied ones It wasshown that introduction of surface-modifications mini-mized toxicity-related problems increased RNAi-bindingand cellular uptake efficacies of the dendrimers102103
Of note in vivo gene expression changes were alsoobserved with drug-free dendrimers104 Therefore well
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
controlled experiments are needed before drawing conclu-sions during RNA interference studies
AtelocollagenAtelocollagen is an organic protein-based moleculederived from type I collagen of calf dermis Sinceit is obtained following a pepsin treatment atelocolla-gen is devoid of telopeptides that are responsible forthe immunogenicity of collagen105 Moreover atelocol-lagen has low toxicity it was shown to stabilize RNAmolecules Increased cellular uptake and sustained deliv-ery was observed in in vivo making atelocollagen an idealagent for gene delivery106 Indeed several studies used ate-locollagen with success for the systemic or local deliveryof RNAi in tumor models107ndash109
ChitosanChitosan is obtained through alkaline deacetylation of thepolysaccharide chitin that forms the exoskeleton of crus-taceans some anthropods and insects Chitosan that is usedin biomedical research is a copolymer of N -acetyl-D-glucosamine and D-glucosamine having a positive chargeIn addition to being biodegradable and biocompatible chi-tosan has a low production cost Mucoadhesive propertiesof chitosan allow the penetration of the substance intoepithelial cell layers including the gastrointestinal barri-ers Nucleic acid encapsulation and sustained release wasproved to be possible using chitosan110ndash112 Moreover chi-tosan prolongs transient time in bowel improving par-enteral drug bioavailability113 Nanoparticles of chitosanare taken up into cells through endocytosis to a cer-tain extent To improve gene delivery efficacies PEG ordeoxycholic acid conjugates or modifications includingtrimethylation thiolation galactosylation may be intro-duced to chitosan111 Moreover chitosan-based carrierspossess functional groups that are suitable for conjugationto ligands relevant for targeted tumor delivery Althoughinefficient endosomal escape is a problem encounteredwith chitosan-based carriers some chemically modifiedforms showed improved escape properties114
CyclodextrinsCyclodextrins are natural polymers They are cyclicoligosaccharides of a glucopyranose generated during thebacterial digestion of cellulose Their central cavity ishydrophobic while the outer surface is a hydrophilicand they can create water-soluble molecular complexes115
Native cyclodextrins do not form stable complexeswith nucleic acids But the DNARNA complex for-mation capacities of the molecule can be modulatedand improved through molecular modifications includ-ing changes in functional groups hydrophilic-hydrophobicbalance charge density spacer length and conjugation toother carrier molecules115116 Cyclodextrins are not onlybiocompatible but they have the capacity to decrease
cytotoxicity of other molecules and carriers that are conju-gated to them117 Moreover cyclodextrins increase cellularadsorption and intake of molecules118 So in addition totheir use as a gene delivery agents cyclodextrins are usedas linking agents or structural modifiers in complex car-rier molecules For example conjugation of cyclodextrinto PEI resulted in lower toxicity and higher transfectionefficiencies119 In addition to the advantages cited abovea cyclodextrin polycation delivery system was reportedto block immune reactions raised against small RNAsthrough a masking effect120121 Importantly studies innon-human primates revealed that cyclodextrin-based car-riers were well tolerated and they do not stimulate signif-icant antibody responses120
AptamersAptamers are nucleic acid-based molecules selectedin vitro according to their capacity to bind target moleculesspecifically and with high affinity The immunogenicity ofaptamers is limited due to chemical modifications min-imizing adverse reactions Moreover nucleic acid natureand small size of aptamers result in improved transport andtissue penetration Since they can be specifically designedaccording to cell or tissue types (eg tumor cell com-ponents) side effects and off-target effects are minimalIn gene therapy applications the nucleic acid nature ofaptamers allows easy conjugation to RNADNA combin-ing targeting advantages with a therapeutic potential122
Alternatively non-covalent adapter linkages might be cre-ated between aptamers and RNA molecules Functionalgroups might be added to the 5prime- or 3prime-termini allowingcovalent or non-covalent conjugation of aptamers to carriernanoparticles123
Inorganic ParticlesInorganic nanoparticals such as carbon nanotubes mag-netic nanoparticles quantum dots and silica are the focusof recent efforts in drug and gene delivery Many of theseparticles actually offer the opportunity to combine imag-ing and therapeutic possibilities in the same particle ren-dering the nanocarrier a valuable ldquotheranosticrdquo device124
Increased surfacevolume ratio of inorganic particles pro-vides an opportunity for surface modifications includingconjugations to drugs oligonucleotides targeting peptidesor other molecules125126 Yet inorganic nanoparticles tendto aggregate and the size of the aggregate might have animpact on its function and biodistribution Such inorganicnanoparticles are hence coated with organic moleculeswhich provide colloid formation in aqueous and physiolog-ical media and stability Nature of the organic coatings hasto be designed for specific purposes but biocompatibilityof the organic molecules themselves andor their degra-dation products are critical for drug delivery purposes126
Chemistry of the coating might influence the half-life inblood and biodistribution as well as the toxicity of inor-ganic nanoparticles and their clearance mechanisms
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Depending on the material they consist of inorganicnanoparticles may possess a number of different propertiessuch as high electron density and strong optical absorption(eg metal particles in particular Au) photoluminescenceor fluorescence (semiconductor quantum dots eg CdSeCdTe CdTeSeZnS) phosphorescence (doped oxide mate-rials eg Y2O3) or magnetic moment (eg iron oxide orcobalt nanoparticles) The shape of the nanoparticle is alsoan important factor influencing its interaction with cellsMany of the above mentioned nanoparticle are sphericalin shape except carbon nanotubes that are tubular
Carbon NanotubesCarbon nanotubes (CNTs) easily cross the plasma mem-brane and translocate directly into the cytoplasm of tar-get cells due to their nanoneedle structure and usingan endocytosis-independent mechanism yet they do notinduce cell death127ndash129 CNTs are classified as single-walled CNTs and multiwalled CNTs Single or multiplegraphine layer(s) might have a length ranging from 50 nmto 100 mm and a diameter of 1 nm to 100 nm Properfunctionalizing of CNTs by covalent or non-covalentstrategies (such as coating with PEG or Tween-20) mayprovide solubility in aqueous solutions and prevent non-specific interactions thus minimizing toxicity observedwith non-functionalized raw particles130131 Modificationsmight also increase biocompatibility and blood circulationhalf-life132133 CNTs have very strong absorption charac-teristics providing an opportunity for photothermal abla-tion therapy in addition to nanocarrier properties
Magnetic NanoparticlesMagnetic nanoparticles are composed of ferromagneticelements such as Ni Co Mn Fe Superparamagneticiron oxide nanoparticles (SPIONS) such as maghemite--Fe2O3 and magnetite-Fe3O4 are one of the most widelyused magnetic particles as nanocarriers due to relativelylow cost of production biocompatability and superpara-magnetic nature134135 SPIONS are approved by FDA forclinical trials They are commonly used as contrast agentsfor magnetic resonance imaging (MRI) SPION crystals(less than 10 nm in diameter) are coated for specificpurposes with organic molecules such as dextran aminodextran BSA PEI dendrimers lipids and trialkoxysi-lanes including aminopropyltriethoxy silane (APTES)Coating chemistry and preparation methods influence over-all hydrodynamic size pharmacokinetics and the contrasttype (dark-T 2 or bright-T 1 agent) Ability to track the fateof nucleic acid carrier magnetic nanoparticles in vivo usingMRI is highly desirable since it provides informationabout the location of the cargo and its biodistribution136
Attachment of ligands provides target specificity andPEGylation may improve biocompatibility and blood half-life These modifications are commonly introduced to SPI-ONs that are used for imaging and therapy purposes Due
to their magnetic nature drug or nucleic acid carrying SPI-ONs can be concentrated at desired diseased sites such astumors and they may be dragged magnetically towards thelesion area136137 Moreover magnetic nanoparticles offerthe possibility of hyperthermia treatment as a result ofmagnetic heating135 Under applied alternating magneticfield SPIONs cause local temperature increase (41ndash42 C)which may be exploited for alternative and efficient cancertherapy Therefore SPIONs are one of the most versatileand multifunctional nanoparticles Consequently SPIONswere used as popular gene delivery vehicles135
Magnetic nanoparticles may be engineered for oligonu-cleotide delivery purposes MRI visible PEI-PEG coatedSPIONs which are tagged with an antibody have beenshown to effectively carry siRNA to cancer cell lines andshowed low toxicity138 SPIONs coated with both thermoresponsive and cationic polymers such as poly[2-(2-methoxyethoxy)ethylmethacrylate]-b-poly-[2-(dimethyl-amino)ethyl methacrylate] were reported to have25ndash100 times better transfection efficiency than branchedPEI 25 kDa when coupled with magnetic targeting139
SPIONs coated with low molecular weight PEI(12ndash2 kDa) which is usually not effective as poly-plexes in transfection were shown succesful in deliveringsiRNA to mouse macrophages (H Yagci Acar WIPOPatent WO2006055447A3) Therefore magnetic nanpar-ticles are under heavy investigation for the developmentof multifunctional nanocarriers for cancer therapy anddiagnosis135
Quantum DotsSemiconductor quantum dots (QDs) are light-emittingnanoparticles of few nanometer in diameter and they havebeen increasingly used as biological imaging and labelingprobes140 Luminescencefluorescence properties of QDsdepend on the crystal size and type Chemical composi-tion of the crystalline semiconductor core determines theband gap of the material therefore the emission wave-length range Within possible spectral window size ofthe crystal determines the specific wavelength of lumines-cencefluorescence for each and every QD due to quan-tum confinement effect Broad absorption of QDs allowexcitation of multiple QDs at a single wavelength andminimal signal mixing due to the narrow emission bandIn addition they are much more resistant to photobleach-ing These two characteristics are the major advantages ofQDs compared to organic fluorophores as imaging probesUtilization of QDs in nucleic acid delivery aims bothimaging and therapy since in vivo localization of cargocan be observed using optical imaging systems141142 Forexample cationic CdTeZnS QDs conjugated with PEGwas demonstrated to form an effective nanoplex with sur-vivin siRNA and successfully transfeced human tonguecancer cells in vitro and provided real time tracking143
However well-established QDs harbour significant toxic-ity due to constituents such as Cd Se Te144 Therefore
J Biomed Nanotechnol 10 1751ndash1783 2014 1761
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
toxicity of these QDs is a drawback for their use in vivoAs an alternative silver (Ag) chalcogenites emerged assafer near-infra red-emitting QDs145146 Ag2S QDs did notinduce cytotoxicity ROS production apoptosis necrosisor DNA damage147 For example Ag2S QDs (coated with2-mercaptopropionic acid) emitting between 750ndash850 nmshowed no cytotoxicity in NIH3T3 cells at even highdoses (600 mgml) along with good cellular imagingpotential148
Gold NanoparticlesGold nanoparticles emerged as popular tools fornanocarrier-mediated gene therapy149 They are easily syn-thesized and biocompatible particles that allow addition offunctional molecules on their surface due to high surface-to-volume ratio114150 A variety of surface changes andfunctional additions were reported including cationic lipidcoating branched PEI addition or functionalization usingcationic quaternary ammonium or cystamine114151152
Indeed cystamine functionalized gold nanoparticles wereshown to effectively bind deliver and release 35 differ-ent miRNA in in vitro studies using neuroblastoma andovarian cancer cell lines153
Silica NanoparticlesSilica-based nanoparticles are inert stable biocompati-ble and biodegradable particles154 They can be renderedhydrophilic hydrophobic anionic or cationic using func-tional surface modifiers through electrostatic interactionsor by formation of any other type covalent bonds (egester amine) Common functionalization strategies to ren-der the molecule cationic and improve nucleic acid bind-ing include grafting of molecules such as PEI PEI-PEGand Poly-L-arginine155 Nucleic acids may also be loadedinside the mesoporous silica particles156 siRNA encapsu-lating mesoporous silica nanoparticles were successfullyused for in vitro and in vivo gene silencing in several stud-ies (For example Ref [156])
RECENT IN VIVO STUDIES USING RNAINTERFERENCE IN CANCER THERAPYThere is an exponential increase in the number of scientificpublications dedicated to gene therapy of diseases usingsmall RNAs and nanoparticles A literature search usingldquonanoparticlerdquo and ldquosiRNA shRNA or miRNArdquo revealedmore than 700 articles published in the last two yearsThis number is roughly equal to the number of all articlespublished in this field until two years ago So the field isexpanding and there seems to form a consensus aroundthe use of nanoparticles as next generation gene therapytools We believe that these high expectations are not onlya consequence of shifting trends in science and technol-ogy The exponential rise in interest in the field of smallRNA carrier nanoparticles is fueled by the advances inthe field of nano materials promising results obtained in
small RNA therapeutics by both academic laboratories andindustry and increasing number of successful clinical tri-als In this section we will summarize results of selectedrecent studies using RNA therapeutics for cancer treatmentin preclinical in vivo experimentsOverview of the works dealing with small RNA treat-
ment of experimental cancers and published within thelast two years were summarized in Table I Although sev-eral studies were performed using lipid-based nanopar-ticles (Liposomes micelles or lipidoids) other particlessuch as polymers organic or inorganic carriers and com-pounds mixtures with functional modifications of vari-able substances were also tested by many research teamswith reasonable success Scheme 4 summarizes the generalstrategy followed in most of these studies
Tumor Types and RNAi TherapyRecent studies in the literature showed that tumors of vari-ous tissue origins could be treated using RNA interferencestrategies (Table I) Fine tuning of nanoparticles throughaddition of functional moieties or modifications alloweddelivery of drugs into almost any kind of tumor tissue withaccompanied therapeutic effects Although several studiesused animal tumor models that resulted from the injectionof cell lines from most commonly seen human cancers(lung breast prostate cervix or ovarian cancer cell lines)animals with kidney urinary bladder head and neckgastric pancreatic melanomas neuroblastomas glioblas-tomas multiple myelomas or sarcomas were also treatedwith RNAinanocarrier strategy81156ndash170 These results givehope about the general use of RNA interference as astrategy to treat cancers of different origins Althoughit is difficult to compare the efficacies of different nucleicacid molecules and their interference effects at this pointsiRNA or microRNAs as well as shRNA vectors wereshown to achieve intratumoral in vivo target gene knock-down and anticancer effects leading to a decrease in tumorsize (For example Refs [156 171]) Since in most studiesin addition to RNAi loaded particles naked nanoparticlesor particles loaded with non-specific control nucleic acidswere also used antitumor effects obtained in these studiesare specific and they may be attributable to small RNAmolecules rather than the particles themselves underliningthe potential of RNA interference in cancer treatmentMajority of recent studies with in vivo models chose
to use human tumor cell line xenografts in immune com-promised mice nude or severe-combined immuno defi-cient SCID mice (Table I) (For example Refs [162 172])Syngeneic transplants and established genetically engi-neered mouse models of cancer were rarely studied in thiscontext167173ndash175 Therefore although antitumor effects andsome of the toxic effects (eg liver toxicity) might berevealed using immune compromised mice hematologicalimmunological and inflammatory side effects of the treat-ment strategies used in recent studies might need to berevisited using immunocompetent mice
1762 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IRec
entstudieswithRNAica
rryingnan
oparticles
forthetrea
tmen
tofex
perim
entalca
nce
rs(P
ublis
hed
within
thelast
twoye
ars)
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGF
Mag
netic
mes
oporou
ssilicana
nopa
rticles
PEIan
dfuso
genicpe
ptide
KALA
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[156
]
siRNA
Polo-likekina
se1(P
LK1)
pH-sen
sitiveca
tioniclip
idYSK05
-MEND
(YSK05
POPEcho
lesterol
=50
2525
)
PEG
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
PLK
1[51]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Bioen
gine
ered
bacterial
outermem
bran
eve
sicles
Hum
anep
idermal
grow
thfactor
rece
ptor
2(H
ER2)-spe
cific
affib
ody
targeting
HCC-195
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
KSP
Dec
reas
edtumor
volume
[81]
siRNA
Luciferase
Dioleoy
lpho
spha
tidic
acid-(DOPA
-)co
ated
nano
-sized
calcium
phos
phate(LCP-II)
DSPE-P
EG-an
dan
isam
idefortargeting
sigm
a-1rece
ptor
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
Xen
ograft
it
ND
Kno
ckdo
wnof
luciferase
[211
]
siRNA
mTERT
N-((2-hyd
roxy
-3-trim
ethy
l-am
mon
ium)propy
l)ch
itosa
nch
lorid
e(H
TCC)na
nopa
rticles
Partic
leload
edwith
paclita
xel
LCC
murinelung
canc
erce
llssy
ngen
eicsc
graft
oral
Noeffect
Kno
ckdo
wnof
mTERT
Dec
reas
edtumor
volume
Syn
ergize
dwith
paclita
xel
[159
]
siRNA
VEGF
Multilay
ered
polyion
complexes
Polyc
ationinterla
yeran
dade
tach
able
PEG
shell
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
[212
]
siRNA
Multid
rug
resistan
ceprotein1
(MRP1)
Nan
opartic
lesas
sembled
vialaye
r-by
laye
rde
positio
nof
siRNA
and
poly-L-arginine
Hya
lurona
n(H
A)co
ating
forHA-C
D44
targeting
MDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
it
Noeffect
Kno
ckdo
wnof
MRP1
Dec
reas
edtumor
volume
[183
]
siRNA
STA
T3-a
Nan
oporou
ssilicon
nano
particles
Argininean
dPEI
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicefat
padxe
nograft
iv
Noeffect
Kno
ckdo
wnof
STA
T3-a
[204
]
siRNA
Luciferase
Lipo
somal
nano
particle
Fou
rtand
emrepe
atsof
human
histon
eH2A
peptideinterven
edby
cathep
sinD
clea
vage
sites
PEG-A
nisa
mide
fortargeting
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
luciferase
[199
]
siRNA
Polo-likekina
se1(P
LK1)
Hya
luronicac
id(H
A)
base
dse
lfass
embling
HA-P
EIP
EG
nano
system
s
Hya
lurona
nforCD44
targeting
B16
F10
amurine
melan
omace
llsA54
9-luchu
man
lung
canc
erce
llsHep
3Bhu
man
liver
canc
erce
llsMDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
graftor
metas
tatic
lung
lesion
sby
IVinjection
it
ND
Kno
ckdo
wnof
PLK
1[160
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1763
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
P-glyco
protein
drug
expo
rter
(P-
gpM
DR1)
Mes
oporou
ssilica
nano
particles
Polye
thylen
eimine
polyethy
lene
glyc
ol(P
EI-PEG)co
polymer
MCF-7M
DR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gpMDR1
Dec
reas
edtumor
volume
Syn
ergy
with
doxo
rubicin
[179
]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Multifun
ctiona
lcarrie
rsy
stem
with
catio
nic
(olig
oethan
amino)am
ide
core
attach
edto
PEG
chain
Folic
acid
fortargeting
Inf7
(Infl
uenz
ape
ptide)
asen
doso
molytic
peptide
coup
ledto
the5prime-end
ofsiRNA
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
itor
iv
ND
Kno
ckdo
wnof
EG5
Dec
reas
edtumor
volume
[161
]
siRNA
Epide
rmal
Growth
Factor
Rec
eptor
(EGFR)
Poly-L-argininean
dde
xtransu
lfate-bas
edna
noco
mplex
FaDuhu
man
pharyn
xsq
uamou
sca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[172
]
siRNA
Cho
line
kina
se(C
hk)
Polye
thylen
imine-
polyethy
lene
glyc
ol(P
EI-PEG)co
grafted
polymer
Con
versionof
nontox
ic5-flu
oroc
ytos
ine(5-FC)to
cytotoxic5-flu
orou
racil
(5-FU)by
activating
bacterialc
ytos
ine
deam
inas
e(bCD)
PC3-PIP
andPC3-Flu
human
pros
tate
canc
erce
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
e[157
]
siRNA
Polo-like
kina
se1
(Plk1)
Cationiclip
idpo
lymer
hybrid
nano
particles
(cationiclip
id(N
N-
bis(2-hy
drox
yethyl)-N-
methy
l-N-(2-
choles
teryloxy
carbon
ylam
inoe
thyl)am
mon
ium
brom
ide
BHEM-C
hol)
andam
phiphilic
polymers(H
ydroph
obic
polylactideco
re)
PEG
shell
BT47
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Plk1
Dec
reas
edtumor
volume
[213
]
siRNA
hTERT
Single-walledca
rbon
nano
tube
s(S
WNTs)
Branc
hedPEIco
njug
ated
DSPE-P
EG20
00-M
aleimide
forco
njug
ationwith
NGR
(Cys
-Asn
-Gly-A
rg-C
ys-)
targetingpe
ptide(rec
ognize
tumor
neov
ascu
lature)
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
hTERT
Dec
reas
edtumor
volume
Syn
ergy
with
photothe
rmal
trea
tmen
t
[139
]
1764 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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cer J Clin 64 9 (2014)2 M J Espiritu A C Collier and J P Bingham A 21st-century
approach to age-old problems The ascension of biologics in clini-cal therapeutics Drug Discov Today (2014)
3 R L Schilsky Personalized medicine in oncology The future isnow Nat Rev Drug Discov 9 363 (2010)
4 M N Patel M D Halling-Brown J E Tym P Workman andB Al-Lazikani Objective assessment of cancer genes for drug dis-covery Nat Rev Drug Discov 12 35 (2013)
5 D Hanahan and R A Weinberg Hallmarks of cancer The nextgeneration Cell 144 646 (2011)
6 N F Sun Z A Liu W B Huang A L Tian and S Y Hu Theresearch of nanoparticles as gene vector for tumor gene therapyCrit Rev Oncol Hematol 89 352 (2013)
1776 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
7 M Rothe U Modlich and A Schambach Biosafety challenges foruse of lentiviral vectors in gene therapy Curr Gene Ther 13 453(2013)
8 D R Corey RNA learns from antisense Nat Chem Biol 3 8(2007)
9 V N Kim MicroRNA biogenesis Coordinated cropping and dic-ing Nat Rev Mol Cell Biol 6 376 (2005)
10 D E Golden V R Gerbasi and E J Sontheimer An inside jobfor siRNAs Mol Cell 31 309 (2008)
11 M Ghildiyal and P D Zamore Small silencing RNAs An expand-ing universe Nat Rev Genet 10 94 (2009)
12 D H Kim M A Behlke S D Rose M S Chang S Choiand J J Rossi Synthetic dsRNA Dicer substrates enhance RNAipotency and efficacy Nat Biotechnol 23 222 (2005)
13 Y Maida M Yasukawa M Furuuchi T Lassmann R PossematoN Okamoto V Kasim Y Hayashizaki W C Hahn and K Masu-tomi An RNA-dependent RNA polymerase formed by TERT andthe RMRP RNA Nature 461 230 (2009)
14 N R Smalheiser The search for endogenous siRNAs in the mam-malian brain Exp Neurol 235 455 (2012)
15 K A Tekirdag G Korkmaz D G Ozturk R Agami andD Gozuacik MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5 Autophagy 9 374(2013)
16 G Korkmaz K A Tekirdag D G Ozturk A Kosar O USezerman and D Gozuacik MIR376A Is a Regulator ofStarvation-Induced Autophagy PLoS One 8 e82556 (2013)
17 D Castanotto and J J Rossi The promises and pitfalls of RNA-interference-based therapeutics Nature 457 426 (2009)
18 E Iorns C J Lord N Turner and A Ashworth Utilizing RNAinterference to enhance cancer drug discovery Nat Rev Drug Dis-cov 6 556 (2007)
19 M A Behlke Chemical modification of siRNAs for in vivo useOligonucleotides 18 305 (2008)
20 S D Rose D H Kim M Amarzguioui J D Heidel M ACollingwood M E Davis J J Rossi and M A Behlke Func-tional polarity is introduced by Dicer processing of short substrateRNAs Nucleic Acids Res 33 4140 (2005)
21 K Nishina T Unno Y Uno T Kubodera T KanouchiH Mizusawa and T Yokota Efficient in vivo delivery of siRNAto the liver by conjugation of alpha-tocopherol Mol Ther 16 734(2008)
22 F Czauderna M Fechtner S Dames H Aygun A Klippel G JPronk K Giese and J Kaufmann Structural variations and sta-bilising modifications of synthetic siRNAs in mammalian cellsNucleic Acids Res 31 2705 (2003)
23 B A Kraynack and B F Baker Small interfering RNAs contain-ing full 2prime-O-methylribonucleotide-modified sense strands displayArgonaute2eIF2C2-dependent activity RNA 12 163 (2006)
24 F V Rivas N H Tolia J J Song J P Aragon J Liu G JHannon and L Joshua-Tor Purified Argonaute2 and an siRNAform recombinant human RISC Nat Struct Mol Biol 12 340(2005)
25 V Hornung M Guenthner-Biller C Bourquin A AblasserM Schlee S Uematsu A Noronha M Manoharan S AkiraA de Fougerolles S Endres and G Hartmann Sequence-specificpotent induction of IFN-alpha by short interfering RNA in plasma-cytoid dendritic cells through TLR7 Nat Med 11 263 (2005)
26 A D Judge G Bola A C Lee and I MacLachlan Design ofnoninflammatory synthetic siRNA mediating potent gene silencingin vivo Mol Ther 13 494 (2006)
27 A L Jackson J Burchard D Leake A Reynolds J SchelterJ Guo J M Johnson L Lim J Karpilow K NicholsW Marshall A Khvorova and P S Linsley Position-specificchemical modification of siRNAs reduces ldquooff-targetrdquo transcriptsilencing RNA 12 1197 (2006)
28 D Bumcrot M Manoharan V Koteliansky and D W Sah RNAitherapeutics A potential new class of pharmaceutical drugs NatChem Biol 2 711 (2006)
29 A S Peek and M A Behlke Design of active small interferingRNAs Curr Opin Mol Ther 9 110 (2007)
30 Y Pei and T Tuschl On the art of identifying effective and specificsiRNAs Nat Methods 3 670 (2006)
31 S Svenson What nanomedicine in the clinic right now really formsnanoparticles Wiley Interdiscip Rev Nanomed Nanobiotechnol 6125 (2014)
32 T S Zimmermann A C Lee A Akinc B Bramlage D BumcrotM N Fedoruk J Harborth J A Heyes L B Jeffs M JohnA D Judge K Lam K McClintock L V Nechev L R PalmerT Racie I Rohl S Seiffert S Shanmugam V Sood J SoutschekI Toudjarska A J Wheat E Yaworski W Zedalis V KotelianskyM Manoharan H P Vornlocher and I MacLachlan RNAi-mediated gene silencing in non-human primates Nature 441 111(2006)
33 D V Morrissey J A Lockridge L Shaw K Blanchard K JensenW Breen K Hartsough L Machemer S Radka V JadhavN Vaish S Zinnen C Vargeese K Bowman C S Shaffer L BJeffs A Judge I MacLachlan and B Polisky Potent and persis-tent in vivo anti-HBV activity of chemically modified siRNAs NatBiotechnol 23 1002 (2005)
34 D C Litzinger A M Buiting N van Rooijen and L HuangEffect of liposome size on the circulation time and intraorgan distri-bution of amphipathic poly(ethylene glycol)-containing liposomesBiochim Biophys Acta 1190 99 (1994)
35 A Akinc A Zumbuehl M Goldberg E S Leshchiner V BusiniN Hossain S A Bacallado D N Nguyen J Fuller R AlvarezA Borodovsky T Borland R Constien A de Fougerolles J RDorkin K Narayanannair Jayaprakash M Jayaraman M JohnV Koteliansky M Manoharan L Nechev J Qin T RacieD Raitcheva K G Rajeev D W Sah J Soutschek I ToudjarskaH P Vornlocher T S Zimmermann R Langer and D G Ander-son A combinatorial library of lipid-like materials for delivery ofRNAi therapeutics Nat Biotechnol 26 561 (2008)
36 S C Semple A Akinc J Chen A P Sandhu B L Mui C KCho D W Sah D Stebbing E J Crosley E Yaworski I MHafez J R Dorkin J Qin K Lam K G Rajeev K F WongL B Jeffs L Nechev M L Eisenhardt M Jayaraman M KazemM A Maier M Srinivasulu M J Weinstein Q Chen R AlvarezS A Barros S De S K Klimuk T Borland V Kosovrasti W LCantley Y K Tam M Manoharan M A Ciufolini M A TracyA de Fougerolles I MacLachlan P R Cullis T D Madden andM J Hope Rational design of cationic lipids for siRNA deliveryNat Biotechnol 28 172 (2010)
37 A Hoeben B Landuyt M S Highley H Wildiers A T VanOosterom and E A De Bruijn Vascular endothelial growth factorand angiogenesis Pharmacol Rev 56 549 (2004)
38 Y Noguchi J Wu R Duncan J Strohalm K Ulbrich T Akaikeand H Maeda Early phase tumor accumulation of macromoleculesA great difference in clearance rate between tumor and normaltissues Jpn J Cancer Res 89 307 (1998)
39 A K Iyer G Khaled J Fang and H Maeda Exploiting theenhanced permeability and retention effect for tumor targetingDrug Discov Today 11 812 (2006)
40 Y Matsumura and H Maeda A new concept for macromoleculartherapeutics in cancer chemotherapy Mechanism of tumoritropicaccumulation of proteins and the antitumor agent smancs CancerRes 46 6387 (1986)
41 T Ishimoto Y Takei Y Yuzawa K Hanai S Nagahara Y TarumiS Matsuo and K Kadomatsu Downregulation of monocytechemoattractant protein-1 involving short interfering RNA atten-uates hapten-induced contact hypersensitivity Mol Ther 16 387(2008)
J Biomed Nanotechnol 10 1751ndash1783 2014 1777
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
42 G J Villares M Zigler H Wang V O Melnikova H WuR Friedman M C Leslie P E Vivas-Mejia G Lopez-Berestein A K Sood and M Bar-Eli Targeting melanoma growthand metastasis with systemic delivery of liposome-incorporatedprotease-activated receptor-1 small interfering RNA Cancer Res68 9078 (2008)
43 E Kawata E Ashihara S Kimura K Takenaka K SatoR Tanaka A Yokota Y Kamitsuji M Takeuchi J KurodaF Tanaka T Yoshikawa and T Maekawa Administration of PLK-1 small interfering RNA with atelocollagen prevents the growth ofliver metastases of lung cancer Mol Cancer Ther 7 2904 (2008)
44 H Maeda J Wu T Sawa Y Matsumura and K Hori Tumorvascular permeability and the EPR effect in macromolecular thera-peutics A review J Control Release 65 271 (2000)
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46 F Iversen C Yang F Dagnaes-Hansen D H Schaffert J Kjemsand S Gao Optimized siRNA-PEG conjugates for extended bloodcirculation and reduced urine excretion in mice Theranostics 3 201(2013)
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1778 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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1780 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
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191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
A Isin Dogan-Ekici MD is an Associate Professor in the Pathology Department atthe Yeditepe University Hospital Istanbul She graduated from Hacettepe UniversitySchool of Medicine in 1997 Dr Dogan-Ekici obtained her pathology specialist degreefrom Hacettepe University School of Medicine Department of Pathology in 2003 Herresearch interests include surgical pathology nephropathology and urogenital systempathology and pathology of gene therapy models
Sinan Ekici MD is a Professor in the Department of Urology at the Maltepe Univer-sity School of Medicine He graduated from Hacettepe University School of Medicinein 1995 He obtained his urology specialist degree from Hacettepe University School ofMedicine Department of Urology in 2000 Dr Ekici worked as a clinical observer inMemorial Sloan Kettering Cancer Center New York and worked as research and clin-ical fellow in the Department of Urooncology Miami University School of MedicineUSA His research interests include urooncology endoscopic urology cancer biologygene therapy of urological cancers
cells in a non-selective way Consequently both of theseapproaches are accompanied with side effects ranging fromhair loss and gastrointestinal (GI) problems (hair folliclesand GI tract cells are amongst most rapidly proliferatingcells in the body) to secondary cancer development (egLeukemias) due to DNA damage Therefore developmentof targeted and cancer cell-selective therapies with minimalshort- and long-term side effects is an important challengeRecent progress in molecular biology genetics and
biotechnology allowed the development of small moleculedrugs targeting cancer-related proteins antibody-baseddrugs immunomodulatory approaches and cellular ther-apies ranging from improved bone marrow transplan-tation to stem cell treatments Some of these novelapproaches already entered clinical use alone or as partof an adjuvant or combinatory therapy with classical treat-ment modalities2 Parallel advances in diagnostic tech-niques cancer genetics and pathology led to a better andmore detailed classification of cancer subtypes allowingsubtype-specific even personalized treatment regimens3
In spite of all these innovations and efforts in the can-cer medicine field disease-free survival rates are lowand prognosis is still bad especially in advanced andormetastatic cases Therefore a better understanding ofcancer biology and development of novel and innovativetreatment approaches is still one of the most importantchallenges of modern science and medicineA great majority of small molecule drugs target disease-
related enzymes or receptors4 Yet we now understandthat complex processes and changes during cancer initia-tion progression and evolution leading to drug resistanceresult in the mutation andor dysregulation of enzyme
and non-enzyme proteins and even nucleic acids such asmicroRNAs and long non-coding RNAs5 In the post-genomic era with the advances in genomics and epigenet-ics of cancer gene therapy is one of the innovative cancertherapy fields gaining momentum in recent years Genetherapy approaches offer the possibility of up or downreg-ulation of dysregulated gene products and replacement ofmodifiedmutated transcripts with non-mutatedwild typeforms6 Experimental treatments using nucleic acids rangefrom DNAcDNA replacement therapies to RNA-basedregimens Although establishment of general concepts ofgene therapy date back to 1960s and 1970s issues relatedto the stability and half-life of the nucleic acid moleculesand most importantly lack of suitable delivery and target-ing systems limited the success of this promising technol-ogy Until recently viral systems were the major focus ofgene delivery studies and gene therapy protocols Modi-fied viruses including adenoviruses retroviruses herpesviruses and lentiviruses were examined and tested in detailas gene delivery agents In addition to severe immunereactions ranging from inflammation to shock insertionalmutagenesis caused by viral integration into the patientgenome constituted major side-effects and drawbacks rais-ing concerns and doubts about the future of gene therapy7
With recent advances in nanotechnology several non-viralgene delivery systems were developed as gene and drugcarriers reviving hopes about the use of nucleic acids aspotent drugs against cancer
SCOPE OF THE REVIEWIn this review we will summarize and discuss accumu-lating data about the use of nanoparticles as nucleic acid
J Biomed Nanotechnol 10 1751ndash1783 2014 1753
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
carriers We will limit ourselves to cancer gene ther-apy studies exploiting nanocarrier loaded small RNADNAmolecules ie RNA interference (RNAi) tools such assiRNAs shRNAs and microRNAs Merits and contribu-tions of antisense oligonucleotides in gene therapy experi-ence were discussed in detail elsewhere8
RNA INTERFERENCEDiscovery of RNA interference (RNAi) by Andrew Fireand Craig Mello was a breakthrough that was awarded bythe Nobel prize in Physiology or Medicine in 2006 SmallRNAs mediating RNA interference control gene expres-sion in organisms ranging from plants and C elegansto human Small interfering RNAs (siRNAs) short hair-pin RNAs (shRNAs) and microRNAs (miRNAs) are themost studied members of regulatory RNAs9 Non-codingsmall RNAs are not translated they mainly act at a post-transcriptional level determining the stability of messen-ger RNAs (mRNAs) and their translation into proteinsEndogenous siRNAs (endo-siRNAs) are coded not only
by transposons and other repeat elements but they mayalso originate from regions where both sense and antisensetranscripts are transcribed as well as from sequences giv-ing rise to potential hairpin structures inside pseudogenes
Scheme 1 RNA interference (RNAi) pathways (a) miRNA pathways (b) siRNA pathways See text for the pathway details RNAPol II RNA polymerase II Dicer Dicer enzyme complex into the siRNA RISC RNA-induced silencing complex (RISC) RdRPRNA-dependent RNA polymerase ORF open reading frame of the target gene AAAAA polyA tail of the mRNA
and even in protein-coding genes1011 On the other handmiRNAs may be intronic or intergenic Intronic miRNAsare transcribed from intron regions of some protein codingmRNAs while intergenic miRNAs are transcribed frommiRNA genes or gene clusters using their own promotersEndogenous siRNAs and miRNAs bear similarities to
each other from a structural and functional point of viewYet pathways leading to their maturation are rather spe-cific to the small RNA type (Scheme 1(a)) miRNAs aretranscribed by RNA polymerase II as primary-miRNAs(pri-miRNAs) and processed by a Drosha-DGCR8 com-plex in the nucleus to produce hairpin-shaped premature-miRNAs (pre-miRNA)12 Transport from nucleus isachieved with the help of the exportin-Ran GTPase com-plexes Further processing of the pre-miRNA hairpin bycytoplasmic DICER proteins produces sim 21ndash22 nt longmiRNAmiRNAlowast duplexes One of the mature miRNAstrands that originate from the duplex is then loaded ontoa complex called the RNA-induced silencing complex(RISC) including the Argonaute (eg AGO2) proteinsRISC then guides the mature miRNA strand towards tar-get messenger RNAs (mRNAs) It is believed that tar-get specificity of the miRNA and the fate of the targetmessenger RNA depends on the degree of complemen-tarity between matching sequences of these two types of
1754 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
RNAs While a partial complementarity may lead to theblockage of the translation machinery protein translationrepression andor sequestration of miRNA-mRNA com-plexes in compartments called P-bodies a perfect matchbetween these two RNAs may result in mRNA degradation(Scheme 1(a))Conversely endo-siRNAs complementary to template
mRNAs are synthesized by RNA-dependent RNA poly-merases (RdRP) and they are not transcribed from thegenomic DNA (Scheme 1(b)) It was long believed thatmammals did not have any RdRPs But this conceptis now changing For example human telomerase cat-alytic subunit (hTERT) was shown possess a mammalianRdRP activity required for double stranded RNA synthe-sis from the mitochondrial RNA processing endoribonu-clease noncoding RNA component1314 In the endogenoussiRNA pathway hairpin containing double-stranded RNAproducts of RdRP are further processed into functionalendogenous siRNAs in either a Dicer-dependent or aDicer-independent manner (Scheme 1(b)) In general thesense guide strand of the endo-siRNAs are loaded onto theRISC with AGO2 proteinsWhile in general mammalian miRNAs show partial
complementary to their mRNA target sequences and con-trol a wide number of functionally-related transcripts strictcomplementarity was thought to be necessary for siRNAfunction9 But even synthetic siRNAs or shRNAs that aredesigned to target one and only mRNA were shown toaffect so called ldquooff-target genesrdquo Therefore although agene with a dominant biological effect will be targeted bysiRNAshRNAs a spectrum of biological events might beaffected by the use of a small RNA Nevertheless in vitrocell culture and animal studies confirmed that the biolog-ical outcomes of siRNAshRNAs and even miRNAs wereusually determined by their effect on a dominant targetgene andor pathway1516
SMALL RNAS AS POTENT DRUGSUse of potent RNA interference strategies might give usnew opportunities for the treatment of diseases such ascancer17 Potential advantages of small RNAs over existingsmall molecule drugs and conventional therapies includeorganic composition natural metabolism lower drug tox-icity minimal immune reactions when designed optimallyand combined with appropriate carriers possibility ofmodulating targets that are considered as ldquoundruggablerdquo byconventional drugs possibility of targeting disease-relatedtissue-specific isoforms andor mutant transcripts and stan-dard chemical synthesis protocols Moreover RNA plat-forms are now widely used in high throughput formats fortarget validation and drug development processes reduc-ing the product development cycle and cost compared toconventional small molecules18
Modifications to the native RNA structure can cre-ate robust drug-like RNA molecules19 Synthetic 21-mer
RNA duplexes mimicking natural siRNAs and miRNAsare commonly used in RNA-based gene therapy protocolsAlternatively asymmetric 2527-mers or 2729-mers blunt25-mers blunt 27-mers and blunt 19-mers were tested fortheir stability and potency as RNA drugs with variablemerits20ndash23 These different synthetic RNAs might directlybe loaded onto the RISC complex or they might firstrequire processing by Dicer In fact even under in vitro con-ditions synthetic siRNAs were shown to directly load ontorecombinant human AGO2 proteins and form functionalcomplexes24 Therefore following delivery small RNAsmay rapidly form functional complexes and alter target pro-tein levels resulting in therapeutic changes in cellsNaked RNA molecules are highly susceptible to degra-
dation by nucleases that are abundant in tissues and in theblood circulation Therefore to stabilize RNA moleculesincrease their half-lives in biological environments andavoid immune reactions a number of chemical changesmight be introduced to the nucleic acid structures19
There are several commonly used RNA modifications2prime-O-methyl modifications into the sugar structure ofsome nucleotides may confer resistance to endonucle-ases decrease off-target effects when introduced into theseed region and minimize Toll-like receptor-mediatedimmune reactions25ndash27 Introduction of phosphorothioateboranophosphate or methylphosphonate backbone linkagesat the 3prime-end of the RNA strands may reduce their suscepti-bility to exonucleases Similarly alternative 2prime sugar mod-ifications such as 2prime-fluoro LNA (Locked nucleic acids)FANA (2prime-deoxy-2prime-Fluoro--d-arabinonucleic acid) and2primeMOE (2prime-O-methoxyethyl) modifications were reportedto increase endonuclease resistance of small RNAs28
While all these modifications result in more robust RNAmolecules they might affect the potency of the RNA inter-ference effects obtained during treatment Therefore evenif the changes were performed according to design criteriaor computer tools experimental testing is required in eachseparate case to confirm potency of modified small RNAmolecules on their mRNA targets2930
RNADNA NANOCARRIERS FORCANCER THERAPYUse of gene therapy and lately small RNAs for can-cer treatment was hindered by the lack of a suitabledelivery system Recent developments in nanotechnologyallowed the introduction of nanoparticles with very differ-ent physico-chemical properties Novel and sophisticatednanocarriers and their functionalized derivatives are beingtested as potent and in many cases targeted RNA drugdelivery agents Some formulations are already in clinicaltrials and a few of them were even approved by majoragencies such as the Food and Drug Agency (FDA) in theUSA31
Nanoparticles to be used as nucleic acid delivery agentsshould meet several criteria The particles should safely
J Biomed Nanotechnol 10 1751ndash1783 2014 1755
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and effectively deliver RNA molecules to cancer cells andtumors Therefore they have to be biocompatible notimmunogenic and they should not get modified or dis-solved into toxic substances under biological conditionsand before reaching the tumor target For effective deliv-ery and dosage nano conjugates have to be stable enoughin the blood circulation and resist shear forces proteasesand nucleases that they face with Complex formation withblood cells proteins and other blood components mightalso affect carrier size charge availability and efficacyClearance is also an important issue For nanocarriers
to reach therapeutic blood levels they should not be read-ily cleared through glomerular filtration in the kidneys ortrapped by the reticuloendothelial system For examplenaked siRNA molecules and nanoparticles less than 10 nmmay be filtrered and excreted through kidneys follow-ing systemic administration Carriers larger than 100 nmmight be phagocytosed and cleared by monocytes andmacrophages residing in the reticuloendothelial system(RES also called mononuclear phagocytic system) tissueswith high blood supply including pulmonary alveoli liversinusoids skin spleen etc32ndash36 In addition to the size of thenanoparticles their geometries surface charges hydropho-bicities and opsonization by serum proteins might affectclearance by monocytes and macrophages Additionallythe efficacy of nucleic acid drugs in specific tissues andorgans may depend on the ability of nanocarriers to pene-trate blood vessels and tissues and pass through biologicalbarriers such as the tight blood-brain-barrier of the centralnervous systemFor cancer treatment small RNA drugs should affect
genetic andor molecular changes specific to cancer cellsand that are rate-limiting for tumor growth The idealnanocarrier should be able to concentrate within the tumortissue and if possible target individual tumor cells in aselective way (eg through receptors or molecules thatare tumor-specific or that are enriched in the tumor tis-sue) and not penetrate normal cells Enhanced permeabilityand retention (EPR) effect offers an advantage for solid-tumor targeting The EPR effect is a result of neovascu-larisation new blood vessel formation to feed tumors withsizes beyond passive oxygen and nutrient diffusion lim-its (beyond 01ndash02 mm diameter)37 Blood vessels feed-ing tumor tissues are irregular and highly permeable Withthe lack of lymphatic drainage macromolecules are eas-ily retained in and around the tumor area3839 For exam-ple low molecular weight drugs may diffuse freely inand out of the tumor tissues but macromolecules (gt 40kDa) and nanoparticles of 100ndash200 nm accumulate inthe tumor tissue3840ndash43 EPR phenomenon was reported invarious human solid tumors as well as in inflammatorytissues44
Different types of nanoparticles were tested as drug car-riers and gene therapy tools (Scheme 2) The core structureof the particle may be a vesicle (liposomes) a polymer(eg PEI PLGA) a dendrimer carbon nanotubes silica or
metal nanoparticles (eg Gold) Porousvesiculate carrierssuch as liposomes polymeric micelles or some inorganicparticles (eg mesoporous silica) may encapsulate orabsorb RNADNA molecules Nanocarriers with a cationicnature including cationic liposomes cationic dendrimers(eg PAMAM) and polymers (eg PEI PDMAEMA) orcationic polymer coated inorganic particles (eg PEI cov-ered iron oxide) may form complexes through electro-static interactions with the negatively charged backboneof nucleic acids The nature and physico-chemical proper-ties of the nanoparticles may also influence their stabilityand half-life in blood criculation efficacy of their deliveryinto tissues and cells and their capacity to escape fromendosomes in the cell All these properties are determiningcriteria for nano drug efficacyTo improve stability RNADNA loading target speci-
ficity tracking cellular internalization endo-lysosomalescape and intracellular robustness additional functionalunits might be introduced to the basic structure ofthe nanocarriers (Scheme 3)45 Possible modificationsand changes include conjugation to proteins (antibodieslectins cytokines thrombin fibrinogen BSA transfer-rin) cellular or viral peptides (eg RGD LHRD TATPep-3 KALA) polysaccharides (eg lipopolysaccharideshyaluronic acid dextran chitosan) low molecular weightligands (eg folic acid anisamide) and polyunsaturatedfatty acids (eg palmitic acid and phospholipids) Thesestructures can be conjugated onto the nanocarrier surfacethough hydrolysable or non-hydrolysable chemical bondsand modifications such as amide ester silane hydrazoneor through the use of high avidity molecules such asavidin-biotin Fluorophores may also be added for par-ticle tracking purposes To improve the availability ofsuch groups and especially the targeting groups spacermolecules may be addedAn important modification relevant for biological func-
tion is ldquoPEGylationrdquo (Scheme 3)45 PEG coordinateswater molecules and forms an aqueous shell aroundnanoparticles shielding their charges PEGylation reducesinteraction with serum proteins decreases opsoniza-tion and clearance of nanoparticles by RES monocyte-macrophages sterically prevent nanocarrier aggregationand due to increased molecular weight above the thresholdfor glomerular filtration reduces elimination of the parti-cles through urinary excretion Hence PEG increases thestability improves biocompatibility prolongs blood circu-lation time and bioavailability of nanocarriers4647 Molec-ular weight and density of PEG chains on the nanocarriersurface may impact the function depending on the natureof the carried molecules ie siRNA47
On the other hand PEGylation significantly attenu-ates uptake of nanocarriers by target cells4849 More-over PEG chains were shown to block endosomal escapeand cytosolic release of chemical drugs and nucleicacids50 Blockage of cellular uptake and endosomal releasein the cell may severely attenuate drug efficacy and
1756 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 2 Major types of nanoparticles used as nucleic acid carriers
therapeutic RNA interference effects Various strategieswere adapted to overcome these negative effects of PEGwhile exploiting its circulatory advantages Cleavage ofPEG-chains upon delivery into the tumor environment wasachieved through addition of tumor-related matrix met-alloproteinase sensitive lipids or peptides51 pH-sensitivelinkers between the PEG moiety and nanocarriers canalso be used to release PEG from the particle in theacidic environment of the endosomes and allow cytosolic
Scheme 3 A representative nanoparticle with functional modifications Various molecules might be added to a nanoparticleto improve its physico-chemical properties and pharmacokinetics (eg PEG) to increase RNADNA binding (eg PEI) to allowbetter targeting (eg antibodies) or tracking (eg fluorophores)
release of small RNAs Modulation of the hydrophobic-ity of the PEGndashnanocarrier conjugate was also testedas a release strategy In lipid-based nanocarriers thelength of the alkyl chain of the PEG-lipid anchor wasshown to determine its affinity for the lipid deliveryvehicle and changing its length modified endosomalescape potential and drug effects52 Cholesterol-anchoredPEG was also shown to improve endosomal escapecapacities52
J Biomed Nanotechnol 10 1751ndash1783 2014 1757
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
LiposomesLiposomes have been tested extensively as gene deliv-ery agents Liposomes are artificial membrane-boundvesicles formed by bilayers of amphipathic lipids Theymight be unilamellar or multilamellar Their biocom-patibility low toxicity and low immunogenicity madethem popular agents for both in vitro and in vivo genedelivery5354 Liposomes are typically made of mix-tures of lipids found in biological membranes or theirderivatives including phosphatidylcholine (PC or DOPC12-Oleoyl-sn-Glycero-3-phosphatidylcholine) phosphatidyl-ethanolamine (PE or DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidylethanolamine) cholesterol and evenceramide53 Although liposomes made of neutral lipids aremore biocompatible than cationic lipids and have betterpharmacokinetics during preparation of gene deliveryvectors they bind less to negatively charged DNA orRNA molecules and have lower entrapment efficiencies55
Therefore despite their more toxic nature cationic lipidsare commonly used as liposome-based transfection agentsCationic lipids posses positively charged headgroupssuch as amines quaternary ammonium salts peptidesaminoacids or guanidiniums which electrostaticly attractand bind to negatively charged phosphate residues innucleic acid backbones The nature of cationic lipid head-groups determines the efficacy of gene delivery Thereforevarious mixtures of lipids with different headgroupsand properties were tested to achieve optimal liposomeformulations for drug andor gene delivery56ndash59
Although liposomes are excellent transfection agentsin vitro some side effects and problems were encoun-tered during in vivo studies56ndash59 These include intracellu-lar instability and failure to release small RNA contentsdose-dependent toxicity and pulmonary inflammation thatcorrelated with the production of reactive oxygen species(ROS) opsonization by serum proteins immunogenic-ity and uptake by the RES components60ndash63 Addition-ally cationic liposome-dependent gene expression changeswere observed during in vitro experiments with someformulations64
In order to minimize such undesired effects special-ized liposomes were produced through addition of vari-ous functional groups PEGylation and crosslinking withinthe bilayer of the liposomes was successfully utilized toimprove stability and decrease side effects65 PEGylationin general improved bioavailability and biocompatibilityas well For example to obtain improved pharmacokinet-ics PEGylated cationic liposomes called ldquosolid nucleicacid lipid particlesrdquo (SNALPs) were created and they weresuccessfully used for siRNA delivery In fact in SNALPsPEG coating neutralized net charge and increased theblood circulation time of the liposomes significantly66ndash72
Moreover fusogenic lipids added to liposome formula-tions improved cellular uptake and endosomal escape33
Most importantly SNALPs were relatively well toler-ated in vivo even in non-human primates3233 The list of
modifiedimproved liposomes performing well in in vivostudies also includes cationic solidndashlipid nanoparticles andcardiolipin-based liposomes3373ndash75 Currently improvedliposomes are one of the most promising tools for genedelivery and patented formulations produced by sev-eral companies were successful enough to reach clinicaltrials31
LipidoidsLipidoids are cationic lipids that are created by the conju-gation of primary or secondary amines to alkyl-acrylatesor alkyl-acrylamides76 They were introduced as novelalternatives to liposome formulations used in gene deliv-ery Changes in the composition lipidoids were shown toimprove their therapeutic properties For example changesin the alkyl chain length of the PEG lipid was reportedto affect PEG deshielding rate and dose kinetics of lipi-doids in the blood76 Moreover cholesterol incorporationwas shown to improve carrier stability Small sized lipi-doids (50ndash60 nm) were successfully used for the deliveryof siRNA into liver cells avoiding engulfment by Kuppfercells76 Lipidoids may also be used for coating inorganicnanoparticles in order to introduce cationic charges77 Lipi-doids have lower toxicity and increased efficacy thereforethey present an alternative to classical liposomes for genedelivery studies
MinicellsMinicells are bacteria-derived non-living anucleatednano-sized vesicles that were used as nano drug carriers78
Inactivation of min genes that control normal division inbacteria such as Salmonella typhimurium result in the for-mation of minicells min gene products ensure that celldivision septum is correctly located to the midpoint ofthe cell In case of min gene product mutations septa-tion defects result in the formation of minicells devoid ofthe chromosomal DNA Therapeutic RNAs may be loadedinto minicells by the introduction of shRNA of interestinto min mutant bacteria and eventually shRNAs segregateinto minicells78 Purified minicells prepared by this methodare pre-packaged with effective copy numbers of the plas-mid For targeting purposes tumor-specific antibodies maybe decorated onto minicells by the exploitation of bac-terial cell surface components such as O-polysaccharideof LPS Minicell-RNAi combinations proved to be effec-tive in experimental cancer treatment79 Other cell derived-vesicles that were tested as nanocarriers include bacterialghosts bacterial outer membranes or mammalian cell-derived exosomes80ndash82
PolyplexesMaterials that self-assemble with nucleic acids intonanocomplexes are called ldquopolyplexesrdquo These complexesgenerally form though the electrostatic interaction of the
1758 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
cationic units of the polymers with the anionic phos-phate groups of the nucleic acids Natural and biocompat-ible (eg chitosan Atelocollagen cyclodextrin) or morefrequently synthetic (eg Polyethylenimine PEI poly-L-lysine PLL poly-dl-lactide-co-glycolide PLGA) poly-mers are used for polyplex formation83ndash86 Flexibility of thesynthetic polymers in terms of chemical nature molecularweight and architecture (linear branched grafted blocky)provide opportunity to balance their toxicity improvenucleic acid binding protection and release efficienciesMoreover surface modifications may be introduced for tar-geting purposes and improved pharmacodynamics Poly-mers such as PLGA also benefit from a biodegradablenature which allows clearance of the nanocarriers in time
PEIPEI is the most widely and most successfully used polyca-tion for polyplexe formation It can be synthesized in lin-ear or branched forms and in variable molecular weights(from 1 kDa to gt 1000 kDa) Higher molecular weightpolymers (70 kDa and above) are very effective in nucleicacid binding but they are significantly toxic Low molec-ular weight forms (2 kDa or less) are less toxic but theyare less effective as transfection agents87 Therefore PEIsat and below 25 kDa with a branched or linear architec-ture are commonly used as gene delivery reagents88ndash91 Thegolden standard gene delivery polymer is branched PEIof 25 kDa which offers a balance between the toxicitynucleic acid bindingprotection and release Abundance ofpositive charges due to protonation under physiologicalconditions allows PEI to spontaneously form complexeswith negatively charged small RNAs and DNAs and pro-tect nucleic acid molecules from nuclease attacks84 More-over buried inside the polymer some off-target effects ofthe small RNAs were shown to be prevented92
The net positive charge of PEI-RNAi complexes alsoallow interactions with the negatively charged polysaccha-rides found on the cell surface93 These interactions arebelieved to be an important factor for the endocytosis ofthe complexes by target cells A key event for the successof gene delivery is the escape of the nucleic acids fromthe endosomal pathway in order to avoid accumulation anddegradation in the lysosomes of the cell93 The escape isthought to be the result of the lsquoproton spongersquo effect wherethe influx of protons and water lead to endosome swellingrupture and release of contents including nucleic acids tothe cytosolPEI-induced toxicity was proposed to be a result of
mitochondrial apoptosis induction by the polymer9495
Moreover PEI itself was shown to cause changes in geneexpression in vivo which might influence biological out-comes of treatment protocols59 PEGylation of the PEIreduces both cytotoxicity of PEI-polyplexes and increaseblood circulation half-life However a critical balanceneed to be achieved since PEGylation decreases the sur-face charge it impacts the binding capacity and cell
internalization of the polyplexes Alternatively short PEIchains attached together with hydrolysable links such asdisulfide and ester may provide initially a high molecu-lar weight PEI system for good nucleic acid condensationand protection but upon dissolution because of intracel-lular redox conditions they may act as a low molecularweight PEI polymers with lower toxicity87 Additionallypluronics that are block copolymers of ethylene glycol-propylene glycol-ethylene glycol can be used instead ofPEG Similar to PEG pluronics were shown to improvethe biocompatibility and bioavailability of the nanocarri-ers but they interact better with the cell membrane due tothe propylene glycol units and enhance cellular uptake ofthe particles87
PLGAPLGA is a biodegradable copolymer of glycolic acid andlactic acid96 It is widely used in biomedical research asan FDA-approved substance PLGA offers several advan-tages The polymer is highly stable biodegradable andallows sustained release During nucleic acid deliveryPLGA is easily taken up by cells through endocytosisand no serious toxicity problems were observed97 PLGAbinds nucleic acids weakly but it might encapsulate themfor drug delivery purposes Indeed PLGA nanoparticleswere used in several studies for delivery of drugs totumors through the EPR effects98 Yet following endocyto-sis PLGA particles do not effectively realease cargo fromendosomes8397 To overcome nucleic acid binding deliv-ery and endosomal release problems the surface of PLGAcan be decorated with various cationic nanoparticles suchas DOTAP PEI or polyamine and may be conjugated topeptides and antibodies99
DendrimersDendrimers are tree-like highly branched generally sym-metrical and three-dimensional macromolecules Theyhave uniform size and molecular weight which increaseswith each new branch (generation) Dendrimers possess ahighly functional outer surface allowing chemical modi-fications and interactions Therefore they may be used asflexible and modifiable gene delivery agents100 Besidesthe ability of dendrimers to encapsulate cargos add to theirpotential as drug carriers101 Dendrimers including poly-amidoamine dendrimers (PAMAM) poly-propylene imine(PPI) dendrimers poly-L-lysine dendrimers triazine den-drimers carbosilane dendrimers poly-glycerol-based den-drimers nanocarbon-based dendrimers and others weretested as RNAi delivery agents PAMAM and PPI den-drimers being the most commonly studied ones It wasshown that introduction of surface-modifications mini-mized toxicity-related problems increased RNAi-bindingand cellular uptake efficacies of the dendrimers102103
Of note in vivo gene expression changes were alsoobserved with drug-free dendrimers104 Therefore well
J Biomed Nanotechnol 10 1751ndash1783 2014 1759
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
controlled experiments are needed before drawing conclu-sions during RNA interference studies
AtelocollagenAtelocollagen is an organic protein-based moleculederived from type I collagen of calf dermis Sinceit is obtained following a pepsin treatment atelocolla-gen is devoid of telopeptides that are responsible forthe immunogenicity of collagen105 Moreover atelocol-lagen has low toxicity it was shown to stabilize RNAmolecules Increased cellular uptake and sustained deliv-ery was observed in in vivo making atelocollagen an idealagent for gene delivery106 Indeed several studies used ate-locollagen with success for the systemic or local deliveryof RNAi in tumor models107ndash109
ChitosanChitosan is obtained through alkaline deacetylation of thepolysaccharide chitin that forms the exoskeleton of crus-taceans some anthropods and insects Chitosan that is usedin biomedical research is a copolymer of N -acetyl-D-glucosamine and D-glucosamine having a positive chargeIn addition to being biodegradable and biocompatible chi-tosan has a low production cost Mucoadhesive propertiesof chitosan allow the penetration of the substance intoepithelial cell layers including the gastrointestinal barri-ers Nucleic acid encapsulation and sustained release wasproved to be possible using chitosan110ndash112 Moreover chi-tosan prolongs transient time in bowel improving par-enteral drug bioavailability113 Nanoparticles of chitosanare taken up into cells through endocytosis to a cer-tain extent To improve gene delivery efficacies PEG ordeoxycholic acid conjugates or modifications includingtrimethylation thiolation galactosylation may be intro-duced to chitosan111 Moreover chitosan-based carrierspossess functional groups that are suitable for conjugationto ligands relevant for targeted tumor delivery Althoughinefficient endosomal escape is a problem encounteredwith chitosan-based carriers some chemically modifiedforms showed improved escape properties114
CyclodextrinsCyclodextrins are natural polymers They are cyclicoligosaccharides of a glucopyranose generated during thebacterial digestion of cellulose Their central cavity ishydrophobic while the outer surface is a hydrophilicand they can create water-soluble molecular complexes115
Native cyclodextrins do not form stable complexeswith nucleic acids But the DNARNA complex for-mation capacities of the molecule can be modulatedand improved through molecular modifications includ-ing changes in functional groups hydrophilic-hydrophobicbalance charge density spacer length and conjugation toother carrier molecules115116 Cyclodextrins are not onlybiocompatible but they have the capacity to decrease
cytotoxicity of other molecules and carriers that are conju-gated to them117 Moreover cyclodextrins increase cellularadsorption and intake of molecules118 So in addition totheir use as a gene delivery agents cyclodextrins are usedas linking agents or structural modifiers in complex car-rier molecules For example conjugation of cyclodextrinto PEI resulted in lower toxicity and higher transfectionefficiencies119 In addition to the advantages cited abovea cyclodextrin polycation delivery system was reportedto block immune reactions raised against small RNAsthrough a masking effect120121 Importantly studies innon-human primates revealed that cyclodextrin-based car-riers were well tolerated and they do not stimulate signif-icant antibody responses120
AptamersAptamers are nucleic acid-based molecules selectedin vitro according to their capacity to bind target moleculesspecifically and with high affinity The immunogenicity ofaptamers is limited due to chemical modifications min-imizing adverse reactions Moreover nucleic acid natureand small size of aptamers result in improved transport andtissue penetration Since they can be specifically designedaccording to cell or tissue types (eg tumor cell com-ponents) side effects and off-target effects are minimalIn gene therapy applications the nucleic acid nature ofaptamers allows easy conjugation to RNADNA combin-ing targeting advantages with a therapeutic potential122
Alternatively non-covalent adapter linkages might be cre-ated between aptamers and RNA molecules Functionalgroups might be added to the 5prime- or 3prime-termini allowingcovalent or non-covalent conjugation of aptamers to carriernanoparticles123
Inorganic ParticlesInorganic nanoparticals such as carbon nanotubes mag-netic nanoparticles quantum dots and silica are the focusof recent efforts in drug and gene delivery Many of theseparticles actually offer the opportunity to combine imag-ing and therapeutic possibilities in the same particle ren-dering the nanocarrier a valuable ldquotheranosticrdquo device124
Increased surfacevolume ratio of inorganic particles pro-vides an opportunity for surface modifications includingconjugations to drugs oligonucleotides targeting peptidesor other molecules125126 Yet inorganic nanoparticles tendto aggregate and the size of the aggregate might have animpact on its function and biodistribution Such inorganicnanoparticles are hence coated with organic moleculeswhich provide colloid formation in aqueous and physiolog-ical media and stability Nature of the organic coatings hasto be designed for specific purposes but biocompatibilityof the organic molecules themselves andor their degra-dation products are critical for drug delivery purposes126
Chemistry of the coating might influence the half-life inblood and biodistribution as well as the toxicity of inor-ganic nanoparticles and their clearance mechanisms
1760 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Depending on the material they consist of inorganicnanoparticles may possess a number of different propertiessuch as high electron density and strong optical absorption(eg metal particles in particular Au) photoluminescenceor fluorescence (semiconductor quantum dots eg CdSeCdTe CdTeSeZnS) phosphorescence (doped oxide mate-rials eg Y2O3) or magnetic moment (eg iron oxide orcobalt nanoparticles) The shape of the nanoparticle is alsoan important factor influencing its interaction with cellsMany of the above mentioned nanoparticle are sphericalin shape except carbon nanotubes that are tubular
Carbon NanotubesCarbon nanotubes (CNTs) easily cross the plasma mem-brane and translocate directly into the cytoplasm of tar-get cells due to their nanoneedle structure and usingan endocytosis-independent mechanism yet they do notinduce cell death127ndash129 CNTs are classified as single-walled CNTs and multiwalled CNTs Single or multiplegraphine layer(s) might have a length ranging from 50 nmto 100 mm and a diameter of 1 nm to 100 nm Properfunctionalizing of CNTs by covalent or non-covalentstrategies (such as coating with PEG or Tween-20) mayprovide solubility in aqueous solutions and prevent non-specific interactions thus minimizing toxicity observedwith non-functionalized raw particles130131 Modificationsmight also increase biocompatibility and blood circulationhalf-life132133 CNTs have very strong absorption charac-teristics providing an opportunity for photothermal abla-tion therapy in addition to nanocarrier properties
Magnetic NanoparticlesMagnetic nanoparticles are composed of ferromagneticelements such as Ni Co Mn Fe Superparamagneticiron oxide nanoparticles (SPIONS) such as maghemite--Fe2O3 and magnetite-Fe3O4 are one of the most widelyused magnetic particles as nanocarriers due to relativelylow cost of production biocompatability and superpara-magnetic nature134135 SPIONS are approved by FDA forclinical trials They are commonly used as contrast agentsfor magnetic resonance imaging (MRI) SPION crystals(less than 10 nm in diameter) are coated for specificpurposes with organic molecules such as dextran aminodextran BSA PEI dendrimers lipids and trialkoxysi-lanes including aminopropyltriethoxy silane (APTES)Coating chemistry and preparation methods influence over-all hydrodynamic size pharmacokinetics and the contrasttype (dark-T 2 or bright-T 1 agent) Ability to track the fateof nucleic acid carrier magnetic nanoparticles in vivo usingMRI is highly desirable since it provides informationabout the location of the cargo and its biodistribution136
Attachment of ligands provides target specificity andPEGylation may improve biocompatibility and blood half-life These modifications are commonly introduced to SPI-ONs that are used for imaging and therapy purposes Due
to their magnetic nature drug or nucleic acid carrying SPI-ONs can be concentrated at desired diseased sites such astumors and they may be dragged magnetically towards thelesion area136137 Moreover magnetic nanoparticles offerthe possibility of hyperthermia treatment as a result ofmagnetic heating135 Under applied alternating magneticfield SPIONs cause local temperature increase (41ndash42 C)which may be exploited for alternative and efficient cancertherapy Therefore SPIONs are one of the most versatileand multifunctional nanoparticles Consequently SPIONswere used as popular gene delivery vehicles135
Magnetic nanoparticles may be engineered for oligonu-cleotide delivery purposes MRI visible PEI-PEG coatedSPIONs which are tagged with an antibody have beenshown to effectively carry siRNA to cancer cell lines andshowed low toxicity138 SPIONs coated with both thermoresponsive and cationic polymers such as poly[2-(2-methoxyethoxy)ethylmethacrylate]-b-poly-[2-(dimethyl-amino)ethyl methacrylate] were reported to have25ndash100 times better transfection efficiency than branchedPEI 25 kDa when coupled with magnetic targeting139
SPIONs coated with low molecular weight PEI(12ndash2 kDa) which is usually not effective as poly-plexes in transfection were shown succesful in deliveringsiRNA to mouse macrophages (H Yagci Acar WIPOPatent WO2006055447A3) Therefore magnetic nanpar-ticles are under heavy investigation for the developmentof multifunctional nanocarriers for cancer therapy anddiagnosis135
Quantum DotsSemiconductor quantum dots (QDs) are light-emittingnanoparticles of few nanometer in diameter and they havebeen increasingly used as biological imaging and labelingprobes140 Luminescencefluorescence properties of QDsdepend on the crystal size and type Chemical composi-tion of the crystalline semiconductor core determines theband gap of the material therefore the emission wave-length range Within possible spectral window size ofthe crystal determines the specific wavelength of lumines-cencefluorescence for each and every QD due to quan-tum confinement effect Broad absorption of QDs allowexcitation of multiple QDs at a single wavelength andminimal signal mixing due to the narrow emission bandIn addition they are much more resistant to photobleach-ing These two characteristics are the major advantages ofQDs compared to organic fluorophores as imaging probesUtilization of QDs in nucleic acid delivery aims bothimaging and therapy since in vivo localization of cargocan be observed using optical imaging systems141142 Forexample cationic CdTeZnS QDs conjugated with PEGwas demonstrated to form an effective nanoplex with sur-vivin siRNA and successfully transfeced human tonguecancer cells in vitro and provided real time tracking143
However well-established QDs harbour significant toxic-ity due to constituents such as Cd Se Te144 Therefore
J Biomed Nanotechnol 10 1751ndash1783 2014 1761
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
toxicity of these QDs is a drawback for their use in vivoAs an alternative silver (Ag) chalcogenites emerged assafer near-infra red-emitting QDs145146 Ag2S QDs did notinduce cytotoxicity ROS production apoptosis necrosisor DNA damage147 For example Ag2S QDs (coated with2-mercaptopropionic acid) emitting between 750ndash850 nmshowed no cytotoxicity in NIH3T3 cells at even highdoses (600 mgml) along with good cellular imagingpotential148
Gold NanoparticlesGold nanoparticles emerged as popular tools fornanocarrier-mediated gene therapy149 They are easily syn-thesized and biocompatible particles that allow addition offunctional molecules on their surface due to high surface-to-volume ratio114150 A variety of surface changes andfunctional additions were reported including cationic lipidcoating branched PEI addition or functionalization usingcationic quaternary ammonium or cystamine114151152
Indeed cystamine functionalized gold nanoparticles wereshown to effectively bind deliver and release 35 differ-ent miRNA in in vitro studies using neuroblastoma andovarian cancer cell lines153
Silica NanoparticlesSilica-based nanoparticles are inert stable biocompati-ble and biodegradable particles154 They can be renderedhydrophilic hydrophobic anionic or cationic using func-tional surface modifiers through electrostatic interactionsor by formation of any other type covalent bonds (egester amine) Common functionalization strategies to ren-der the molecule cationic and improve nucleic acid bind-ing include grafting of molecules such as PEI PEI-PEGand Poly-L-arginine155 Nucleic acids may also be loadedinside the mesoporous silica particles156 siRNA encapsu-lating mesoporous silica nanoparticles were successfullyused for in vitro and in vivo gene silencing in several stud-ies (For example Ref [156])
RECENT IN VIVO STUDIES USING RNAINTERFERENCE IN CANCER THERAPYThere is an exponential increase in the number of scientificpublications dedicated to gene therapy of diseases usingsmall RNAs and nanoparticles A literature search usingldquonanoparticlerdquo and ldquosiRNA shRNA or miRNArdquo revealedmore than 700 articles published in the last two yearsThis number is roughly equal to the number of all articlespublished in this field until two years ago So the field isexpanding and there seems to form a consensus aroundthe use of nanoparticles as next generation gene therapytools We believe that these high expectations are not onlya consequence of shifting trends in science and technol-ogy The exponential rise in interest in the field of smallRNA carrier nanoparticles is fueled by the advances inthe field of nano materials promising results obtained in
small RNA therapeutics by both academic laboratories andindustry and increasing number of successful clinical tri-als In this section we will summarize results of selectedrecent studies using RNA therapeutics for cancer treatmentin preclinical in vivo experimentsOverview of the works dealing with small RNA treat-
ment of experimental cancers and published within thelast two years were summarized in Table I Although sev-eral studies were performed using lipid-based nanopar-ticles (Liposomes micelles or lipidoids) other particlessuch as polymers organic or inorganic carriers and com-pounds mixtures with functional modifications of vari-able substances were also tested by many research teamswith reasonable success Scheme 4 summarizes the generalstrategy followed in most of these studies
Tumor Types and RNAi TherapyRecent studies in the literature showed that tumors of vari-ous tissue origins could be treated using RNA interferencestrategies (Table I) Fine tuning of nanoparticles throughaddition of functional moieties or modifications alloweddelivery of drugs into almost any kind of tumor tissue withaccompanied therapeutic effects Although several studiesused animal tumor models that resulted from the injectionof cell lines from most commonly seen human cancers(lung breast prostate cervix or ovarian cancer cell lines)animals with kidney urinary bladder head and neckgastric pancreatic melanomas neuroblastomas glioblas-tomas multiple myelomas or sarcomas were also treatedwith RNAinanocarrier strategy81156ndash170 These results givehope about the general use of RNA interference as astrategy to treat cancers of different origins Althoughit is difficult to compare the efficacies of different nucleicacid molecules and their interference effects at this pointsiRNA or microRNAs as well as shRNA vectors wereshown to achieve intratumoral in vivo target gene knock-down and anticancer effects leading to a decrease in tumorsize (For example Refs [156 171]) Since in most studiesin addition to RNAi loaded particles naked nanoparticlesor particles loaded with non-specific control nucleic acidswere also used antitumor effects obtained in these studiesare specific and they may be attributable to small RNAmolecules rather than the particles themselves underliningthe potential of RNA interference in cancer treatmentMajority of recent studies with in vivo models chose
to use human tumor cell line xenografts in immune com-promised mice nude or severe-combined immuno defi-cient SCID mice (Table I) (For example Refs [162 172])Syngeneic transplants and established genetically engi-neered mouse models of cancer were rarely studied in thiscontext167173ndash175 Therefore although antitumor effects andsome of the toxic effects (eg liver toxicity) might berevealed using immune compromised mice hematologicalimmunological and inflammatory side effects of the treat-ment strategies used in recent studies might need to berevisited using immunocompetent mice
1762 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IRec
entstudieswithRNAica
rryingnan
oparticles
forthetrea
tmen
tofex
perim
entalca
nce
rs(P
ublis
hed
within
thelast
twoye
ars)
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGF
Mag
netic
mes
oporou
ssilicana
nopa
rticles
PEIan
dfuso
genicpe
ptide
KALA
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[156
]
siRNA
Polo-likekina
se1(P
LK1)
pH-sen
sitiveca
tioniclip
idYSK05
-MEND
(YSK05
POPEcho
lesterol
=50
2525
)
PEG
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
PLK
1[51]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Bioen
gine
ered
bacterial
outermem
bran
eve
sicles
Hum
anep
idermal
grow
thfactor
rece
ptor
2(H
ER2)-spe
cific
affib
ody
targeting
HCC-195
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
KSP
Dec
reas
edtumor
volume
[81]
siRNA
Luciferase
Dioleoy
lpho
spha
tidic
acid-(DOPA
-)co
ated
nano
-sized
calcium
phos
phate(LCP-II)
DSPE-P
EG-an
dan
isam
idefortargeting
sigm
a-1rece
ptor
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
Xen
ograft
it
ND
Kno
ckdo
wnof
luciferase
[211
]
siRNA
mTERT
N-((2-hyd
roxy
-3-trim
ethy
l-am
mon
ium)propy
l)ch
itosa
nch
lorid
e(H
TCC)na
nopa
rticles
Partic
leload
edwith
paclita
xel
LCC
murinelung
canc
erce
llssy
ngen
eicsc
graft
oral
Noeffect
Kno
ckdo
wnof
mTERT
Dec
reas
edtumor
volume
Syn
ergize
dwith
paclita
xel
[159
]
siRNA
VEGF
Multilay
ered
polyion
complexes
Polyc
ationinterla
yeran
dade
tach
able
PEG
shell
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
[212
]
siRNA
Multid
rug
resistan
ceprotein1
(MRP1)
Nan
opartic
lesas
sembled
vialaye
r-by
laye
rde
positio
nof
siRNA
and
poly-L-arginine
Hya
lurona
n(H
A)co
ating
forHA-C
D44
targeting
MDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
it
Noeffect
Kno
ckdo
wnof
MRP1
Dec
reas
edtumor
volume
[183
]
siRNA
STA
T3-a
Nan
oporou
ssilicon
nano
particles
Argininean
dPEI
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicefat
padxe
nograft
iv
Noeffect
Kno
ckdo
wnof
STA
T3-a
[204
]
siRNA
Luciferase
Lipo
somal
nano
particle
Fou
rtand
emrepe
atsof
human
histon
eH2A
peptideinterven
edby
cathep
sinD
clea
vage
sites
PEG-A
nisa
mide
fortargeting
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
luciferase
[199
]
siRNA
Polo-likekina
se1(P
LK1)
Hya
luronicac
id(H
A)
base
dse
lfass
embling
HA-P
EIP
EG
nano
system
s
Hya
lurona
nforCD44
targeting
B16
F10
amurine
melan
omace
llsA54
9-luchu
man
lung
canc
erce
llsHep
3Bhu
man
liver
canc
erce
llsMDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
graftor
metas
tatic
lung
lesion
sby
IVinjection
it
ND
Kno
ckdo
wnof
PLK
1[160
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1763
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
P-glyco
protein
drug
expo
rter
(P-
gpM
DR1)
Mes
oporou
ssilica
nano
particles
Polye
thylen
eimine
polyethy
lene
glyc
ol(P
EI-PEG)co
polymer
MCF-7M
DR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gpMDR1
Dec
reas
edtumor
volume
Syn
ergy
with
doxo
rubicin
[179
]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Multifun
ctiona
lcarrie
rsy
stem
with
catio
nic
(olig
oethan
amino)am
ide
core
attach
edto
PEG
chain
Folic
acid
fortargeting
Inf7
(Infl
uenz
ape
ptide)
asen
doso
molytic
peptide
coup
ledto
the5prime-end
ofsiRNA
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
itor
iv
ND
Kno
ckdo
wnof
EG5
Dec
reas
edtumor
volume
[161
]
siRNA
Epide
rmal
Growth
Factor
Rec
eptor
(EGFR)
Poly-L-argininean
dde
xtransu
lfate-bas
edna
noco
mplex
FaDuhu
man
pharyn
xsq
uamou
sca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[172
]
siRNA
Cho
line
kina
se(C
hk)
Polye
thylen
imine-
polyethy
lene
glyc
ol(P
EI-PEG)co
grafted
polymer
Con
versionof
nontox
ic5-flu
oroc
ytos
ine(5-FC)to
cytotoxic5-flu
orou
racil
(5-FU)by
activating
bacterialc
ytos
ine
deam
inas
e(bCD)
PC3-PIP
andPC3-Flu
human
pros
tate
canc
erce
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
e[157
]
siRNA
Polo-like
kina
se1
(Plk1)
Cationiclip
idpo
lymer
hybrid
nano
particles
(cationiclip
id(N
N-
bis(2-hy
drox
yethyl)-N-
methy
l-N-(2-
choles
teryloxy
carbon
ylam
inoe
thyl)am
mon
ium
brom
ide
BHEM-C
hol)
andam
phiphilic
polymers(H
ydroph
obic
polylactideco
re)
PEG
shell
BT47
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Plk1
Dec
reas
edtumor
volume
[213
]
siRNA
hTERT
Single-walledca
rbon
nano
tube
s(S
WNTs)
Branc
hedPEIco
njug
ated
DSPE-P
EG20
00-M
aleimide
forco
njug
ationwith
NGR
(Cys
-Asn
-Gly-A
rg-C
ys-)
targetingpe
ptide(rec
ognize
tumor
neov
ascu
lature)
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
hTERT
Dec
reas
edtumor
volume
Syn
ergy
with
photothe
rmal
trea
tmen
t
[139
]
1764 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
carriers We will limit ourselves to cancer gene ther-apy studies exploiting nanocarrier loaded small RNADNAmolecules ie RNA interference (RNAi) tools such assiRNAs shRNAs and microRNAs Merits and contribu-tions of antisense oligonucleotides in gene therapy experi-ence were discussed in detail elsewhere8
RNA INTERFERENCEDiscovery of RNA interference (RNAi) by Andrew Fireand Craig Mello was a breakthrough that was awarded bythe Nobel prize in Physiology or Medicine in 2006 SmallRNAs mediating RNA interference control gene expres-sion in organisms ranging from plants and C elegansto human Small interfering RNAs (siRNAs) short hair-pin RNAs (shRNAs) and microRNAs (miRNAs) are themost studied members of regulatory RNAs9 Non-codingsmall RNAs are not translated they mainly act at a post-transcriptional level determining the stability of messen-ger RNAs (mRNAs) and their translation into proteinsEndogenous siRNAs (endo-siRNAs) are coded not only
by transposons and other repeat elements but they mayalso originate from regions where both sense and antisensetranscripts are transcribed as well as from sequences giv-ing rise to potential hairpin structures inside pseudogenes
Scheme 1 RNA interference (RNAi) pathways (a) miRNA pathways (b) siRNA pathways See text for the pathway details RNAPol II RNA polymerase II Dicer Dicer enzyme complex into the siRNA RISC RNA-induced silencing complex (RISC) RdRPRNA-dependent RNA polymerase ORF open reading frame of the target gene AAAAA polyA tail of the mRNA
and even in protein-coding genes1011 On the other handmiRNAs may be intronic or intergenic Intronic miRNAsare transcribed from intron regions of some protein codingmRNAs while intergenic miRNAs are transcribed frommiRNA genes or gene clusters using their own promotersEndogenous siRNAs and miRNAs bear similarities to
each other from a structural and functional point of viewYet pathways leading to their maturation are rather spe-cific to the small RNA type (Scheme 1(a)) miRNAs aretranscribed by RNA polymerase II as primary-miRNAs(pri-miRNAs) and processed by a Drosha-DGCR8 com-plex in the nucleus to produce hairpin-shaped premature-miRNAs (pre-miRNA)12 Transport from nucleus isachieved with the help of the exportin-Ran GTPase com-plexes Further processing of the pre-miRNA hairpin bycytoplasmic DICER proteins produces sim 21ndash22 nt longmiRNAmiRNAlowast duplexes One of the mature miRNAstrands that originate from the duplex is then loaded ontoa complex called the RNA-induced silencing complex(RISC) including the Argonaute (eg AGO2) proteinsRISC then guides the mature miRNA strand towards tar-get messenger RNAs (mRNAs) It is believed that tar-get specificity of the miRNA and the fate of the targetmessenger RNA depends on the degree of complemen-tarity between matching sequences of these two types of
1754 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
RNAs While a partial complementarity may lead to theblockage of the translation machinery protein translationrepression andor sequestration of miRNA-mRNA com-plexes in compartments called P-bodies a perfect matchbetween these two RNAs may result in mRNA degradation(Scheme 1(a))Conversely endo-siRNAs complementary to template
mRNAs are synthesized by RNA-dependent RNA poly-merases (RdRP) and they are not transcribed from thegenomic DNA (Scheme 1(b)) It was long believed thatmammals did not have any RdRPs But this conceptis now changing For example human telomerase cat-alytic subunit (hTERT) was shown possess a mammalianRdRP activity required for double stranded RNA synthe-sis from the mitochondrial RNA processing endoribonu-clease noncoding RNA component1314 In the endogenoussiRNA pathway hairpin containing double-stranded RNAproducts of RdRP are further processed into functionalendogenous siRNAs in either a Dicer-dependent or aDicer-independent manner (Scheme 1(b)) In general thesense guide strand of the endo-siRNAs are loaded onto theRISC with AGO2 proteinsWhile in general mammalian miRNAs show partial
complementary to their mRNA target sequences and con-trol a wide number of functionally-related transcripts strictcomplementarity was thought to be necessary for siRNAfunction9 But even synthetic siRNAs or shRNAs that aredesigned to target one and only mRNA were shown toaffect so called ldquooff-target genesrdquo Therefore although agene with a dominant biological effect will be targeted bysiRNAshRNAs a spectrum of biological events might beaffected by the use of a small RNA Nevertheless in vitrocell culture and animal studies confirmed that the biolog-ical outcomes of siRNAshRNAs and even miRNAs wereusually determined by their effect on a dominant targetgene andor pathway1516
SMALL RNAS AS POTENT DRUGSUse of potent RNA interference strategies might give usnew opportunities for the treatment of diseases such ascancer17 Potential advantages of small RNAs over existingsmall molecule drugs and conventional therapies includeorganic composition natural metabolism lower drug tox-icity minimal immune reactions when designed optimallyand combined with appropriate carriers possibility ofmodulating targets that are considered as ldquoundruggablerdquo byconventional drugs possibility of targeting disease-relatedtissue-specific isoforms andor mutant transcripts and stan-dard chemical synthesis protocols Moreover RNA plat-forms are now widely used in high throughput formats fortarget validation and drug development processes reduc-ing the product development cycle and cost compared toconventional small molecules18
Modifications to the native RNA structure can cre-ate robust drug-like RNA molecules19 Synthetic 21-mer
RNA duplexes mimicking natural siRNAs and miRNAsare commonly used in RNA-based gene therapy protocolsAlternatively asymmetric 2527-mers or 2729-mers blunt25-mers blunt 27-mers and blunt 19-mers were tested fortheir stability and potency as RNA drugs with variablemerits20ndash23 These different synthetic RNAs might directlybe loaded onto the RISC complex or they might firstrequire processing by Dicer In fact even under in vitro con-ditions synthetic siRNAs were shown to directly load ontorecombinant human AGO2 proteins and form functionalcomplexes24 Therefore following delivery small RNAsmay rapidly form functional complexes and alter target pro-tein levels resulting in therapeutic changes in cellsNaked RNA molecules are highly susceptible to degra-
dation by nucleases that are abundant in tissues and in theblood circulation Therefore to stabilize RNA moleculesincrease their half-lives in biological environments andavoid immune reactions a number of chemical changesmight be introduced to the nucleic acid structures19
There are several commonly used RNA modifications2prime-O-methyl modifications into the sugar structure ofsome nucleotides may confer resistance to endonucle-ases decrease off-target effects when introduced into theseed region and minimize Toll-like receptor-mediatedimmune reactions25ndash27 Introduction of phosphorothioateboranophosphate or methylphosphonate backbone linkagesat the 3prime-end of the RNA strands may reduce their suscepti-bility to exonucleases Similarly alternative 2prime sugar mod-ifications such as 2prime-fluoro LNA (Locked nucleic acids)FANA (2prime-deoxy-2prime-Fluoro--d-arabinonucleic acid) and2primeMOE (2prime-O-methoxyethyl) modifications were reportedto increase endonuclease resistance of small RNAs28
While all these modifications result in more robust RNAmolecules they might affect the potency of the RNA inter-ference effects obtained during treatment Therefore evenif the changes were performed according to design criteriaor computer tools experimental testing is required in eachseparate case to confirm potency of modified small RNAmolecules on their mRNA targets2930
RNADNA NANOCARRIERS FORCANCER THERAPYUse of gene therapy and lately small RNAs for can-cer treatment was hindered by the lack of a suitabledelivery system Recent developments in nanotechnologyallowed the introduction of nanoparticles with very differ-ent physico-chemical properties Novel and sophisticatednanocarriers and their functionalized derivatives are beingtested as potent and in many cases targeted RNA drugdelivery agents Some formulations are already in clinicaltrials and a few of them were even approved by majoragencies such as the Food and Drug Agency (FDA) in theUSA31
Nanoparticles to be used as nucleic acid delivery agentsshould meet several criteria The particles should safely
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and effectively deliver RNA molecules to cancer cells andtumors Therefore they have to be biocompatible notimmunogenic and they should not get modified or dis-solved into toxic substances under biological conditionsand before reaching the tumor target For effective deliv-ery and dosage nano conjugates have to be stable enoughin the blood circulation and resist shear forces proteasesand nucleases that they face with Complex formation withblood cells proteins and other blood components mightalso affect carrier size charge availability and efficacyClearance is also an important issue For nanocarriers
to reach therapeutic blood levels they should not be read-ily cleared through glomerular filtration in the kidneys ortrapped by the reticuloendothelial system For examplenaked siRNA molecules and nanoparticles less than 10 nmmay be filtrered and excreted through kidneys follow-ing systemic administration Carriers larger than 100 nmmight be phagocytosed and cleared by monocytes andmacrophages residing in the reticuloendothelial system(RES also called mononuclear phagocytic system) tissueswith high blood supply including pulmonary alveoli liversinusoids skin spleen etc32ndash36 In addition to the size of thenanoparticles their geometries surface charges hydropho-bicities and opsonization by serum proteins might affectclearance by monocytes and macrophages Additionallythe efficacy of nucleic acid drugs in specific tissues andorgans may depend on the ability of nanocarriers to pene-trate blood vessels and tissues and pass through biologicalbarriers such as the tight blood-brain-barrier of the centralnervous systemFor cancer treatment small RNA drugs should affect
genetic andor molecular changes specific to cancer cellsand that are rate-limiting for tumor growth The idealnanocarrier should be able to concentrate within the tumortissue and if possible target individual tumor cells in aselective way (eg through receptors or molecules thatare tumor-specific or that are enriched in the tumor tis-sue) and not penetrate normal cells Enhanced permeabilityand retention (EPR) effect offers an advantage for solid-tumor targeting The EPR effect is a result of neovascu-larisation new blood vessel formation to feed tumors withsizes beyond passive oxygen and nutrient diffusion lim-its (beyond 01ndash02 mm diameter)37 Blood vessels feed-ing tumor tissues are irregular and highly permeable Withthe lack of lymphatic drainage macromolecules are eas-ily retained in and around the tumor area3839 For exam-ple low molecular weight drugs may diffuse freely inand out of the tumor tissues but macromolecules (gt 40kDa) and nanoparticles of 100ndash200 nm accumulate inthe tumor tissue3840ndash43 EPR phenomenon was reported invarious human solid tumors as well as in inflammatorytissues44
Different types of nanoparticles were tested as drug car-riers and gene therapy tools (Scheme 2) The core structureof the particle may be a vesicle (liposomes) a polymer(eg PEI PLGA) a dendrimer carbon nanotubes silica or
metal nanoparticles (eg Gold) Porousvesiculate carrierssuch as liposomes polymeric micelles or some inorganicparticles (eg mesoporous silica) may encapsulate orabsorb RNADNA molecules Nanocarriers with a cationicnature including cationic liposomes cationic dendrimers(eg PAMAM) and polymers (eg PEI PDMAEMA) orcationic polymer coated inorganic particles (eg PEI cov-ered iron oxide) may form complexes through electro-static interactions with the negatively charged backboneof nucleic acids The nature and physico-chemical proper-ties of the nanoparticles may also influence their stabilityand half-life in blood criculation efficacy of their deliveryinto tissues and cells and their capacity to escape fromendosomes in the cell All these properties are determiningcriteria for nano drug efficacyTo improve stability RNADNA loading target speci-
ficity tracking cellular internalization endo-lysosomalescape and intracellular robustness additional functionalunits might be introduced to the basic structure ofthe nanocarriers (Scheme 3)45 Possible modificationsand changes include conjugation to proteins (antibodieslectins cytokines thrombin fibrinogen BSA transfer-rin) cellular or viral peptides (eg RGD LHRD TATPep-3 KALA) polysaccharides (eg lipopolysaccharideshyaluronic acid dextran chitosan) low molecular weightligands (eg folic acid anisamide) and polyunsaturatedfatty acids (eg palmitic acid and phospholipids) Thesestructures can be conjugated onto the nanocarrier surfacethough hydrolysable or non-hydrolysable chemical bondsand modifications such as amide ester silane hydrazoneor through the use of high avidity molecules such asavidin-biotin Fluorophores may also be added for par-ticle tracking purposes To improve the availability ofsuch groups and especially the targeting groups spacermolecules may be addedAn important modification relevant for biological func-
tion is ldquoPEGylationrdquo (Scheme 3)45 PEG coordinateswater molecules and forms an aqueous shell aroundnanoparticles shielding their charges PEGylation reducesinteraction with serum proteins decreases opsoniza-tion and clearance of nanoparticles by RES monocyte-macrophages sterically prevent nanocarrier aggregationand due to increased molecular weight above the thresholdfor glomerular filtration reduces elimination of the parti-cles through urinary excretion Hence PEG increases thestability improves biocompatibility prolongs blood circu-lation time and bioavailability of nanocarriers4647 Molec-ular weight and density of PEG chains on the nanocarriersurface may impact the function depending on the natureof the carried molecules ie siRNA47
On the other hand PEGylation significantly attenu-ates uptake of nanocarriers by target cells4849 More-over PEG chains were shown to block endosomal escapeand cytosolic release of chemical drugs and nucleicacids50 Blockage of cellular uptake and endosomal releasein the cell may severely attenuate drug efficacy and
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 2 Major types of nanoparticles used as nucleic acid carriers
therapeutic RNA interference effects Various strategieswere adapted to overcome these negative effects of PEGwhile exploiting its circulatory advantages Cleavage ofPEG-chains upon delivery into the tumor environment wasachieved through addition of tumor-related matrix met-alloproteinase sensitive lipids or peptides51 pH-sensitivelinkers between the PEG moiety and nanocarriers canalso be used to release PEG from the particle in theacidic environment of the endosomes and allow cytosolic
Scheme 3 A representative nanoparticle with functional modifications Various molecules might be added to a nanoparticleto improve its physico-chemical properties and pharmacokinetics (eg PEG) to increase RNADNA binding (eg PEI) to allowbetter targeting (eg antibodies) or tracking (eg fluorophores)
release of small RNAs Modulation of the hydrophobic-ity of the PEGndashnanocarrier conjugate was also testedas a release strategy In lipid-based nanocarriers thelength of the alkyl chain of the PEG-lipid anchor wasshown to determine its affinity for the lipid deliveryvehicle and changing its length modified endosomalescape potential and drug effects52 Cholesterol-anchoredPEG was also shown to improve endosomal escapecapacities52
J Biomed Nanotechnol 10 1751ndash1783 2014 1757
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
LiposomesLiposomes have been tested extensively as gene deliv-ery agents Liposomes are artificial membrane-boundvesicles formed by bilayers of amphipathic lipids Theymight be unilamellar or multilamellar Their biocom-patibility low toxicity and low immunogenicity madethem popular agents for both in vitro and in vivo genedelivery5354 Liposomes are typically made of mix-tures of lipids found in biological membranes or theirderivatives including phosphatidylcholine (PC or DOPC12-Oleoyl-sn-Glycero-3-phosphatidylcholine) phosphatidyl-ethanolamine (PE or DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidylethanolamine) cholesterol and evenceramide53 Although liposomes made of neutral lipids aremore biocompatible than cationic lipids and have betterpharmacokinetics during preparation of gene deliveryvectors they bind less to negatively charged DNA orRNA molecules and have lower entrapment efficiencies55
Therefore despite their more toxic nature cationic lipidsare commonly used as liposome-based transfection agentsCationic lipids posses positively charged headgroupssuch as amines quaternary ammonium salts peptidesaminoacids or guanidiniums which electrostaticly attractand bind to negatively charged phosphate residues innucleic acid backbones The nature of cationic lipid head-groups determines the efficacy of gene delivery Thereforevarious mixtures of lipids with different headgroupsand properties were tested to achieve optimal liposomeformulations for drug andor gene delivery56ndash59
Although liposomes are excellent transfection agentsin vitro some side effects and problems were encoun-tered during in vivo studies56ndash59 These include intracellu-lar instability and failure to release small RNA contentsdose-dependent toxicity and pulmonary inflammation thatcorrelated with the production of reactive oxygen species(ROS) opsonization by serum proteins immunogenic-ity and uptake by the RES components60ndash63 Addition-ally cationic liposome-dependent gene expression changeswere observed during in vitro experiments with someformulations64
In order to minimize such undesired effects special-ized liposomes were produced through addition of vari-ous functional groups PEGylation and crosslinking withinthe bilayer of the liposomes was successfully utilized toimprove stability and decrease side effects65 PEGylationin general improved bioavailability and biocompatibilityas well For example to obtain improved pharmacokinet-ics PEGylated cationic liposomes called ldquosolid nucleicacid lipid particlesrdquo (SNALPs) were created and they weresuccessfully used for siRNA delivery In fact in SNALPsPEG coating neutralized net charge and increased theblood circulation time of the liposomes significantly66ndash72
Moreover fusogenic lipids added to liposome formula-tions improved cellular uptake and endosomal escape33
Most importantly SNALPs were relatively well toler-ated in vivo even in non-human primates3233 The list of
modifiedimproved liposomes performing well in in vivostudies also includes cationic solidndashlipid nanoparticles andcardiolipin-based liposomes3373ndash75 Currently improvedliposomes are one of the most promising tools for genedelivery and patented formulations produced by sev-eral companies were successful enough to reach clinicaltrials31
LipidoidsLipidoids are cationic lipids that are created by the conju-gation of primary or secondary amines to alkyl-acrylatesor alkyl-acrylamides76 They were introduced as novelalternatives to liposome formulations used in gene deliv-ery Changes in the composition lipidoids were shown toimprove their therapeutic properties For example changesin the alkyl chain length of the PEG lipid was reportedto affect PEG deshielding rate and dose kinetics of lipi-doids in the blood76 Moreover cholesterol incorporationwas shown to improve carrier stability Small sized lipi-doids (50ndash60 nm) were successfully used for the deliveryof siRNA into liver cells avoiding engulfment by Kuppfercells76 Lipidoids may also be used for coating inorganicnanoparticles in order to introduce cationic charges77 Lipi-doids have lower toxicity and increased efficacy thereforethey present an alternative to classical liposomes for genedelivery studies
MinicellsMinicells are bacteria-derived non-living anucleatednano-sized vesicles that were used as nano drug carriers78
Inactivation of min genes that control normal division inbacteria such as Salmonella typhimurium result in the for-mation of minicells min gene products ensure that celldivision septum is correctly located to the midpoint ofthe cell In case of min gene product mutations septa-tion defects result in the formation of minicells devoid ofthe chromosomal DNA Therapeutic RNAs may be loadedinto minicells by the introduction of shRNA of interestinto min mutant bacteria and eventually shRNAs segregateinto minicells78 Purified minicells prepared by this methodare pre-packaged with effective copy numbers of the plas-mid For targeting purposes tumor-specific antibodies maybe decorated onto minicells by the exploitation of bac-terial cell surface components such as O-polysaccharideof LPS Minicell-RNAi combinations proved to be effec-tive in experimental cancer treatment79 Other cell derived-vesicles that were tested as nanocarriers include bacterialghosts bacterial outer membranes or mammalian cell-derived exosomes80ndash82
PolyplexesMaterials that self-assemble with nucleic acids intonanocomplexes are called ldquopolyplexesrdquo These complexesgenerally form though the electrostatic interaction of the
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
cationic units of the polymers with the anionic phos-phate groups of the nucleic acids Natural and biocompat-ible (eg chitosan Atelocollagen cyclodextrin) or morefrequently synthetic (eg Polyethylenimine PEI poly-L-lysine PLL poly-dl-lactide-co-glycolide PLGA) poly-mers are used for polyplex formation83ndash86 Flexibility of thesynthetic polymers in terms of chemical nature molecularweight and architecture (linear branched grafted blocky)provide opportunity to balance their toxicity improvenucleic acid binding protection and release efficienciesMoreover surface modifications may be introduced for tar-geting purposes and improved pharmacodynamics Poly-mers such as PLGA also benefit from a biodegradablenature which allows clearance of the nanocarriers in time
PEIPEI is the most widely and most successfully used polyca-tion for polyplexe formation It can be synthesized in lin-ear or branched forms and in variable molecular weights(from 1 kDa to gt 1000 kDa) Higher molecular weightpolymers (70 kDa and above) are very effective in nucleicacid binding but they are significantly toxic Low molec-ular weight forms (2 kDa or less) are less toxic but theyare less effective as transfection agents87 Therefore PEIsat and below 25 kDa with a branched or linear architec-ture are commonly used as gene delivery reagents88ndash91 Thegolden standard gene delivery polymer is branched PEIof 25 kDa which offers a balance between the toxicitynucleic acid bindingprotection and release Abundance ofpositive charges due to protonation under physiologicalconditions allows PEI to spontaneously form complexeswith negatively charged small RNAs and DNAs and pro-tect nucleic acid molecules from nuclease attacks84 More-over buried inside the polymer some off-target effects ofthe small RNAs were shown to be prevented92
The net positive charge of PEI-RNAi complexes alsoallow interactions with the negatively charged polysaccha-rides found on the cell surface93 These interactions arebelieved to be an important factor for the endocytosis ofthe complexes by target cells A key event for the successof gene delivery is the escape of the nucleic acids fromthe endosomal pathway in order to avoid accumulation anddegradation in the lysosomes of the cell93 The escape isthought to be the result of the lsquoproton spongersquo effect wherethe influx of protons and water lead to endosome swellingrupture and release of contents including nucleic acids tothe cytosolPEI-induced toxicity was proposed to be a result of
mitochondrial apoptosis induction by the polymer9495
Moreover PEI itself was shown to cause changes in geneexpression in vivo which might influence biological out-comes of treatment protocols59 PEGylation of the PEIreduces both cytotoxicity of PEI-polyplexes and increaseblood circulation half-life However a critical balanceneed to be achieved since PEGylation decreases the sur-face charge it impacts the binding capacity and cell
internalization of the polyplexes Alternatively short PEIchains attached together with hydrolysable links such asdisulfide and ester may provide initially a high molecu-lar weight PEI system for good nucleic acid condensationand protection but upon dissolution because of intracel-lular redox conditions they may act as a low molecularweight PEI polymers with lower toxicity87 Additionallypluronics that are block copolymers of ethylene glycol-propylene glycol-ethylene glycol can be used instead ofPEG Similar to PEG pluronics were shown to improvethe biocompatibility and bioavailability of the nanocarri-ers but they interact better with the cell membrane due tothe propylene glycol units and enhance cellular uptake ofthe particles87
PLGAPLGA is a biodegradable copolymer of glycolic acid andlactic acid96 It is widely used in biomedical research asan FDA-approved substance PLGA offers several advan-tages The polymer is highly stable biodegradable andallows sustained release During nucleic acid deliveryPLGA is easily taken up by cells through endocytosisand no serious toxicity problems were observed97 PLGAbinds nucleic acids weakly but it might encapsulate themfor drug delivery purposes Indeed PLGA nanoparticleswere used in several studies for delivery of drugs totumors through the EPR effects98 Yet following endocyto-sis PLGA particles do not effectively realease cargo fromendosomes8397 To overcome nucleic acid binding deliv-ery and endosomal release problems the surface of PLGAcan be decorated with various cationic nanoparticles suchas DOTAP PEI or polyamine and may be conjugated topeptides and antibodies99
DendrimersDendrimers are tree-like highly branched generally sym-metrical and three-dimensional macromolecules Theyhave uniform size and molecular weight which increaseswith each new branch (generation) Dendrimers possess ahighly functional outer surface allowing chemical modi-fications and interactions Therefore they may be used asflexible and modifiable gene delivery agents100 Besidesthe ability of dendrimers to encapsulate cargos add to theirpotential as drug carriers101 Dendrimers including poly-amidoamine dendrimers (PAMAM) poly-propylene imine(PPI) dendrimers poly-L-lysine dendrimers triazine den-drimers carbosilane dendrimers poly-glycerol-based den-drimers nanocarbon-based dendrimers and others weretested as RNAi delivery agents PAMAM and PPI den-drimers being the most commonly studied ones It wasshown that introduction of surface-modifications mini-mized toxicity-related problems increased RNAi-bindingand cellular uptake efficacies of the dendrimers102103
Of note in vivo gene expression changes were alsoobserved with drug-free dendrimers104 Therefore well
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
controlled experiments are needed before drawing conclu-sions during RNA interference studies
AtelocollagenAtelocollagen is an organic protein-based moleculederived from type I collagen of calf dermis Sinceit is obtained following a pepsin treatment atelocolla-gen is devoid of telopeptides that are responsible forthe immunogenicity of collagen105 Moreover atelocol-lagen has low toxicity it was shown to stabilize RNAmolecules Increased cellular uptake and sustained deliv-ery was observed in in vivo making atelocollagen an idealagent for gene delivery106 Indeed several studies used ate-locollagen with success for the systemic or local deliveryof RNAi in tumor models107ndash109
ChitosanChitosan is obtained through alkaline deacetylation of thepolysaccharide chitin that forms the exoskeleton of crus-taceans some anthropods and insects Chitosan that is usedin biomedical research is a copolymer of N -acetyl-D-glucosamine and D-glucosamine having a positive chargeIn addition to being biodegradable and biocompatible chi-tosan has a low production cost Mucoadhesive propertiesof chitosan allow the penetration of the substance intoepithelial cell layers including the gastrointestinal barri-ers Nucleic acid encapsulation and sustained release wasproved to be possible using chitosan110ndash112 Moreover chi-tosan prolongs transient time in bowel improving par-enteral drug bioavailability113 Nanoparticles of chitosanare taken up into cells through endocytosis to a cer-tain extent To improve gene delivery efficacies PEG ordeoxycholic acid conjugates or modifications includingtrimethylation thiolation galactosylation may be intro-duced to chitosan111 Moreover chitosan-based carrierspossess functional groups that are suitable for conjugationto ligands relevant for targeted tumor delivery Althoughinefficient endosomal escape is a problem encounteredwith chitosan-based carriers some chemically modifiedforms showed improved escape properties114
CyclodextrinsCyclodextrins are natural polymers They are cyclicoligosaccharides of a glucopyranose generated during thebacterial digestion of cellulose Their central cavity ishydrophobic while the outer surface is a hydrophilicand they can create water-soluble molecular complexes115
Native cyclodextrins do not form stable complexeswith nucleic acids But the DNARNA complex for-mation capacities of the molecule can be modulatedand improved through molecular modifications includ-ing changes in functional groups hydrophilic-hydrophobicbalance charge density spacer length and conjugation toother carrier molecules115116 Cyclodextrins are not onlybiocompatible but they have the capacity to decrease
cytotoxicity of other molecules and carriers that are conju-gated to them117 Moreover cyclodextrins increase cellularadsorption and intake of molecules118 So in addition totheir use as a gene delivery agents cyclodextrins are usedas linking agents or structural modifiers in complex car-rier molecules For example conjugation of cyclodextrinto PEI resulted in lower toxicity and higher transfectionefficiencies119 In addition to the advantages cited abovea cyclodextrin polycation delivery system was reportedto block immune reactions raised against small RNAsthrough a masking effect120121 Importantly studies innon-human primates revealed that cyclodextrin-based car-riers were well tolerated and they do not stimulate signif-icant antibody responses120
AptamersAptamers are nucleic acid-based molecules selectedin vitro according to their capacity to bind target moleculesspecifically and with high affinity The immunogenicity ofaptamers is limited due to chemical modifications min-imizing adverse reactions Moreover nucleic acid natureand small size of aptamers result in improved transport andtissue penetration Since they can be specifically designedaccording to cell or tissue types (eg tumor cell com-ponents) side effects and off-target effects are minimalIn gene therapy applications the nucleic acid nature ofaptamers allows easy conjugation to RNADNA combin-ing targeting advantages with a therapeutic potential122
Alternatively non-covalent adapter linkages might be cre-ated between aptamers and RNA molecules Functionalgroups might be added to the 5prime- or 3prime-termini allowingcovalent or non-covalent conjugation of aptamers to carriernanoparticles123
Inorganic ParticlesInorganic nanoparticals such as carbon nanotubes mag-netic nanoparticles quantum dots and silica are the focusof recent efforts in drug and gene delivery Many of theseparticles actually offer the opportunity to combine imag-ing and therapeutic possibilities in the same particle ren-dering the nanocarrier a valuable ldquotheranosticrdquo device124
Increased surfacevolume ratio of inorganic particles pro-vides an opportunity for surface modifications includingconjugations to drugs oligonucleotides targeting peptidesor other molecules125126 Yet inorganic nanoparticles tendto aggregate and the size of the aggregate might have animpact on its function and biodistribution Such inorganicnanoparticles are hence coated with organic moleculeswhich provide colloid formation in aqueous and physiolog-ical media and stability Nature of the organic coatings hasto be designed for specific purposes but biocompatibilityof the organic molecules themselves andor their degra-dation products are critical for drug delivery purposes126
Chemistry of the coating might influence the half-life inblood and biodistribution as well as the toxicity of inor-ganic nanoparticles and their clearance mechanisms
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Depending on the material they consist of inorganicnanoparticles may possess a number of different propertiessuch as high electron density and strong optical absorption(eg metal particles in particular Au) photoluminescenceor fluorescence (semiconductor quantum dots eg CdSeCdTe CdTeSeZnS) phosphorescence (doped oxide mate-rials eg Y2O3) or magnetic moment (eg iron oxide orcobalt nanoparticles) The shape of the nanoparticle is alsoan important factor influencing its interaction with cellsMany of the above mentioned nanoparticle are sphericalin shape except carbon nanotubes that are tubular
Carbon NanotubesCarbon nanotubes (CNTs) easily cross the plasma mem-brane and translocate directly into the cytoplasm of tar-get cells due to their nanoneedle structure and usingan endocytosis-independent mechanism yet they do notinduce cell death127ndash129 CNTs are classified as single-walled CNTs and multiwalled CNTs Single or multiplegraphine layer(s) might have a length ranging from 50 nmto 100 mm and a diameter of 1 nm to 100 nm Properfunctionalizing of CNTs by covalent or non-covalentstrategies (such as coating with PEG or Tween-20) mayprovide solubility in aqueous solutions and prevent non-specific interactions thus minimizing toxicity observedwith non-functionalized raw particles130131 Modificationsmight also increase biocompatibility and blood circulationhalf-life132133 CNTs have very strong absorption charac-teristics providing an opportunity for photothermal abla-tion therapy in addition to nanocarrier properties
Magnetic NanoparticlesMagnetic nanoparticles are composed of ferromagneticelements such as Ni Co Mn Fe Superparamagneticiron oxide nanoparticles (SPIONS) such as maghemite--Fe2O3 and magnetite-Fe3O4 are one of the most widelyused magnetic particles as nanocarriers due to relativelylow cost of production biocompatability and superpara-magnetic nature134135 SPIONS are approved by FDA forclinical trials They are commonly used as contrast agentsfor magnetic resonance imaging (MRI) SPION crystals(less than 10 nm in diameter) are coated for specificpurposes with organic molecules such as dextran aminodextran BSA PEI dendrimers lipids and trialkoxysi-lanes including aminopropyltriethoxy silane (APTES)Coating chemistry and preparation methods influence over-all hydrodynamic size pharmacokinetics and the contrasttype (dark-T 2 or bright-T 1 agent) Ability to track the fateof nucleic acid carrier magnetic nanoparticles in vivo usingMRI is highly desirable since it provides informationabout the location of the cargo and its biodistribution136
Attachment of ligands provides target specificity andPEGylation may improve biocompatibility and blood half-life These modifications are commonly introduced to SPI-ONs that are used for imaging and therapy purposes Due
to their magnetic nature drug or nucleic acid carrying SPI-ONs can be concentrated at desired diseased sites such astumors and they may be dragged magnetically towards thelesion area136137 Moreover magnetic nanoparticles offerthe possibility of hyperthermia treatment as a result ofmagnetic heating135 Under applied alternating magneticfield SPIONs cause local temperature increase (41ndash42 C)which may be exploited for alternative and efficient cancertherapy Therefore SPIONs are one of the most versatileand multifunctional nanoparticles Consequently SPIONswere used as popular gene delivery vehicles135
Magnetic nanoparticles may be engineered for oligonu-cleotide delivery purposes MRI visible PEI-PEG coatedSPIONs which are tagged with an antibody have beenshown to effectively carry siRNA to cancer cell lines andshowed low toxicity138 SPIONs coated with both thermoresponsive and cationic polymers such as poly[2-(2-methoxyethoxy)ethylmethacrylate]-b-poly-[2-(dimethyl-amino)ethyl methacrylate] were reported to have25ndash100 times better transfection efficiency than branchedPEI 25 kDa when coupled with magnetic targeting139
SPIONs coated with low molecular weight PEI(12ndash2 kDa) which is usually not effective as poly-plexes in transfection were shown succesful in deliveringsiRNA to mouse macrophages (H Yagci Acar WIPOPatent WO2006055447A3) Therefore magnetic nanpar-ticles are under heavy investigation for the developmentof multifunctional nanocarriers for cancer therapy anddiagnosis135
Quantum DotsSemiconductor quantum dots (QDs) are light-emittingnanoparticles of few nanometer in diameter and they havebeen increasingly used as biological imaging and labelingprobes140 Luminescencefluorescence properties of QDsdepend on the crystal size and type Chemical composi-tion of the crystalline semiconductor core determines theband gap of the material therefore the emission wave-length range Within possible spectral window size ofthe crystal determines the specific wavelength of lumines-cencefluorescence for each and every QD due to quan-tum confinement effect Broad absorption of QDs allowexcitation of multiple QDs at a single wavelength andminimal signal mixing due to the narrow emission bandIn addition they are much more resistant to photobleach-ing These two characteristics are the major advantages ofQDs compared to organic fluorophores as imaging probesUtilization of QDs in nucleic acid delivery aims bothimaging and therapy since in vivo localization of cargocan be observed using optical imaging systems141142 Forexample cationic CdTeZnS QDs conjugated with PEGwas demonstrated to form an effective nanoplex with sur-vivin siRNA and successfully transfeced human tonguecancer cells in vitro and provided real time tracking143
However well-established QDs harbour significant toxic-ity due to constituents such as Cd Se Te144 Therefore
J Biomed Nanotechnol 10 1751ndash1783 2014 1761
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
toxicity of these QDs is a drawback for their use in vivoAs an alternative silver (Ag) chalcogenites emerged assafer near-infra red-emitting QDs145146 Ag2S QDs did notinduce cytotoxicity ROS production apoptosis necrosisor DNA damage147 For example Ag2S QDs (coated with2-mercaptopropionic acid) emitting between 750ndash850 nmshowed no cytotoxicity in NIH3T3 cells at even highdoses (600 mgml) along with good cellular imagingpotential148
Gold NanoparticlesGold nanoparticles emerged as popular tools fornanocarrier-mediated gene therapy149 They are easily syn-thesized and biocompatible particles that allow addition offunctional molecules on their surface due to high surface-to-volume ratio114150 A variety of surface changes andfunctional additions were reported including cationic lipidcoating branched PEI addition or functionalization usingcationic quaternary ammonium or cystamine114151152
Indeed cystamine functionalized gold nanoparticles wereshown to effectively bind deliver and release 35 differ-ent miRNA in in vitro studies using neuroblastoma andovarian cancer cell lines153
Silica NanoparticlesSilica-based nanoparticles are inert stable biocompati-ble and biodegradable particles154 They can be renderedhydrophilic hydrophobic anionic or cationic using func-tional surface modifiers through electrostatic interactionsor by formation of any other type covalent bonds (egester amine) Common functionalization strategies to ren-der the molecule cationic and improve nucleic acid bind-ing include grafting of molecules such as PEI PEI-PEGand Poly-L-arginine155 Nucleic acids may also be loadedinside the mesoporous silica particles156 siRNA encapsu-lating mesoporous silica nanoparticles were successfullyused for in vitro and in vivo gene silencing in several stud-ies (For example Ref [156])
RECENT IN VIVO STUDIES USING RNAINTERFERENCE IN CANCER THERAPYThere is an exponential increase in the number of scientificpublications dedicated to gene therapy of diseases usingsmall RNAs and nanoparticles A literature search usingldquonanoparticlerdquo and ldquosiRNA shRNA or miRNArdquo revealedmore than 700 articles published in the last two yearsThis number is roughly equal to the number of all articlespublished in this field until two years ago So the field isexpanding and there seems to form a consensus aroundthe use of nanoparticles as next generation gene therapytools We believe that these high expectations are not onlya consequence of shifting trends in science and technol-ogy The exponential rise in interest in the field of smallRNA carrier nanoparticles is fueled by the advances inthe field of nano materials promising results obtained in
small RNA therapeutics by both academic laboratories andindustry and increasing number of successful clinical tri-als In this section we will summarize results of selectedrecent studies using RNA therapeutics for cancer treatmentin preclinical in vivo experimentsOverview of the works dealing with small RNA treat-
ment of experimental cancers and published within thelast two years were summarized in Table I Although sev-eral studies were performed using lipid-based nanopar-ticles (Liposomes micelles or lipidoids) other particlessuch as polymers organic or inorganic carriers and com-pounds mixtures with functional modifications of vari-able substances were also tested by many research teamswith reasonable success Scheme 4 summarizes the generalstrategy followed in most of these studies
Tumor Types and RNAi TherapyRecent studies in the literature showed that tumors of vari-ous tissue origins could be treated using RNA interferencestrategies (Table I) Fine tuning of nanoparticles throughaddition of functional moieties or modifications alloweddelivery of drugs into almost any kind of tumor tissue withaccompanied therapeutic effects Although several studiesused animal tumor models that resulted from the injectionof cell lines from most commonly seen human cancers(lung breast prostate cervix or ovarian cancer cell lines)animals with kidney urinary bladder head and neckgastric pancreatic melanomas neuroblastomas glioblas-tomas multiple myelomas or sarcomas were also treatedwith RNAinanocarrier strategy81156ndash170 These results givehope about the general use of RNA interference as astrategy to treat cancers of different origins Althoughit is difficult to compare the efficacies of different nucleicacid molecules and their interference effects at this pointsiRNA or microRNAs as well as shRNA vectors wereshown to achieve intratumoral in vivo target gene knock-down and anticancer effects leading to a decrease in tumorsize (For example Refs [156 171]) Since in most studiesin addition to RNAi loaded particles naked nanoparticlesor particles loaded with non-specific control nucleic acidswere also used antitumor effects obtained in these studiesare specific and they may be attributable to small RNAmolecules rather than the particles themselves underliningthe potential of RNA interference in cancer treatmentMajority of recent studies with in vivo models chose
to use human tumor cell line xenografts in immune com-promised mice nude or severe-combined immuno defi-cient SCID mice (Table I) (For example Refs [162 172])Syngeneic transplants and established genetically engi-neered mouse models of cancer were rarely studied in thiscontext167173ndash175 Therefore although antitumor effects andsome of the toxic effects (eg liver toxicity) might berevealed using immune compromised mice hematologicalimmunological and inflammatory side effects of the treat-ment strategies used in recent studies might need to berevisited using immunocompetent mice
1762 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IRec
entstudieswithRNAica
rryingnan
oparticles
forthetrea
tmen
tofex
perim
entalca
nce
rs(P
ublis
hed
within
thelast
twoye
ars)
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGF
Mag
netic
mes
oporou
ssilicana
nopa
rticles
PEIan
dfuso
genicpe
ptide
KALA
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[156
]
siRNA
Polo-likekina
se1(P
LK1)
pH-sen
sitiveca
tioniclip
idYSK05
-MEND
(YSK05
POPEcho
lesterol
=50
2525
)
PEG
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
PLK
1[51]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Bioen
gine
ered
bacterial
outermem
bran
eve
sicles
Hum
anep
idermal
grow
thfactor
rece
ptor
2(H
ER2)-spe
cific
affib
ody
targeting
HCC-195
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
KSP
Dec
reas
edtumor
volume
[81]
siRNA
Luciferase
Dioleoy
lpho
spha
tidic
acid-(DOPA
-)co
ated
nano
-sized
calcium
phos
phate(LCP-II)
DSPE-P
EG-an
dan
isam
idefortargeting
sigm
a-1rece
ptor
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
Xen
ograft
it
ND
Kno
ckdo
wnof
luciferase
[211
]
siRNA
mTERT
N-((2-hyd
roxy
-3-trim
ethy
l-am
mon
ium)propy
l)ch
itosa
nch
lorid
e(H
TCC)na
nopa
rticles
Partic
leload
edwith
paclita
xel
LCC
murinelung
canc
erce
llssy
ngen
eicsc
graft
oral
Noeffect
Kno
ckdo
wnof
mTERT
Dec
reas
edtumor
volume
Syn
ergize
dwith
paclita
xel
[159
]
siRNA
VEGF
Multilay
ered
polyion
complexes
Polyc
ationinterla
yeran
dade
tach
able
PEG
shell
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
[212
]
siRNA
Multid
rug
resistan
ceprotein1
(MRP1)
Nan
opartic
lesas
sembled
vialaye
r-by
laye
rde
positio
nof
siRNA
and
poly-L-arginine
Hya
lurona
n(H
A)co
ating
forHA-C
D44
targeting
MDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
it
Noeffect
Kno
ckdo
wnof
MRP1
Dec
reas
edtumor
volume
[183
]
siRNA
STA
T3-a
Nan
oporou
ssilicon
nano
particles
Argininean
dPEI
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicefat
padxe
nograft
iv
Noeffect
Kno
ckdo
wnof
STA
T3-a
[204
]
siRNA
Luciferase
Lipo
somal
nano
particle
Fou
rtand
emrepe
atsof
human
histon
eH2A
peptideinterven
edby
cathep
sinD
clea
vage
sites
PEG-A
nisa
mide
fortargeting
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
luciferase
[199
]
siRNA
Polo-likekina
se1(P
LK1)
Hya
luronicac
id(H
A)
base
dse
lfass
embling
HA-P
EIP
EG
nano
system
s
Hya
lurona
nforCD44
targeting
B16
F10
amurine
melan
omace
llsA54
9-luchu
man
lung
canc
erce
llsHep
3Bhu
man
liver
canc
erce
llsMDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
graftor
metas
tatic
lung
lesion
sby
IVinjection
it
ND
Kno
ckdo
wnof
PLK
1[160
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1763
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
P-glyco
protein
drug
expo
rter
(P-
gpM
DR1)
Mes
oporou
ssilica
nano
particles
Polye
thylen
eimine
polyethy
lene
glyc
ol(P
EI-PEG)co
polymer
MCF-7M
DR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gpMDR1
Dec
reas
edtumor
volume
Syn
ergy
with
doxo
rubicin
[179
]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Multifun
ctiona
lcarrie
rsy
stem
with
catio
nic
(olig
oethan
amino)am
ide
core
attach
edto
PEG
chain
Folic
acid
fortargeting
Inf7
(Infl
uenz
ape
ptide)
asen
doso
molytic
peptide
coup
ledto
the5prime-end
ofsiRNA
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
itor
iv
ND
Kno
ckdo
wnof
EG5
Dec
reas
edtumor
volume
[161
]
siRNA
Epide
rmal
Growth
Factor
Rec
eptor
(EGFR)
Poly-L-argininean
dde
xtransu
lfate-bas
edna
noco
mplex
FaDuhu
man
pharyn
xsq
uamou
sca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[172
]
siRNA
Cho
line
kina
se(C
hk)
Polye
thylen
imine-
polyethy
lene
glyc
ol(P
EI-PEG)co
grafted
polymer
Con
versionof
nontox
ic5-flu
oroc
ytos
ine(5-FC)to
cytotoxic5-flu
orou
racil
(5-FU)by
activating
bacterialc
ytos
ine
deam
inas
e(bCD)
PC3-PIP
andPC3-Flu
human
pros
tate
canc
erce
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
e[157
]
siRNA
Polo-like
kina
se1
(Plk1)
Cationiclip
idpo
lymer
hybrid
nano
particles
(cationiclip
id(N
N-
bis(2-hy
drox
yethyl)-N-
methy
l-N-(2-
choles
teryloxy
carbon
ylam
inoe
thyl)am
mon
ium
brom
ide
BHEM-C
hol)
andam
phiphilic
polymers(H
ydroph
obic
polylactideco
re)
PEG
shell
BT47
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Plk1
Dec
reas
edtumor
volume
[213
]
siRNA
hTERT
Single-walledca
rbon
nano
tube
s(S
WNTs)
Branc
hedPEIco
njug
ated
DSPE-P
EG20
00-M
aleimide
forco
njug
ationwith
NGR
(Cys
-Asn
-Gly-A
rg-C
ys-)
targetingpe
ptide(rec
ognize
tumor
neov
ascu
lature)
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
hTERT
Dec
reas
edtumor
volume
Syn
ergy
with
photothe
rmal
trea
tmen
t
[139
]
1764 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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cer J Clin 64 9 (2014)2 M J Espiritu A C Collier and J P Bingham A 21st-century
approach to age-old problems The ascension of biologics in clini-cal therapeutics Drug Discov Today (2014)
3 R L Schilsky Personalized medicine in oncology The future isnow Nat Rev Drug Discov 9 363 (2010)
4 M N Patel M D Halling-Brown J E Tym P Workman andB Al-Lazikani Objective assessment of cancer genes for drug dis-covery Nat Rev Drug Discov 12 35 (2013)
5 D Hanahan and R A Weinberg Hallmarks of cancer The nextgeneration Cell 144 646 (2011)
6 N F Sun Z A Liu W B Huang A L Tian and S Y Hu Theresearch of nanoparticles as gene vector for tumor gene therapyCrit Rev Oncol Hematol 89 352 (2013)
1776 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
7 M Rothe U Modlich and A Schambach Biosafety challenges foruse of lentiviral vectors in gene therapy Curr Gene Ther 13 453(2013)
8 D R Corey RNA learns from antisense Nat Chem Biol 3 8(2007)
9 V N Kim MicroRNA biogenesis Coordinated cropping and dic-ing Nat Rev Mol Cell Biol 6 376 (2005)
10 D E Golden V R Gerbasi and E J Sontheimer An inside jobfor siRNAs Mol Cell 31 309 (2008)
11 M Ghildiyal and P D Zamore Small silencing RNAs An expand-ing universe Nat Rev Genet 10 94 (2009)
12 D H Kim M A Behlke S D Rose M S Chang S Choiand J J Rossi Synthetic dsRNA Dicer substrates enhance RNAipotency and efficacy Nat Biotechnol 23 222 (2005)
13 Y Maida M Yasukawa M Furuuchi T Lassmann R PossematoN Okamoto V Kasim Y Hayashizaki W C Hahn and K Masu-tomi An RNA-dependent RNA polymerase formed by TERT andthe RMRP RNA Nature 461 230 (2009)
14 N R Smalheiser The search for endogenous siRNAs in the mam-malian brain Exp Neurol 235 455 (2012)
15 K A Tekirdag G Korkmaz D G Ozturk R Agami andD Gozuacik MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5 Autophagy 9 374(2013)
16 G Korkmaz K A Tekirdag D G Ozturk A Kosar O USezerman and D Gozuacik MIR376A Is a Regulator ofStarvation-Induced Autophagy PLoS One 8 e82556 (2013)
17 D Castanotto and J J Rossi The promises and pitfalls of RNA-interference-based therapeutics Nature 457 426 (2009)
18 E Iorns C J Lord N Turner and A Ashworth Utilizing RNAinterference to enhance cancer drug discovery Nat Rev Drug Dis-cov 6 556 (2007)
19 M A Behlke Chemical modification of siRNAs for in vivo useOligonucleotides 18 305 (2008)
20 S D Rose D H Kim M Amarzguioui J D Heidel M ACollingwood M E Davis J J Rossi and M A Behlke Func-tional polarity is introduced by Dicer processing of short substrateRNAs Nucleic Acids Res 33 4140 (2005)
21 K Nishina T Unno Y Uno T Kubodera T KanouchiH Mizusawa and T Yokota Efficient in vivo delivery of siRNAto the liver by conjugation of alpha-tocopherol Mol Ther 16 734(2008)
22 F Czauderna M Fechtner S Dames H Aygun A Klippel G JPronk K Giese and J Kaufmann Structural variations and sta-bilising modifications of synthetic siRNAs in mammalian cellsNucleic Acids Res 31 2705 (2003)
23 B A Kraynack and B F Baker Small interfering RNAs contain-ing full 2prime-O-methylribonucleotide-modified sense strands displayArgonaute2eIF2C2-dependent activity RNA 12 163 (2006)
24 F V Rivas N H Tolia J J Song J P Aragon J Liu G JHannon and L Joshua-Tor Purified Argonaute2 and an siRNAform recombinant human RISC Nat Struct Mol Biol 12 340(2005)
25 V Hornung M Guenthner-Biller C Bourquin A AblasserM Schlee S Uematsu A Noronha M Manoharan S AkiraA de Fougerolles S Endres and G Hartmann Sequence-specificpotent induction of IFN-alpha by short interfering RNA in plasma-cytoid dendritic cells through TLR7 Nat Med 11 263 (2005)
26 A D Judge G Bola A C Lee and I MacLachlan Design ofnoninflammatory synthetic siRNA mediating potent gene silencingin vivo Mol Ther 13 494 (2006)
27 A L Jackson J Burchard D Leake A Reynolds J SchelterJ Guo J M Johnson L Lim J Karpilow K NicholsW Marshall A Khvorova and P S Linsley Position-specificchemical modification of siRNAs reduces ldquooff-targetrdquo transcriptsilencing RNA 12 1197 (2006)
28 D Bumcrot M Manoharan V Koteliansky and D W Sah RNAitherapeutics A potential new class of pharmaceutical drugs NatChem Biol 2 711 (2006)
29 A S Peek and M A Behlke Design of active small interferingRNAs Curr Opin Mol Ther 9 110 (2007)
30 Y Pei and T Tuschl On the art of identifying effective and specificsiRNAs Nat Methods 3 670 (2006)
31 S Svenson What nanomedicine in the clinic right now really formsnanoparticles Wiley Interdiscip Rev Nanomed Nanobiotechnol 6125 (2014)
32 T S Zimmermann A C Lee A Akinc B Bramlage D BumcrotM N Fedoruk J Harborth J A Heyes L B Jeffs M JohnA D Judge K Lam K McClintock L V Nechev L R PalmerT Racie I Rohl S Seiffert S Shanmugam V Sood J SoutschekI Toudjarska A J Wheat E Yaworski W Zedalis V KotelianskyM Manoharan H P Vornlocher and I MacLachlan RNAi-mediated gene silencing in non-human primates Nature 441 111(2006)
33 D V Morrissey J A Lockridge L Shaw K Blanchard K JensenW Breen K Hartsough L Machemer S Radka V JadhavN Vaish S Zinnen C Vargeese K Bowman C S Shaffer L BJeffs A Judge I MacLachlan and B Polisky Potent and persis-tent in vivo anti-HBV activity of chemically modified siRNAs NatBiotechnol 23 1002 (2005)
34 D C Litzinger A M Buiting N van Rooijen and L HuangEffect of liposome size on the circulation time and intraorgan distri-bution of amphipathic poly(ethylene glycol)-containing liposomesBiochim Biophys Acta 1190 99 (1994)
35 A Akinc A Zumbuehl M Goldberg E S Leshchiner V BusiniN Hossain S A Bacallado D N Nguyen J Fuller R AlvarezA Borodovsky T Borland R Constien A de Fougerolles J RDorkin K Narayanannair Jayaprakash M Jayaraman M JohnV Koteliansky M Manoharan L Nechev J Qin T RacieD Raitcheva K G Rajeev D W Sah J Soutschek I ToudjarskaH P Vornlocher T S Zimmermann R Langer and D G Ander-son A combinatorial library of lipid-like materials for delivery ofRNAi therapeutics Nat Biotechnol 26 561 (2008)
36 S C Semple A Akinc J Chen A P Sandhu B L Mui C KCho D W Sah D Stebbing E J Crosley E Yaworski I MHafez J R Dorkin J Qin K Lam K G Rajeev K F WongL B Jeffs L Nechev M L Eisenhardt M Jayaraman M KazemM A Maier M Srinivasulu M J Weinstein Q Chen R AlvarezS A Barros S De S K Klimuk T Borland V Kosovrasti W LCantley Y K Tam M Manoharan M A Ciufolini M A TracyA de Fougerolles I MacLachlan P R Cullis T D Madden andM J Hope Rational design of cationic lipids for siRNA deliveryNat Biotechnol 28 172 (2010)
37 A Hoeben B Landuyt M S Highley H Wildiers A T VanOosterom and E A De Bruijn Vascular endothelial growth factorand angiogenesis Pharmacol Rev 56 549 (2004)
38 Y Noguchi J Wu R Duncan J Strohalm K Ulbrich T Akaikeand H Maeda Early phase tumor accumulation of macromoleculesA great difference in clearance rate between tumor and normaltissues Jpn J Cancer Res 89 307 (1998)
39 A K Iyer G Khaled J Fang and H Maeda Exploiting theenhanced permeability and retention effect for tumor targetingDrug Discov Today 11 812 (2006)
40 Y Matsumura and H Maeda A new concept for macromoleculartherapeutics in cancer chemotherapy Mechanism of tumoritropicaccumulation of proteins and the antitumor agent smancs CancerRes 46 6387 (1986)
41 T Ishimoto Y Takei Y Yuzawa K Hanai S Nagahara Y TarumiS Matsuo and K Kadomatsu Downregulation of monocytechemoattractant protein-1 involving short interfering RNA atten-uates hapten-induced contact hypersensitivity Mol Ther 16 387(2008)
J Biomed Nanotechnol 10 1751ndash1783 2014 1777
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
42 G J Villares M Zigler H Wang V O Melnikova H WuR Friedman M C Leslie P E Vivas-Mejia G Lopez-Berestein A K Sood and M Bar-Eli Targeting melanoma growthand metastasis with systemic delivery of liposome-incorporatedprotease-activated receptor-1 small interfering RNA Cancer Res68 9078 (2008)
43 E Kawata E Ashihara S Kimura K Takenaka K SatoR Tanaka A Yokota Y Kamitsuji M Takeuchi J KurodaF Tanaka T Yoshikawa and T Maekawa Administration of PLK-1 small interfering RNA with atelocollagen prevents the growth ofliver metastases of lung cancer Mol Cancer Ther 7 2904 (2008)
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1778 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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147 Y Zhang G Hong G Chen F Li H Dai and Q Wang Ag2Squantum dot A bright and biocompatible fluorescent nanoprobe inthe second near-infrared window ACS Nano 6 3695 (2012)
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
155 H Lee D Sung M Veerapandian K Yun and S W Seo PEGy-lated polyethyleneimine grafted silica nanoparticles Enhanced cel-lular uptake and efficient siRNA delivery Anal Bioanal Chem400 535 (2011)
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163 H Arima A Yoshimatsu H Ikeda A Ohyama K MotoyamaT Higashi A Tsuchiya T Niidome Y Katayama K Hattoriand T Takeuchi Folate-PEG-appended dendrimer conjugate withalpha-cyclodextrin as a novel cancer cell-selective siRNA deliverycarrier Mol Pharm 9 2591 (2012)
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173 F Abedini H Hosseinkhani M Ismail A J Domb A R OmarP P Chong P D Hong D S Yu and I Y Farber Cationizeddextran nanoparticle-encapsulated CXCR4-siRNA enhanced corre-lation between CXCR4 expression and serum alkaline phosphatasein a mouse model of colorectal cancer Int J Nanomedicine 7 4159(2012)
174 F Yang W Huang Y Li S Liu M Jin Y Wang L Jia andZ Gao Anti-tumor effects in mice induced by survivin-targetedsiRNA delivered through polysaccharide nanoparticles Biomateri-als 34 5689 (2013)
175 L Chen Y Ding Y Wang X Liu R Babu W Ravis and W YanCodelivery of zoledronic acid and doublestranded RNA from corendashshell nanoparticles Int J Nanomedicine 8 137 (2013)
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177 L A Tobin Y Xie M Tsokos S I Chung A A Merz M AArnold G Li H L Malech and K F Kwong Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of can-cer cell internalization in vivo Biomaterials 34 2980 (2013)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
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188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
RNAs While a partial complementarity may lead to theblockage of the translation machinery protein translationrepression andor sequestration of miRNA-mRNA com-plexes in compartments called P-bodies a perfect matchbetween these two RNAs may result in mRNA degradation(Scheme 1(a))Conversely endo-siRNAs complementary to template
mRNAs are synthesized by RNA-dependent RNA poly-merases (RdRP) and they are not transcribed from thegenomic DNA (Scheme 1(b)) It was long believed thatmammals did not have any RdRPs But this conceptis now changing For example human telomerase cat-alytic subunit (hTERT) was shown possess a mammalianRdRP activity required for double stranded RNA synthe-sis from the mitochondrial RNA processing endoribonu-clease noncoding RNA component1314 In the endogenoussiRNA pathway hairpin containing double-stranded RNAproducts of RdRP are further processed into functionalendogenous siRNAs in either a Dicer-dependent or aDicer-independent manner (Scheme 1(b)) In general thesense guide strand of the endo-siRNAs are loaded onto theRISC with AGO2 proteinsWhile in general mammalian miRNAs show partial
complementary to their mRNA target sequences and con-trol a wide number of functionally-related transcripts strictcomplementarity was thought to be necessary for siRNAfunction9 But even synthetic siRNAs or shRNAs that aredesigned to target one and only mRNA were shown toaffect so called ldquooff-target genesrdquo Therefore although agene with a dominant biological effect will be targeted bysiRNAshRNAs a spectrum of biological events might beaffected by the use of a small RNA Nevertheless in vitrocell culture and animal studies confirmed that the biolog-ical outcomes of siRNAshRNAs and even miRNAs wereusually determined by their effect on a dominant targetgene andor pathway1516
SMALL RNAS AS POTENT DRUGSUse of potent RNA interference strategies might give usnew opportunities for the treatment of diseases such ascancer17 Potential advantages of small RNAs over existingsmall molecule drugs and conventional therapies includeorganic composition natural metabolism lower drug tox-icity minimal immune reactions when designed optimallyand combined with appropriate carriers possibility ofmodulating targets that are considered as ldquoundruggablerdquo byconventional drugs possibility of targeting disease-relatedtissue-specific isoforms andor mutant transcripts and stan-dard chemical synthesis protocols Moreover RNA plat-forms are now widely used in high throughput formats fortarget validation and drug development processes reduc-ing the product development cycle and cost compared toconventional small molecules18
Modifications to the native RNA structure can cre-ate robust drug-like RNA molecules19 Synthetic 21-mer
RNA duplexes mimicking natural siRNAs and miRNAsare commonly used in RNA-based gene therapy protocolsAlternatively asymmetric 2527-mers or 2729-mers blunt25-mers blunt 27-mers and blunt 19-mers were tested fortheir stability and potency as RNA drugs with variablemerits20ndash23 These different synthetic RNAs might directlybe loaded onto the RISC complex or they might firstrequire processing by Dicer In fact even under in vitro con-ditions synthetic siRNAs were shown to directly load ontorecombinant human AGO2 proteins and form functionalcomplexes24 Therefore following delivery small RNAsmay rapidly form functional complexes and alter target pro-tein levels resulting in therapeutic changes in cellsNaked RNA molecules are highly susceptible to degra-
dation by nucleases that are abundant in tissues and in theblood circulation Therefore to stabilize RNA moleculesincrease their half-lives in biological environments andavoid immune reactions a number of chemical changesmight be introduced to the nucleic acid structures19
There are several commonly used RNA modifications2prime-O-methyl modifications into the sugar structure ofsome nucleotides may confer resistance to endonucle-ases decrease off-target effects when introduced into theseed region and minimize Toll-like receptor-mediatedimmune reactions25ndash27 Introduction of phosphorothioateboranophosphate or methylphosphonate backbone linkagesat the 3prime-end of the RNA strands may reduce their suscepti-bility to exonucleases Similarly alternative 2prime sugar mod-ifications such as 2prime-fluoro LNA (Locked nucleic acids)FANA (2prime-deoxy-2prime-Fluoro--d-arabinonucleic acid) and2primeMOE (2prime-O-methoxyethyl) modifications were reportedto increase endonuclease resistance of small RNAs28
While all these modifications result in more robust RNAmolecules they might affect the potency of the RNA inter-ference effects obtained during treatment Therefore evenif the changes were performed according to design criteriaor computer tools experimental testing is required in eachseparate case to confirm potency of modified small RNAmolecules on their mRNA targets2930
RNADNA NANOCARRIERS FORCANCER THERAPYUse of gene therapy and lately small RNAs for can-cer treatment was hindered by the lack of a suitabledelivery system Recent developments in nanotechnologyallowed the introduction of nanoparticles with very differ-ent physico-chemical properties Novel and sophisticatednanocarriers and their functionalized derivatives are beingtested as potent and in many cases targeted RNA drugdelivery agents Some formulations are already in clinicaltrials and a few of them were even approved by majoragencies such as the Food and Drug Agency (FDA) in theUSA31
Nanoparticles to be used as nucleic acid delivery agentsshould meet several criteria The particles should safely
J Biomed Nanotechnol 10 1751ndash1783 2014 1755
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and effectively deliver RNA molecules to cancer cells andtumors Therefore they have to be biocompatible notimmunogenic and they should not get modified or dis-solved into toxic substances under biological conditionsand before reaching the tumor target For effective deliv-ery and dosage nano conjugates have to be stable enoughin the blood circulation and resist shear forces proteasesand nucleases that they face with Complex formation withblood cells proteins and other blood components mightalso affect carrier size charge availability and efficacyClearance is also an important issue For nanocarriers
to reach therapeutic blood levels they should not be read-ily cleared through glomerular filtration in the kidneys ortrapped by the reticuloendothelial system For examplenaked siRNA molecules and nanoparticles less than 10 nmmay be filtrered and excreted through kidneys follow-ing systemic administration Carriers larger than 100 nmmight be phagocytosed and cleared by monocytes andmacrophages residing in the reticuloendothelial system(RES also called mononuclear phagocytic system) tissueswith high blood supply including pulmonary alveoli liversinusoids skin spleen etc32ndash36 In addition to the size of thenanoparticles their geometries surface charges hydropho-bicities and opsonization by serum proteins might affectclearance by monocytes and macrophages Additionallythe efficacy of nucleic acid drugs in specific tissues andorgans may depend on the ability of nanocarriers to pene-trate blood vessels and tissues and pass through biologicalbarriers such as the tight blood-brain-barrier of the centralnervous systemFor cancer treatment small RNA drugs should affect
genetic andor molecular changes specific to cancer cellsand that are rate-limiting for tumor growth The idealnanocarrier should be able to concentrate within the tumortissue and if possible target individual tumor cells in aselective way (eg through receptors or molecules thatare tumor-specific or that are enriched in the tumor tis-sue) and not penetrate normal cells Enhanced permeabilityand retention (EPR) effect offers an advantage for solid-tumor targeting The EPR effect is a result of neovascu-larisation new blood vessel formation to feed tumors withsizes beyond passive oxygen and nutrient diffusion lim-its (beyond 01ndash02 mm diameter)37 Blood vessels feed-ing tumor tissues are irregular and highly permeable Withthe lack of lymphatic drainage macromolecules are eas-ily retained in and around the tumor area3839 For exam-ple low molecular weight drugs may diffuse freely inand out of the tumor tissues but macromolecules (gt 40kDa) and nanoparticles of 100ndash200 nm accumulate inthe tumor tissue3840ndash43 EPR phenomenon was reported invarious human solid tumors as well as in inflammatorytissues44
Different types of nanoparticles were tested as drug car-riers and gene therapy tools (Scheme 2) The core structureof the particle may be a vesicle (liposomes) a polymer(eg PEI PLGA) a dendrimer carbon nanotubes silica or
metal nanoparticles (eg Gold) Porousvesiculate carrierssuch as liposomes polymeric micelles or some inorganicparticles (eg mesoporous silica) may encapsulate orabsorb RNADNA molecules Nanocarriers with a cationicnature including cationic liposomes cationic dendrimers(eg PAMAM) and polymers (eg PEI PDMAEMA) orcationic polymer coated inorganic particles (eg PEI cov-ered iron oxide) may form complexes through electro-static interactions with the negatively charged backboneof nucleic acids The nature and physico-chemical proper-ties of the nanoparticles may also influence their stabilityand half-life in blood criculation efficacy of their deliveryinto tissues and cells and their capacity to escape fromendosomes in the cell All these properties are determiningcriteria for nano drug efficacyTo improve stability RNADNA loading target speci-
ficity tracking cellular internalization endo-lysosomalescape and intracellular robustness additional functionalunits might be introduced to the basic structure ofthe nanocarriers (Scheme 3)45 Possible modificationsand changes include conjugation to proteins (antibodieslectins cytokines thrombin fibrinogen BSA transfer-rin) cellular or viral peptides (eg RGD LHRD TATPep-3 KALA) polysaccharides (eg lipopolysaccharideshyaluronic acid dextran chitosan) low molecular weightligands (eg folic acid anisamide) and polyunsaturatedfatty acids (eg palmitic acid and phospholipids) Thesestructures can be conjugated onto the nanocarrier surfacethough hydrolysable or non-hydrolysable chemical bondsand modifications such as amide ester silane hydrazoneor through the use of high avidity molecules such asavidin-biotin Fluorophores may also be added for par-ticle tracking purposes To improve the availability ofsuch groups and especially the targeting groups spacermolecules may be addedAn important modification relevant for biological func-
tion is ldquoPEGylationrdquo (Scheme 3)45 PEG coordinateswater molecules and forms an aqueous shell aroundnanoparticles shielding their charges PEGylation reducesinteraction with serum proteins decreases opsoniza-tion and clearance of nanoparticles by RES monocyte-macrophages sterically prevent nanocarrier aggregationand due to increased molecular weight above the thresholdfor glomerular filtration reduces elimination of the parti-cles through urinary excretion Hence PEG increases thestability improves biocompatibility prolongs blood circu-lation time and bioavailability of nanocarriers4647 Molec-ular weight and density of PEG chains on the nanocarriersurface may impact the function depending on the natureof the carried molecules ie siRNA47
On the other hand PEGylation significantly attenu-ates uptake of nanocarriers by target cells4849 More-over PEG chains were shown to block endosomal escapeand cytosolic release of chemical drugs and nucleicacids50 Blockage of cellular uptake and endosomal releasein the cell may severely attenuate drug efficacy and
1756 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 2 Major types of nanoparticles used as nucleic acid carriers
therapeutic RNA interference effects Various strategieswere adapted to overcome these negative effects of PEGwhile exploiting its circulatory advantages Cleavage ofPEG-chains upon delivery into the tumor environment wasachieved through addition of tumor-related matrix met-alloproteinase sensitive lipids or peptides51 pH-sensitivelinkers between the PEG moiety and nanocarriers canalso be used to release PEG from the particle in theacidic environment of the endosomes and allow cytosolic
Scheme 3 A representative nanoparticle with functional modifications Various molecules might be added to a nanoparticleto improve its physico-chemical properties and pharmacokinetics (eg PEG) to increase RNADNA binding (eg PEI) to allowbetter targeting (eg antibodies) or tracking (eg fluorophores)
release of small RNAs Modulation of the hydrophobic-ity of the PEGndashnanocarrier conjugate was also testedas a release strategy In lipid-based nanocarriers thelength of the alkyl chain of the PEG-lipid anchor wasshown to determine its affinity for the lipid deliveryvehicle and changing its length modified endosomalescape potential and drug effects52 Cholesterol-anchoredPEG was also shown to improve endosomal escapecapacities52
J Biomed Nanotechnol 10 1751ndash1783 2014 1757
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
LiposomesLiposomes have been tested extensively as gene deliv-ery agents Liposomes are artificial membrane-boundvesicles formed by bilayers of amphipathic lipids Theymight be unilamellar or multilamellar Their biocom-patibility low toxicity and low immunogenicity madethem popular agents for both in vitro and in vivo genedelivery5354 Liposomes are typically made of mix-tures of lipids found in biological membranes or theirderivatives including phosphatidylcholine (PC or DOPC12-Oleoyl-sn-Glycero-3-phosphatidylcholine) phosphatidyl-ethanolamine (PE or DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidylethanolamine) cholesterol and evenceramide53 Although liposomes made of neutral lipids aremore biocompatible than cationic lipids and have betterpharmacokinetics during preparation of gene deliveryvectors they bind less to negatively charged DNA orRNA molecules and have lower entrapment efficiencies55
Therefore despite their more toxic nature cationic lipidsare commonly used as liposome-based transfection agentsCationic lipids posses positively charged headgroupssuch as amines quaternary ammonium salts peptidesaminoacids or guanidiniums which electrostaticly attractand bind to negatively charged phosphate residues innucleic acid backbones The nature of cationic lipid head-groups determines the efficacy of gene delivery Thereforevarious mixtures of lipids with different headgroupsand properties were tested to achieve optimal liposomeformulations for drug andor gene delivery56ndash59
Although liposomes are excellent transfection agentsin vitro some side effects and problems were encoun-tered during in vivo studies56ndash59 These include intracellu-lar instability and failure to release small RNA contentsdose-dependent toxicity and pulmonary inflammation thatcorrelated with the production of reactive oxygen species(ROS) opsonization by serum proteins immunogenic-ity and uptake by the RES components60ndash63 Addition-ally cationic liposome-dependent gene expression changeswere observed during in vitro experiments with someformulations64
In order to minimize such undesired effects special-ized liposomes were produced through addition of vari-ous functional groups PEGylation and crosslinking withinthe bilayer of the liposomes was successfully utilized toimprove stability and decrease side effects65 PEGylationin general improved bioavailability and biocompatibilityas well For example to obtain improved pharmacokinet-ics PEGylated cationic liposomes called ldquosolid nucleicacid lipid particlesrdquo (SNALPs) were created and they weresuccessfully used for siRNA delivery In fact in SNALPsPEG coating neutralized net charge and increased theblood circulation time of the liposomes significantly66ndash72
Moreover fusogenic lipids added to liposome formula-tions improved cellular uptake and endosomal escape33
Most importantly SNALPs were relatively well toler-ated in vivo even in non-human primates3233 The list of
modifiedimproved liposomes performing well in in vivostudies also includes cationic solidndashlipid nanoparticles andcardiolipin-based liposomes3373ndash75 Currently improvedliposomes are one of the most promising tools for genedelivery and patented formulations produced by sev-eral companies were successful enough to reach clinicaltrials31
LipidoidsLipidoids are cationic lipids that are created by the conju-gation of primary or secondary amines to alkyl-acrylatesor alkyl-acrylamides76 They were introduced as novelalternatives to liposome formulations used in gene deliv-ery Changes in the composition lipidoids were shown toimprove their therapeutic properties For example changesin the alkyl chain length of the PEG lipid was reportedto affect PEG deshielding rate and dose kinetics of lipi-doids in the blood76 Moreover cholesterol incorporationwas shown to improve carrier stability Small sized lipi-doids (50ndash60 nm) were successfully used for the deliveryof siRNA into liver cells avoiding engulfment by Kuppfercells76 Lipidoids may also be used for coating inorganicnanoparticles in order to introduce cationic charges77 Lipi-doids have lower toxicity and increased efficacy thereforethey present an alternative to classical liposomes for genedelivery studies
MinicellsMinicells are bacteria-derived non-living anucleatednano-sized vesicles that were used as nano drug carriers78
Inactivation of min genes that control normal division inbacteria such as Salmonella typhimurium result in the for-mation of minicells min gene products ensure that celldivision septum is correctly located to the midpoint ofthe cell In case of min gene product mutations septa-tion defects result in the formation of minicells devoid ofthe chromosomal DNA Therapeutic RNAs may be loadedinto minicells by the introduction of shRNA of interestinto min mutant bacteria and eventually shRNAs segregateinto minicells78 Purified minicells prepared by this methodare pre-packaged with effective copy numbers of the plas-mid For targeting purposes tumor-specific antibodies maybe decorated onto minicells by the exploitation of bac-terial cell surface components such as O-polysaccharideof LPS Minicell-RNAi combinations proved to be effec-tive in experimental cancer treatment79 Other cell derived-vesicles that were tested as nanocarriers include bacterialghosts bacterial outer membranes or mammalian cell-derived exosomes80ndash82
PolyplexesMaterials that self-assemble with nucleic acids intonanocomplexes are called ldquopolyplexesrdquo These complexesgenerally form though the electrostatic interaction of the
1758 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
cationic units of the polymers with the anionic phos-phate groups of the nucleic acids Natural and biocompat-ible (eg chitosan Atelocollagen cyclodextrin) or morefrequently synthetic (eg Polyethylenimine PEI poly-L-lysine PLL poly-dl-lactide-co-glycolide PLGA) poly-mers are used for polyplex formation83ndash86 Flexibility of thesynthetic polymers in terms of chemical nature molecularweight and architecture (linear branched grafted blocky)provide opportunity to balance their toxicity improvenucleic acid binding protection and release efficienciesMoreover surface modifications may be introduced for tar-geting purposes and improved pharmacodynamics Poly-mers such as PLGA also benefit from a biodegradablenature which allows clearance of the nanocarriers in time
PEIPEI is the most widely and most successfully used polyca-tion for polyplexe formation It can be synthesized in lin-ear or branched forms and in variable molecular weights(from 1 kDa to gt 1000 kDa) Higher molecular weightpolymers (70 kDa and above) are very effective in nucleicacid binding but they are significantly toxic Low molec-ular weight forms (2 kDa or less) are less toxic but theyare less effective as transfection agents87 Therefore PEIsat and below 25 kDa with a branched or linear architec-ture are commonly used as gene delivery reagents88ndash91 Thegolden standard gene delivery polymer is branched PEIof 25 kDa which offers a balance between the toxicitynucleic acid bindingprotection and release Abundance ofpositive charges due to protonation under physiologicalconditions allows PEI to spontaneously form complexeswith negatively charged small RNAs and DNAs and pro-tect nucleic acid molecules from nuclease attacks84 More-over buried inside the polymer some off-target effects ofthe small RNAs were shown to be prevented92
The net positive charge of PEI-RNAi complexes alsoallow interactions with the negatively charged polysaccha-rides found on the cell surface93 These interactions arebelieved to be an important factor for the endocytosis ofthe complexes by target cells A key event for the successof gene delivery is the escape of the nucleic acids fromthe endosomal pathway in order to avoid accumulation anddegradation in the lysosomes of the cell93 The escape isthought to be the result of the lsquoproton spongersquo effect wherethe influx of protons and water lead to endosome swellingrupture and release of contents including nucleic acids tothe cytosolPEI-induced toxicity was proposed to be a result of
mitochondrial apoptosis induction by the polymer9495
Moreover PEI itself was shown to cause changes in geneexpression in vivo which might influence biological out-comes of treatment protocols59 PEGylation of the PEIreduces both cytotoxicity of PEI-polyplexes and increaseblood circulation half-life However a critical balanceneed to be achieved since PEGylation decreases the sur-face charge it impacts the binding capacity and cell
internalization of the polyplexes Alternatively short PEIchains attached together with hydrolysable links such asdisulfide and ester may provide initially a high molecu-lar weight PEI system for good nucleic acid condensationand protection but upon dissolution because of intracel-lular redox conditions they may act as a low molecularweight PEI polymers with lower toxicity87 Additionallypluronics that are block copolymers of ethylene glycol-propylene glycol-ethylene glycol can be used instead ofPEG Similar to PEG pluronics were shown to improvethe biocompatibility and bioavailability of the nanocarri-ers but they interact better with the cell membrane due tothe propylene glycol units and enhance cellular uptake ofthe particles87
PLGAPLGA is a biodegradable copolymer of glycolic acid andlactic acid96 It is widely used in biomedical research asan FDA-approved substance PLGA offers several advan-tages The polymer is highly stable biodegradable andallows sustained release During nucleic acid deliveryPLGA is easily taken up by cells through endocytosisand no serious toxicity problems were observed97 PLGAbinds nucleic acids weakly but it might encapsulate themfor drug delivery purposes Indeed PLGA nanoparticleswere used in several studies for delivery of drugs totumors through the EPR effects98 Yet following endocyto-sis PLGA particles do not effectively realease cargo fromendosomes8397 To overcome nucleic acid binding deliv-ery and endosomal release problems the surface of PLGAcan be decorated with various cationic nanoparticles suchas DOTAP PEI or polyamine and may be conjugated topeptides and antibodies99
DendrimersDendrimers are tree-like highly branched generally sym-metrical and three-dimensional macromolecules Theyhave uniform size and molecular weight which increaseswith each new branch (generation) Dendrimers possess ahighly functional outer surface allowing chemical modi-fications and interactions Therefore they may be used asflexible and modifiable gene delivery agents100 Besidesthe ability of dendrimers to encapsulate cargos add to theirpotential as drug carriers101 Dendrimers including poly-amidoamine dendrimers (PAMAM) poly-propylene imine(PPI) dendrimers poly-L-lysine dendrimers triazine den-drimers carbosilane dendrimers poly-glycerol-based den-drimers nanocarbon-based dendrimers and others weretested as RNAi delivery agents PAMAM and PPI den-drimers being the most commonly studied ones It wasshown that introduction of surface-modifications mini-mized toxicity-related problems increased RNAi-bindingand cellular uptake efficacies of the dendrimers102103
Of note in vivo gene expression changes were alsoobserved with drug-free dendrimers104 Therefore well
J Biomed Nanotechnol 10 1751ndash1783 2014 1759
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
controlled experiments are needed before drawing conclu-sions during RNA interference studies
AtelocollagenAtelocollagen is an organic protein-based moleculederived from type I collagen of calf dermis Sinceit is obtained following a pepsin treatment atelocolla-gen is devoid of telopeptides that are responsible forthe immunogenicity of collagen105 Moreover atelocol-lagen has low toxicity it was shown to stabilize RNAmolecules Increased cellular uptake and sustained deliv-ery was observed in in vivo making atelocollagen an idealagent for gene delivery106 Indeed several studies used ate-locollagen with success for the systemic or local deliveryof RNAi in tumor models107ndash109
ChitosanChitosan is obtained through alkaline deacetylation of thepolysaccharide chitin that forms the exoskeleton of crus-taceans some anthropods and insects Chitosan that is usedin biomedical research is a copolymer of N -acetyl-D-glucosamine and D-glucosamine having a positive chargeIn addition to being biodegradable and biocompatible chi-tosan has a low production cost Mucoadhesive propertiesof chitosan allow the penetration of the substance intoepithelial cell layers including the gastrointestinal barri-ers Nucleic acid encapsulation and sustained release wasproved to be possible using chitosan110ndash112 Moreover chi-tosan prolongs transient time in bowel improving par-enteral drug bioavailability113 Nanoparticles of chitosanare taken up into cells through endocytosis to a cer-tain extent To improve gene delivery efficacies PEG ordeoxycholic acid conjugates or modifications includingtrimethylation thiolation galactosylation may be intro-duced to chitosan111 Moreover chitosan-based carrierspossess functional groups that are suitable for conjugationto ligands relevant for targeted tumor delivery Althoughinefficient endosomal escape is a problem encounteredwith chitosan-based carriers some chemically modifiedforms showed improved escape properties114
CyclodextrinsCyclodextrins are natural polymers They are cyclicoligosaccharides of a glucopyranose generated during thebacterial digestion of cellulose Their central cavity ishydrophobic while the outer surface is a hydrophilicand they can create water-soluble molecular complexes115
Native cyclodextrins do not form stable complexeswith nucleic acids But the DNARNA complex for-mation capacities of the molecule can be modulatedand improved through molecular modifications includ-ing changes in functional groups hydrophilic-hydrophobicbalance charge density spacer length and conjugation toother carrier molecules115116 Cyclodextrins are not onlybiocompatible but they have the capacity to decrease
cytotoxicity of other molecules and carriers that are conju-gated to them117 Moreover cyclodextrins increase cellularadsorption and intake of molecules118 So in addition totheir use as a gene delivery agents cyclodextrins are usedas linking agents or structural modifiers in complex car-rier molecules For example conjugation of cyclodextrinto PEI resulted in lower toxicity and higher transfectionefficiencies119 In addition to the advantages cited abovea cyclodextrin polycation delivery system was reportedto block immune reactions raised against small RNAsthrough a masking effect120121 Importantly studies innon-human primates revealed that cyclodextrin-based car-riers were well tolerated and they do not stimulate signif-icant antibody responses120
AptamersAptamers are nucleic acid-based molecules selectedin vitro according to their capacity to bind target moleculesspecifically and with high affinity The immunogenicity ofaptamers is limited due to chemical modifications min-imizing adverse reactions Moreover nucleic acid natureand small size of aptamers result in improved transport andtissue penetration Since they can be specifically designedaccording to cell or tissue types (eg tumor cell com-ponents) side effects and off-target effects are minimalIn gene therapy applications the nucleic acid nature ofaptamers allows easy conjugation to RNADNA combin-ing targeting advantages with a therapeutic potential122
Alternatively non-covalent adapter linkages might be cre-ated between aptamers and RNA molecules Functionalgroups might be added to the 5prime- or 3prime-termini allowingcovalent or non-covalent conjugation of aptamers to carriernanoparticles123
Inorganic ParticlesInorganic nanoparticals such as carbon nanotubes mag-netic nanoparticles quantum dots and silica are the focusof recent efforts in drug and gene delivery Many of theseparticles actually offer the opportunity to combine imag-ing and therapeutic possibilities in the same particle ren-dering the nanocarrier a valuable ldquotheranosticrdquo device124
Increased surfacevolume ratio of inorganic particles pro-vides an opportunity for surface modifications includingconjugations to drugs oligonucleotides targeting peptidesor other molecules125126 Yet inorganic nanoparticles tendto aggregate and the size of the aggregate might have animpact on its function and biodistribution Such inorganicnanoparticles are hence coated with organic moleculeswhich provide colloid formation in aqueous and physiolog-ical media and stability Nature of the organic coatings hasto be designed for specific purposes but biocompatibilityof the organic molecules themselves andor their degra-dation products are critical for drug delivery purposes126
Chemistry of the coating might influence the half-life inblood and biodistribution as well as the toxicity of inor-ganic nanoparticles and their clearance mechanisms
1760 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Depending on the material they consist of inorganicnanoparticles may possess a number of different propertiessuch as high electron density and strong optical absorption(eg metal particles in particular Au) photoluminescenceor fluorescence (semiconductor quantum dots eg CdSeCdTe CdTeSeZnS) phosphorescence (doped oxide mate-rials eg Y2O3) or magnetic moment (eg iron oxide orcobalt nanoparticles) The shape of the nanoparticle is alsoan important factor influencing its interaction with cellsMany of the above mentioned nanoparticle are sphericalin shape except carbon nanotubes that are tubular
Carbon NanotubesCarbon nanotubes (CNTs) easily cross the plasma mem-brane and translocate directly into the cytoplasm of tar-get cells due to their nanoneedle structure and usingan endocytosis-independent mechanism yet they do notinduce cell death127ndash129 CNTs are classified as single-walled CNTs and multiwalled CNTs Single or multiplegraphine layer(s) might have a length ranging from 50 nmto 100 mm and a diameter of 1 nm to 100 nm Properfunctionalizing of CNTs by covalent or non-covalentstrategies (such as coating with PEG or Tween-20) mayprovide solubility in aqueous solutions and prevent non-specific interactions thus minimizing toxicity observedwith non-functionalized raw particles130131 Modificationsmight also increase biocompatibility and blood circulationhalf-life132133 CNTs have very strong absorption charac-teristics providing an opportunity for photothermal abla-tion therapy in addition to nanocarrier properties
Magnetic NanoparticlesMagnetic nanoparticles are composed of ferromagneticelements such as Ni Co Mn Fe Superparamagneticiron oxide nanoparticles (SPIONS) such as maghemite--Fe2O3 and magnetite-Fe3O4 are one of the most widelyused magnetic particles as nanocarriers due to relativelylow cost of production biocompatability and superpara-magnetic nature134135 SPIONS are approved by FDA forclinical trials They are commonly used as contrast agentsfor magnetic resonance imaging (MRI) SPION crystals(less than 10 nm in diameter) are coated for specificpurposes with organic molecules such as dextran aminodextran BSA PEI dendrimers lipids and trialkoxysi-lanes including aminopropyltriethoxy silane (APTES)Coating chemistry and preparation methods influence over-all hydrodynamic size pharmacokinetics and the contrasttype (dark-T 2 or bright-T 1 agent) Ability to track the fateof nucleic acid carrier magnetic nanoparticles in vivo usingMRI is highly desirable since it provides informationabout the location of the cargo and its biodistribution136
Attachment of ligands provides target specificity andPEGylation may improve biocompatibility and blood half-life These modifications are commonly introduced to SPI-ONs that are used for imaging and therapy purposes Due
to their magnetic nature drug or nucleic acid carrying SPI-ONs can be concentrated at desired diseased sites such astumors and they may be dragged magnetically towards thelesion area136137 Moreover magnetic nanoparticles offerthe possibility of hyperthermia treatment as a result ofmagnetic heating135 Under applied alternating magneticfield SPIONs cause local temperature increase (41ndash42 C)which may be exploited for alternative and efficient cancertherapy Therefore SPIONs are one of the most versatileand multifunctional nanoparticles Consequently SPIONswere used as popular gene delivery vehicles135
Magnetic nanoparticles may be engineered for oligonu-cleotide delivery purposes MRI visible PEI-PEG coatedSPIONs which are tagged with an antibody have beenshown to effectively carry siRNA to cancer cell lines andshowed low toxicity138 SPIONs coated with both thermoresponsive and cationic polymers such as poly[2-(2-methoxyethoxy)ethylmethacrylate]-b-poly-[2-(dimethyl-amino)ethyl methacrylate] were reported to have25ndash100 times better transfection efficiency than branchedPEI 25 kDa when coupled with magnetic targeting139
SPIONs coated with low molecular weight PEI(12ndash2 kDa) which is usually not effective as poly-plexes in transfection were shown succesful in deliveringsiRNA to mouse macrophages (H Yagci Acar WIPOPatent WO2006055447A3) Therefore magnetic nanpar-ticles are under heavy investigation for the developmentof multifunctional nanocarriers for cancer therapy anddiagnosis135
Quantum DotsSemiconductor quantum dots (QDs) are light-emittingnanoparticles of few nanometer in diameter and they havebeen increasingly used as biological imaging and labelingprobes140 Luminescencefluorescence properties of QDsdepend on the crystal size and type Chemical composi-tion of the crystalline semiconductor core determines theband gap of the material therefore the emission wave-length range Within possible spectral window size ofthe crystal determines the specific wavelength of lumines-cencefluorescence for each and every QD due to quan-tum confinement effect Broad absorption of QDs allowexcitation of multiple QDs at a single wavelength andminimal signal mixing due to the narrow emission bandIn addition they are much more resistant to photobleach-ing These two characteristics are the major advantages ofQDs compared to organic fluorophores as imaging probesUtilization of QDs in nucleic acid delivery aims bothimaging and therapy since in vivo localization of cargocan be observed using optical imaging systems141142 Forexample cationic CdTeZnS QDs conjugated with PEGwas demonstrated to form an effective nanoplex with sur-vivin siRNA and successfully transfeced human tonguecancer cells in vitro and provided real time tracking143
However well-established QDs harbour significant toxic-ity due to constituents such as Cd Se Te144 Therefore
J Biomed Nanotechnol 10 1751ndash1783 2014 1761
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
toxicity of these QDs is a drawback for their use in vivoAs an alternative silver (Ag) chalcogenites emerged assafer near-infra red-emitting QDs145146 Ag2S QDs did notinduce cytotoxicity ROS production apoptosis necrosisor DNA damage147 For example Ag2S QDs (coated with2-mercaptopropionic acid) emitting between 750ndash850 nmshowed no cytotoxicity in NIH3T3 cells at even highdoses (600 mgml) along with good cellular imagingpotential148
Gold NanoparticlesGold nanoparticles emerged as popular tools fornanocarrier-mediated gene therapy149 They are easily syn-thesized and biocompatible particles that allow addition offunctional molecules on their surface due to high surface-to-volume ratio114150 A variety of surface changes andfunctional additions were reported including cationic lipidcoating branched PEI addition or functionalization usingcationic quaternary ammonium or cystamine114151152
Indeed cystamine functionalized gold nanoparticles wereshown to effectively bind deliver and release 35 differ-ent miRNA in in vitro studies using neuroblastoma andovarian cancer cell lines153
Silica NanoparticlesSilica-based nanoparticles are inert stable biocompati-ble and biodegradable particles154 They can be renderedhydrophilic hydrophobic anionic or cationic using func-tional surface modifiers through electrostatic interactionsor by formation of any other type covalent bonds (egester amine) Common functionalization strategies to ren-der the molecule cationic and improve nucleic acid bind-ing include grafting of molecules such as PEI PEI-PEGand Poly-L-arginine155 Nucleic acids may also be loadedinside the mesoporous silica particles156 siRNA encapsu-lating mesoporous silica nanoparticles were successfullyused for in vitro and in vivo gene silencing in several stud-ies (For example Ref [156])
RECENT IN VIVO STUDIES USING RNAINTERFERENCE IN CANCER THERAPYThere is an exponential increase in the number of scientificpublications dedicated to gene therapy of diseases usingsmall RNAs and nanoparticles A literature search usingldquonanoparticlerdquo and ldquosiRNA shRNA or miRNArdquo revealedmore than 700 articles published in the last two yearsThis number is roughly equal to the number of all articlespublished in this field until two years ago So the field isexpanding and there seems to form a consensus aroundthe use of nanoparticles as next generation gene therapytools We believe that these high expectations are not onlya consequence of shifting trends in science and technol-ogy The exponential rise in interest in the field of smallRNA carrier nanoparticles is fueled by the advances inthe field of nano materials promising results obtained in
small RNA therapeutics by both academic laboratories andindustry and increasing number of successful clinical tri-als In this section we will summarize results of selectedrecent studies using RNA therapeutics for cancer treatmentin preclinical in vivo experimentsOverview of the works dealing with small RNA treat-
ment of experimental cancers and published within thelast two years were summarized in Table I Although sev-eral studies were performed using lipid-based nanopar-ticles (Liposomes micelles or lipidoids) other particlessuch as polymers organic or inorganic carriers and com-pounds mixtures with functional modifications of vari-able substances were also tested by many research teamswith reasonable success Scheme 4 summarizes the generalstrategy followed in most of these studies
Tumor Types and RNAi TherapyRecent studies in the literature showed that tumors of vari-ous tissue origins could be treated using RNA interferencestrategies (Table I) Fine tuning of nanoparticles throughaddition of functional moieties or modifications alloweddelivery of drugs into almost any kind of tumor tissue withaccompanied therapeutic effects Although several studiesused animal tumor models that resulted from the injectionof cell lines from most commonly seen human cancers(lung breast prostate cervix or ovarian cancer cell lines)animals with kidney urinary bladder head and neckgastric pancreatic melanomas neuroblastomas glioblas-tomas multiple myelomas or sarcomas were also treatedwith RNAinanocarrier strategy81156ndash170 These results givehope about the general use of RNA interference as astrategy to treat cancers of different origins Althoughit is difficult to compare the efficacies of different nucleicacid molecules and their interference effects at this pointsiRNA or microRNAs as well as shRNA vectors wereshown to achieve intratumoral in vivo target gene knock-down and anticancer effects leading to a decrease in tumorsize (For example Refs [156 171]) Since in most studiesin addition to RNAi loaded particles naked nanoparticlesor particles loaded with non-specific control nucleic acidswere also used antitumor effects obtained in these studiesare specific and they may be attributable to small RNAmolecules rather than the particles themselves underliningthe potential of RNA interference in cancer treatmentMajority of recent studies with in vivo models chose
to use human tumor cell line xenografts in immune com-promised mice nude or severe-combined immuno defi-cient SCID mice (Table I) (For example Refs [162 172])Syngeneic transplants and established genetically engi-neered mouse models of cancer were rarely studied in thiscontext167173ndash175 Therefore although antitumor effects andsome of the toxic effects (eg liver toxicity) might berevealed using immune compromised mice hematologicalimmunological and inflammatory side effects of the treat-ment strategies used in recent studies might need to berevisited using immunocompetent mice
1762 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IRec
entstudieswithRNAica
rryingnan
oparticles
forthetrea
tmen
tofex
perim
entalca
nce
rs(P
ublis
hed
within
thelast
twoye
ars)
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGF
Mag
netic
mes
oporou
ssilicana
nopa
rticles
PEIan
dfuso
genicpe
ptide
KALA
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[156
]
siRNA
Polo-likekina
se1(P
LK1)
pH-sen
sitiveca
tioniclip
idYSK05
-MEND
(YSK05
POPEcho
lesterol
=50
2525
)
PEG
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
PLK
1[51]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Bioen
gine
ered
bacterial
outermem
bran
eve
sicles
Hum
anep
idermal
grow
thfactor
rece
ptor
2(H
ER2)-spe
cific
affib
ody
targeting
HCC-195
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
KSP
Dec
reas
edtumor
volume
[81]
siRNA
Luciferase
Dioleoy
lpho
spha
tidic
acid-(DOPA
-)co
ated
nano
-sized
calcium
phos
phate(LCP-II)
DSPE-P
EG-an
dan
isam
idefortargeting
sigm
a-1rece
ptor
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
Xen
ograft
it
ND
Kno
ckdo
wnof
luciferase
[211
]
siRNA
mTERT
N-((2-hyd
roxy
-3-trim
ethy
l-am
mon
ium)propy
l)ch
itosa
nch
lorid
e(H
TCC)na
nopa
rticles
Partic
leload
edwith
paclita
xel
LCC
murinelung
canc
erce
llssy
ngen
eicsc
graft
oral
Noeffect
Kno
ckdo
wnof
mTERT
Dec
reas
edtumor
volume
Syn
ergize
dwith
paclita
xel
[159
]
siRNA
VEGF
Multilay
ered
polyion
complexes
Polyc
ationinterla
yeran
dade
tach
able
PEG
shell
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
[212
]
siRNA
Multid
rug
resistan
ceprotein1
(MRP1)
Nan
opartic
lesas
sembled
vialaye
r-by
laye
rde
positio
nof
siRNA
and
poly-L-arginine
Hya
lurona
n(H
A)co
ating
forHA-C
D44
targeting
MDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
it
Noeffect
Kno
ckdo
wnof
MRP1
Dec
reas
edtumor
volume
[183
]
siRNA
STA
T3-a
Nan
oporou
ssilicon
nano
particles
Argininean
dPEI
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicefat
padxe
nograft
iv
Noeffect
Kno
ckdo
wnof
STA
T3-a
[204
]
siRNA
Luciferase
Lipo
somal
nano
particle
Fou
rtand
emrepe
atsof
human
histon
eH2A
peptideinterven
edby
cathep
sinD
clea
vage
sites
PEG-A
nisa
mide
fortargeting
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
luciferase
[199
]
siRNA
Polo-likekina
se1(P
LK1)
Hya
luronicac
id(H
A)
base
dse
lfass
embling
HA-P
EIP
EG
nano
system
s
Hya
lurona
nforCD44
targeting
B16
F10
amurine
melan
omace
llsA54
9-luchu
man
lung
canc
erce
llsHep
3Bhu
man
liver
canc
erce
llsMDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
graftor
metas
tatic
lung
lesion
sby
IVinjection
it
ND
Kno
ckdo
wnof
PLK
1[160
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1763
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
P-glyco
protein
drug
expo
rter
(P-
gpM
DR1)
Mes
oporou
ssilica
nano
particles
Polye
thylen
eimine
polyethy
lene
glyc
ol(P
EI-PEG)co
polymer
MCF-7M
DR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gpMDR1
Dec
reas
edtumor
volume
Syn
ergy
with
doxo
rubicin
[179
]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Multifun
ctiona
lcarrie
rsy
stem
with
catio
nic
(olig
oethan
amino)am
ide
core
attach
edto
PEG
chain
Folic
acid
fortargeting
Inf7
(Infl
uenz
ape
ptide)
asen
doso
molytic
peptide
coup
ledto
the5prime-end
ofsiRNA
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
itor
iv
ND
Kno
ckdo
wnof
EG5
Dec
reas
edtumor
volume
[161
]
siRNA
Epide
rmal
Growth
Factor
Rec
eptor
(EGFR)
Poly-L-argininean
dde
xtransu
lfate-bas
edna
noco
mplex
FaDuhu
man
pharyn
xsq
uamou
sca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[172
]
siRNA
Cho
line
kina
se(C
hk)
Polye
thylen
imine-
polyethy
lene
glyc
ol(P
EI-PEG)co
grafted
polymer
Con
versionof
nontox
ic5-flu
oroc
ytos
ine(5-FC)to
cytotoxic5-flu
orou
racil
(5-FU)by
activating
bacterialc
ytos
ine
deam
inas
e(bCD)
PC3-PIP
andPC3-Flu
human
pros
tate
canc
erce
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
e[157
]
siRNA
Polo-like
kina
se1
(Plk1)
Cationiclip
idpo
lymer
hybrid
nano
particles
(cationiclip
id(N
N-
bis(2-hy
drox
yethyl)-N-
methy
l-N-(2-
choles
teryloxy
carbon
ylam
inoe
thyl)am
mon
ium
brom
ide
BHEM-C
hol)
andam
phiphilic
polymers(H
ydroph
obic
polylactideco
re)
PEG
shell
BT47
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Plk1
Dec
reas
edtumor
volume
[213
]
siRNA
hTERT
Single-walledca
rbon
nano
tube
s(S
WNTs)
Branc
hedPEIco
njug
ated
DSPE-P
EG20
00-M
aleimide
forco
njug
ationwith
NGR
(Cys
-Asn
-Gly-A
rg-C
ys-)
targetingpe
ptide(rec
ognize
tumor
neov
ascu
lature)
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
hTERT
Dec
reas
edtumor
volume
Syn
ergy
with
photothe
rmal
trea
tmen
t
[139
]
1764 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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146 G Hong J T Robinson Y Zhang S Diao A L AntarisQ Wang and H Dai In vivo fluorescence imaging with Ag2Squantum dots in the second near-infrared region Angew Chem IntEd Engl 51 9818 (2012)
147 Y Zhang G Hong G Chen F Li H Dai and Q Wang Ag2Squantum dot A bright and biocompatible fluorescent nanoprobe inthe second near-infrared window ACS Nano 6 3695 (2012)
148 I Hocaoglu M N Ccedilizmeciyan R Erdem C Ozen A KurtA Sennaroglu and H Y Acar Development of highly luminescentand cytocompatible near-IR-emitting aqueous Ag2S quantum dotsJ Mater Chem 22 14674 (2012)
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152 W H Kong K H Bae S D Jo J S Kim and T G Park Cationiclipid-coated gold nanoparticles as efficient and non-cytotoxic intra-cellular siRNA delivery vehicles Pharm Res 29 362 (2012)
153 R Ghosh L C Singh J M Shohet and P H Gunaratne A goldnanoparticle platform for the delivery of functional microRNAs intocancer cells Biomaterials 34 807 (2013)
154 A Bitar N M Ahmad H Fessi and A Elaissari Silica-basednanoparticles for biomedical applications Drug Discov Today17 1147 (2012)
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
155 H Lee D Sung M Veerapandian K Yun and S W Seo PEGy-lated polyethyleneimine grafted silica nanoparticles Enhanced cel-lular uptake and efficient siRNA delivery Anal Bioanal Chem400 535 (2011)
156 X Li Y Chen M Wang Y Ma W Xia and H Gu A mesoporoussilica nanoparticlendashPEIndashfusogenic peptide system for siRNA deliv-ery in cancer therapy Biomaterials 34 1391 (2013)
157 Z Chen M F Penet S Nimmagadda C Li S R Banerjee P TWinnard Jr D Artemov K Glunde M G Pomper and Z MBhujwalla PSMA-targeted theranostic nanoplex for prostate cancertherapy ACS Nano 6 7752 (2012)
158 F Haque D Shu Y Shu L S Shlyakhtenko P G RychahouB M Evers and P Guo Ultrastable synergistic tetravalent RNAnanoparticles for targeting to cancers Nano Today 7 245 (2012)
159 W Wei P P Lv X M Chen Z G Yue Q Fu S Y Liu H Yueand G H Ma Codelivery of mTERT siRNA and paclitaxel bychitosan-based nanoparticles promoted synergistic tumor suppres-sion Biomaterials 34 3912 (2013)
160 S Ganesh A K Iyer D V Morrissey and M M AmijiHyaluronic acid based self-assembling nanosystems for CD44 tar-get mediated siRNA delivery to solid tumors Biomaterials 34 3489(2013)
161 C Dohmen D Edinger T Frohlich L Schreiner U LacheltC Troiber J Radler P Hadwiger H P Vornlocher and E WagnerNanosized multifunctional polyplexes for receptor-mediated siRNAdelivery ACS Nano 6 5198 (2012)
162 S A Jensen E S Day C H Ko L A Hurley J P LucianoF M Kouri T J Merkel A J Luthi P C Patel J I Cutler W LDaniel A W Scott M W Rotz T J Meade D A GiljohannC A Mirkin and A H Stegh Spherical nucleic acid nanoparticleconjugates as an RNAi-based therapy for glioblastoma Sci TranslMed 5 209ra152 (2013)
163 H Arima A Yoshimatsu H Ikeda A Ohyama K MotoyamaT Higashi A Tsuchiya T Niidome Y Katayama K Hattoriand T Takeuchi Folate-PEG-appended dendrimer conjugate withalpha-cyclodextrin as a novel cancer cell-selective siRNA deliverycarrier Mol Pharm 9 2591 (2012)
164 J Wei T Cheang B Tang H Xia Z Xing Z Chen Y FangW Chen A Xu S Wang and J Luo The inhibition of humanbladder cancer growth by calcium carbonateCaIP6 nanocompositeparticles delivering AIB1 siRNA Biomaterials 34 1246 (2013)
165 T Kanazawa K Sugawara K Tanaka S Horiuchi Y Takashimaand H Okada Suppression of tumor growth by systemic delivery ofanti-VEGF siRNA with cell-penetrating peptide-modified MPEG-PCL nanomicelles Eur J Pharm Biopharm 81 470 (2012)
166 M A Rahman A R Amin X Wang J E Zuckerman C HChoi B Zhou D Wang S Nannapaneni L Koenig Z ChenZ G Chen Y Yen M E Davis and D M Shin Systemic deliveryof siRNA nanoparticles targeting RRM2 suppresses head and necktumor growth J Control Release 159 384 (2012)
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168 M Shen F Gong P Pang K Zhu X Meng C Wu J WangH Shan and X Shuai An MRI-visible non-viral vector for tar-geted Bcl-2 siRNA delivery to neuroblastoma Int J Nanomedicine7 3319 (2012)
169 D Lin Q Jiang Q Cheng Y Huang P Huang S Han S GuoZ Liang and A Dong Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and invivo siRNA delivery Acta Biomater 9 7746 (2013)
170 L Zou X Song T Yi S Li H Deng X Chen Z Li Y BaiQ Zhong Y Wei and X Zhao Administration of PLGA nanopar-ticles carrying shRNA against focal adhesion kinase and CD44results in enhanced antitumor effects against ovarian cancer CancerGene Ther 20 242 (2013)
171 T Yin P Wang J Li R Zheng B Zheng D Cheng R Li J Laiand X Shuai Ultrasound-sensitive siRNA-loaded nanobubblesformed by hetero-assembly of polymeric micelles and liposomesand their therapeutic effect in gliomas Biomaterials 34 4532(2013)
172 H J Cho S Chong S J Chung C K Shim and D D Kim Poly-L-arginine and dextran sulfate-based nanocomplex for epidermalgrowth factor receptor (EGFR) siRNA delivery Its application forhead and neck cancer treatment Pharm Res 29 1007 (2012)
173 F Abedini H Hosseinkhani M Ismail A J Domb A R OmarP P Chong P D Hong D S Yu and I Y Farber Cationizeddextran nanoparticle-encapsulated CXCR4-siRNA enhanced corre-lation between CXCR4 expression and serum alkaline phosphatasein a mouse model of colorectal cancer Int J Nanomedicine 7 4159(2012)
174 F Yang W Huang Y Li S Liu M Jin Y Wang L Jia andZ Gao Anti-tumor effects in mice induced by survivin-targetedsiRNA delivered through polysaccharide nanoparticles Biomateri-als 34 5689 (2013)
175 L Chen Y Ding Y Wang X Liu R Babu W Ravis and W YanCodelivery of zoledronic acid and doublestranded RNA from corendashshell nanoparticles Int J Nanomedicine 8 137 (2013)
176 H Jagani J V Rao V R Palanimuthu R C Hariharapura andS Gang A nanoformulation of siRNA and its role in cancer ther-apy In vitro and in vivo evaluation Cell Mol Biol Lett 18 120(2013)
177 L A Tobin Y Xie M Tsokos S I Chung A A Merz M AArnold G Li H L Malech and K F Kwong Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of can-cer cell internalization in vivo Biomaterials 34 2980 (2013)
178 J Shen H Sun P Xu Q Yin Z Zhang S Wang H Yu and Y LiSimultaneous inhibition of metastasis and growth of breast cancerby co-delivery of twist shRNA and paclitaxel using pluronic P85-PEITPGS complex nanoparticles Biomaterials 34 1581 (2013)
179 H Meng W X Mai H Zhang M Xue T Xia S Lin X WangY Zhao Z Ji J I Zink and A E Nel Codelivery of an optimaldrugsiRNA combination using mesoporous silica nanoparticles toovercome drug resistance in breast cancer in vitro and in vivo ACSNano 7 994 (2013)
180 C Zheng M Zheng P Gong J Deng H Yi P Zhang Y ZhangP Liu Y Ma and L Cai Polypeptide cationic micelles mediatedco-delivery of docetaxel and siRNA for synergistic tumor therapyBiomaterials 34 3431 (2013)
181 Q Hu W Li X Hu J Shen X Jin J Zhou G Tang and P KChu Synergistic treatment of ovarian cancer by co-delivery of sur-vivin shRNA and paclitaxel via supramolecular micellar assemblyBiomaterials 33 6580 (2012)
182 Y H Yu E Kim D E Park G Shim S Lee Y B KimC W Kim and Y K Oh Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA Eur J Pharm Biopharm 80 268(2012)
183 Z J Deng S W Morton E Ben-Akiva E C Dreaden K EShopsowitz and P T Hammond Layer-by-layer nanoparticles forsystemic codelivery of an anticancer drug and siRNA for potentialtriple-negative breast cancer treatment ACS Nano 7 9571 (2013)
184 X Q Liu M H Xiong X T Shu R Z Tang and J WangTherapeutic delivery of siRNA silencing HIF-1 alpha with micellarnanoparticles inhibits hypoxic tumor growth Mol Pharm 9 2863(2012)
185 J Xiao X Duan Q Yin Z Miao H Yu C Chen Z ZhangJ Wang and Y Li The inhibition of metastasis and growth ofbreast cancer by blocking the NF-kappaB signaling pathway usingbioreducible PEI-basedp65 shRNA complex nanoparticles Bioma-terials 34 5381 (2013)
186 R J Christie Y Matsumoto K Miyata T Nomoto S FukushimaK Osada J Halnaut F Pittella H J Kim N Nishiyama and
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
187 S Ganesh A K Iyer F Gattacceca D V Morrissey and M MAmiji In vivo biodistribution of siRNA and cisplatin adminis-tered using CD44-targeted hyaluronic acid nanoparticles J ControlRelease 172 699 (2013)
188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and effectively deliver RNA molecules to cancer cells andtumors Therefore they have to be biocompatible notimmunogenic and they should not get modified or dis-solved into toxic substances under biological conditionsand before reaching the tumor target For effective deliv-ery and dosage nano conjugates have to be stable enoughin the blood circulation and resist shear forces proteasesand nucleases that they face with Complex formation withblood cells proteins and other blood components mightalso affect carrier size charge availability and efficacyClearance is also an important issue For nanocarriers
to reach therapeutic blood levels they should not be read-ily cleared through glomerular filtration in the kidneys ortrapped by the reticuloendothelial system For examplenaked siRNA molecules and nanoparticles less than 10 nmmay be filtrered and excreted through kidneys follow-ing systemic administration Carriers larger than 100 nmmight be phagocytosed and cleared by monocytes andmacrophages residing in the reticuloendothelial system(RES also called mononuclear phagocytic system) tissueswith high blood supply including pulmonary alveoli liversinusoids skin spleen etc32ndash36 In addition to the size of thenanoparticles their geometries surface charges hydropho-bicities and opsonization by serum proteins might affectclearance by monocytes and macrophages Additionallythe efficacy of nucleic acid drugs in specific tissues andorgans may depend on the ability of nanocarriers to pene-trate blood vessels and tissues and pass through biologicalbarriers such as the tight blood-brain-barrier of the centralnervous systemFor cancer treatment small RNA drugs should affect
genetic andor molecular changes specific to cancer cellsand that are rate-limiting for tumor growth The idealnanocarrier should be able to concentrate within the tumortissue and if possible target individual tumor cells in aselective way (eg through receptors or molecules thatare tumor-specific or that are enriched in the tumor tis-sue) and not penetrate normal cells Enhanced permeabilityand retention (EPR) effect offers an advantage for solid-tumor targeting The EPR effect is a result of neovascu-larisation new blood vessel formation to feed tumors withsizes beyond passive oxygen and nutrient diffusion lim-its (beyond 01ndash02 mm diameter)37 Blood vessels feed-ing tumor tissues are irregular and highly permeable Withthe lack of lymphatic drainage macromolecules are eas-ily retained in and around the tumor area3839 For exam-ple low molecular weight drugs may diffuse freely inand out of the tumor tissues but macromolecules (gt 40kDa) and nanoparticles of 100ndash200 nm accumulate inthe tumor tissue3840ndash43 EPR phenomenon was reported invarious human solid tumors as well as in inflammatorytissues44
Different types of nanoparticles were tested as drug car-riers and gene therapy tools (Scheme 2) The core structureof the particle may be a vesicle (liposomes) a polymer(eg PEI PLGA) a dendrimer carbon nanotubes silica or
metal nanoparticles (eg Gold) Porousvesiculate carrierssuch as liposomes polymeric micelles or some inorganicparticles (eg mesoporous silica) may encapsulate orabsorb RNADNA molecules Nanocarriers with a cationicnature including cationic liposomes cationic dendrimers(eg PAMAM) and polymers (eg PEI PDMAEMA) orcationic polymer coated inorganic particles (eg PEI cov-ered iron oxide) may form complexes through electro-static interactions with the negatively charged backboneof nucleic acids The nature and physico-chemical proper-ties of the nanoparticles may also influence their stabilityand half-life in blood criculation efficacy of their deliveryinto tissues and cells and their capacity to escape fromendosomes in the cell All these properties are determiningcriteria for nano drug efficacyTo improve stability RNADNA loading target speci-
ficity tracking cellular internalization endo-lysosomalescape and intracellular robustness additional functionalunits might be introduced to the basic structure ofthe nanocarriers (Scheme 3)45 Possible modificationsand changes include conjugation to proteins (antibodieslectins cytokines thrombin fibrinogen BSA transfer-rin) cellular or viral peptides (eg RGD LHRD TATPep-3 KALA) polysaccharides (eg lipopolysaccharideshyaluronic acid dextran chitosan) low molecular weightligands (eg folic acid anisamide) and polyunsaturatedfatty acids (eg palmitic acid and phospholipids) Thesestructures can be conjugated onto the nanocarrier surfacethough hydrolysable or non-hydrolysable chemical bondsand modifications such as amide ester silane hydrazoneor through the use of high avidity molecules such asavidin-biotin Fluorophores may also be added for par-ticle tracking purposes To improve the availability ofsuch groups and especially the targeting groups spacermolecules may be addedAn important modification relevant for biological func-
tion is ldquoPEGylationrdquo (Scheme 3)45 PEG coordinateswater molecules and forms an aqueous shell aroundnanoparticles shielding their charges PEGylation reducesinteraction with serum proteins decreases opsoniza-tion and clearance of nanoparticles by RES monocyte-macrophages sterically prevent nanocarrier aggregationand due to increased molecular weight above the thresholdfor glomerular filtration reduces elimination of the parti-cles through urinary excretion Hence PEG increases thestability improves biocompatibility prolongs blood circu-lation time and bioavailability of nanocarriers4647 Molec-ular weight and density of PEG chains on the nanocarriersurface may impact the function depending on the natureof the carried molecules ie siRNA47
On the other hand PEGylation significantly attenu-ates uptake of nanocarriers by target cells4849 More-over PEG chains were shown to block endosomal escapeand cytosolic release of chemical drugs and nucleicacids50 Blockage of cellular uptake and endosomal releasein the cell may severely attenuate drug efficacy and
1756 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 2 Major types of nanoparticles used as nucleic acid carriers
therapeutic RNA interference effects Various strategieswere adapted to overcome these negative effects of PEGwhile exploiting its circulatory advantages Cleavage ofPEG-chains upon delivery into the tumor environment wasachieved through addition of tumor-related matrix met-alloproteinase sensitive lipids or peptides51 pH-sensitivelinkers between the PEG moiety and nanocarriers canalso be used to release PEG from the particle in theacidic environment of the endosomes and allow cytosolic
Scheme 3 A representative nanoparticle with functional modifications Various molecules might be added to a nanoparticleto improve its physico-chemical properties and pharmacokinetics (eg PEG) to increase RNADNA binding (eg PEI) to allowbetter targeting (eg antibodies) or tracking (eg fluorophores)
release of small RNAs Modulation of the hydrophobic-ity of the PEGndashnanocarrier conjugate was also testedas a release strategy In lipid-based nanocarriers thelength of the alkyl chain of the PEG-lipid anchor wasshown to determine its affinity for the lipid deliveryvehicle and changing its length modified endosomalescape potential and drug effects52 Cholesterol-anchoredPEG was also shown to improve endosomal escapecapacities52
J Biomed Nanotechnol 10 1751ndash1783 2014 1757
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
LiposomesLiposomes have been tested extensively as gene deliv-ery agents Liposomes are artificial membrane-boundvesicles formed by bilayers of amphipathic lipids Theymight be unilamellar or multilamellar Their biocom-patibility low toxicity and low immunogenicity madethem popular agents for both in vitro and in vivo genedelivery5354 Liposomes are typically made of mix-tures of lipids found in biological membranes or theirderivatives including phosphatidylcholine (PC or DOPC12-Oleoyl-sn-Glycero-3-phosphatidylcholine) phosphatidyl-ethanolamine (PE or DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidylethanolamine) cholesterol and evenceramide53 Although liposomes made of neutral lipids aremore biocompatible than cationic lipids and have betterpharmacokinetics during preparation of gene deliveryvectors they bind less to negatively charged DNA orRNA molecules and have lower entrapment efficiencies55
Therefore despite their more toxic nature cationic lipidsare commonly used as liposome-based transfection agentsCationic lipids posses positively charged headgroupssuch as amines quaternary ammonium salts peptidesaminoacids or guanidiniums which electrostaticly attractand bind to negatively charged phosphate residues innucleic acid backbones The nature of cationic lipid head-groups determines the efficacy of gene delivery Thereforevarious mixtures of lipids with different headgroupsand properties were tested to achieve optimal liposomeformulations for drug andor gene delivery56ndash59
Although liposomes are excellent transfection agentsin vitro some side effects and problems were encoun-tered during in vivo studies56ndash59 These include intracellu-lar instability and failure to release small RNA contentsdose-dependent toxicity and pulmonary inflammation thatcorrelated with the production of reactive oxygen species(ROS) opsonization by serum proteins immunogenic-ity and uptake by the RES components60ndash63 Addition-ally cationic liposome-dependent gene expression changeswere observed during in vitro experiments with someformulations64
In order to minimize such undesired effects special-ized liposomes were produced through addition of vari-ous functional groups PEGylation and crosslinking withinthe bilayer of the liposomes was successfully utilized toimprove stability and decrease side effects65 PEGylationin general improved bioavailability and biocompatibilityas well For example to obtain improved pharmacokinet-ics PEGylated cationic liposomes called ldquosolid nucleicacid lipid particlesrdquo (SNALPs) were created and they weresuccessfully used for siRNA delivery In fact in SNALPsPEG coating neutralized net charge and increased theblood circulation time of the liposomes significantly66ndash72
Moreover fusogenic lipids added to liposome formula-tions improved cellular uptake and endosomal escape33
Most importantly SNALPs were relatively well toler-ated in vivo even in non-human primates3233 The list of
modifiedimproved liposomes performing well in in vivostudies also includes cationic solidndashlipid nanoparticles andcardiolipin-based liposomes3373ndash75 Currently improvedliposomes are one of the most promising tools for genedelivery and patented formulations produced by sev-eral companies were successful enough to reach clinicaltrials31
LipidoidsLipidoids are cationic lipids that are created by the conju-gation of primary or secondary amines to alkyl-acrylatesor alkyl-acrylamides76 They were introduced as novelalternatives to liposome formulations used in gene deliv-ery Changes in the composition lipidoids were shown toimprove their therapeutic properties For example changesin the alkyl chain length of the PEG lipid was reportedto affect PEG deshielding rate and dose kinetics of lipi-doids in the blood76 Moreover cholesterol incorporationwas shown to improve carrier stability Small sized lipi-doids (50ndash60 nm) were successfully used for the deliveryof siRNA into liver cells avoiding engulfment by Kuppfercells76 Lipidoids may also be used for coating inorganicnanoparticles in order to introduce cationic charges77 Lipi-doids have lower toxicity and increased efficacy thereforethey present an alternative to classical liposomes for genedelivery studies
MinicellsMinicells are bacteria-derived non-living anucleatednano-sized vesicles that were used as nano drug carriers78
Inactivation of min genes that control normal division inbacteria such as Salmonella typhimurium result in the for-mation of minicells min gene products ensure that celldivision septum is correctly located to the midpoint ofthe cell In case of min gene product mutations septa-tion defects result in the formation of minicells devoid ofthe chromosomal DNA Therapeutic RNAs may be loadedinto minicells by the introduction of shRNA of interestinto min mutant bacteria and eventually shRNAs segregateinto minicells78 Purified minicells prepared by this methodare pre-packaged with effective copy numbers of the plas-mid For targeting purposes tumor-specific antibodies maybe decorated onto minicells by the exploitation of bac-terial cell surface components such as O-polysaccharideof LPS Minicell-RNAi combinations proved to be effec-tive in experimental cancer treatment79 Other cell derived-vesicles that were tested as nanocarriers include bacterialghosts bacterial outer membranes or mammalian cell-derived exosomes80ndash82
PolyplexesMaterials that self-assemble with nucleic acids intonanocomplexes are called ldquopolyplexesrdquo These complexesgenerally form though the electrostatic interaction of the
1758 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
cationic units of the polymers with the anionic phos-phate groups of the nucleic acids Natural and biocompat-ible (eg chitosan Atelocollagen cyclodextrin) or morefrequently synthetic (eg Polyethylenimine PEI poly-L-lysine PLL poly-dl-lactide-co-glycolide PLGA) poly-mers are used for polyplex formation83ndash86 Flexibility of thesynthetic polymers in terms of chemical nature molecularweight and architecture (linear branched grafted blocky)provide opportunity to balance their toxicity improvenucleic acid binding protection and release efficienciesMoreover surface modifications may be introduced for tar-geting purposes and improved pharmacodynamics Poly-mers such as PLGA also benefit from a biodegradablenature which allows clearance of the nanocarriers in time
PEIPEI is the most widely and most successfully used polyca-tion for polyplexe formation It can be synthesized in lin-ear or branched forms and in variable molecular weights(from 1 kDa to gt 1000 kDa) Higher molecular weightpolymers (70 kDa and above) are very effective in nucleicacid binding but they are significantly toxic Low molec-ular weight forms (2 kDa or less) are less toxic but theyare less effective as transfection agents87 Therefore PEIsat and below 25 kDa with a branched or linear architec-ture are commonly used as gene delivery reagents88ndash91 Thegolden standard gene delivery polymer is branched PEIof 25 kDa which offers a balance between the toxicitynucleic acid bindingprotection and release Abundance ofpositive charges due to protonation under physiologicalconditions allows PEI to spontaneously form complexeswith negatively charged small RNAs and DNAs and pro-tect nucleic acid molecules from nuclease attacks84 More-over buried inside the polymer some off-target effects ofthe small RNAs were shown to be prevented92
The net positive charge of PEI-RNAi complexes alsoallow interactions with the negatively charged polysaccha-rides found on the cell surface93 These interactions arebelieved to be an important factor for the endocytosis ofthe complexes by target cells A key event for the successof gene delivery is the escape of the nucleic acids fromthe endosomal pathway in order to avoid accumulation anddegradation in the lysosomes of the cell93 The escape isthought to be the result of the lsquoproton spongersquo effect wherethe influx of protons and water lead to endosome swellingrupture and release of contents including nucleic acids tothe cytosolPEI-induced toxicity was proposed to be a result of
mitochondrial apoptosis induction by the polymer9495
Moreover PEI itself was shown to cause changes in geneexpression in vivo which might influence biological out-comes of treatment protocols59 PEGylation of the PEIreduces both cytotoxicity of PEI-polyplexes and increaseblood circulation half-life However a critical balanceneed to be achieved since PEGylation decreases the sur-face charge it impacts the binding capacity and cell
internalization of the polyplexes Alternatively short PEIchains attached together with hydrolysable links such asdisulfide and ester may provide initially a high molecu-lar weight PEI system for good nucleic acid condensationand protection but upon dissolution because of intracel-lular redox conditions they may act as a low molecularweight PEI polymers with lower toxicity87 Additionallypluronics that are block copolymers of ethylene glycol-propylene glycol-ethylene glycol can be used instead ofPEG Similar to PEG pluronics were shown to improvethe biocompatibility and bioavailability of the nanocarri-ers but they interact better with the cell membrane due tothe propylene glycol units and enhance cellular uptake ofthe particles87
PLGAPLGA is a biodegradable copolymer of glycolic acid andlactic acid96 It is widely used in biomedical research asan FDA-approved substance PLGA offers several advan-tages The polymer is highly stable biodegradable andallows sustained release During nucleic acid deliveryPLGA is easily taken up by cells through endocytosisand no serious toxicity problems were observed97 PLGAbinds nucleic acids weakly but it might encapsulate themfor drug delivery purposes Indeed PLGA nanoparticleswere used in several studies for delivery of drugs totumors through the EPR effects98 Yet following endocyto-sis PLGA particles do not effectively realease cargo fromendosomes8397 To overcome nucleic acid binding deliv-ery and endosomal release problems the surface of PLGAcan be decorated with various cationic nanoparticles suchas DOTAP PEI or polyamine and may be conjugated topeptides and antibodies99
DendrimersDendrimers are tree-like highly branched generally sym-metrical and three-dimensional macromolecules Theyhave uniform size and molecular weight which increaseswith each new branch (generation) Dendrimers possess ahighly functional outer surface allowing chemical modi-fications and interactions Therefore they may be used asflexible and modifiable gene delivery agents100 Besidesthe ability of dendrimers to encapsulate cargos add to theirpotential as drug carriers101 Dendrimers including poly-amidoamine dendrimers (PAMAM) poly-propylene imine(PPI) dendrimers poly-L-lysine dendrimers triazine den-drimers carbosilane dendrimers poly-glycerol-based den-drimers nanocarbon-based dendrimers and others weretested as RNAi delivery agents PAMAM and PPI den-drimers being the most commonly studied ones It wasshown that introduction of surface-modifications mini-mized toxicity-related problems increased RNAi-bindingand cellular uptake efficacies of the dendrimers102103
Of note in vivo gene expression changes were alsoobserved with drug-free dendrimers104 Therefore well
J Biomed Nanotechnol 10 1751ndash1783 2014 1759
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
controlled experiments are needed before drawing conclu-sions during RNA interference studies
AtelocollagenAtelocollagen is an organic protein-based moleculederived from type I collagen of calf dermis Sinceit is obtained following a pepsin treatment atelocolla-gen is devoid of telopeptides that are responsible forthe immunogenicity of collagen105 Moreover atelocol-lagen has low toxicity it was shown to stabilize RNAmolecules Increased cellular uptake and sustained deliv-ery was observed in in vivo making atelocollagen an idealagent for gene delivery106 Indeed several studies used ate-locollagen with success for the systemic or local deliveryof RNAi in tumor models107ndash109
ChitosanChitosan is obtained through alkaline deacetylation of thepolysaccharide chitin that forms the exoskeleton of crus-taceans some anthropods and insects Chitosan that is usedin biomedical research is a copolymer of N -acetyl-D-glucosamine and D-glucosamine having a positive chargeIn addition to being biodegradable and biocompatible chi-tosan has a low production cost Mucoadhesive propertiesof chitosan allow the penetration of the substance intoepithelial cell layers including the gastrointestinal barri-ers Nucleic acid encapsulation and sustained release wasproved to be possible using chitosan110ndash112 Moreover chi-tosan prolongs transient time in bowel improving par-enteral drug bioavailability113 Nanoparticles of chitosanare taken up into cells through endocytosis to a cer-tain extent To improve gene delivery efficacies PEG ordeoxycholic acid conjugates or modifications includingtrimethylation thiolation galactosylation may be intro-duced to chitosan111 Moreover chitosan-based carrierspossess functional groups that are suitable for conjugationto ligands relevant for targeted tumor delivery Althoughinefficient endosomal escape is a problem encounteredwith chitosan-based carriers some chemically modifiedforms showed improved escape properties114
CyclodextrinsCyclodextrins are natural polymers They are cyclicoligosaccharides of a glucopyranose generated during thebacterial digestion of cellulose Their central cavity ishydrophobic while the outer surface is a hydrophilicand they can create water-soluble molecular complexes115
Native cyclodextrins do not form stable complexeswith nucleic acids But the DNARNA complex for-mation capacities of the molecule can be modulatedand improved through molecular modifications includ-ing changes in functional groups hydrophilic-hydrophobicbalance charge density spacer length and conjugation toother carrier molecules115116 Cyclodextrins are not onlybiocompatible but they have the capacity to decrease
cytotoxicity of other molecules and carriers that are conju-gated to them117 Moreover cyclodextrins increase cellularadsorption and intake of molecules118 So in addition totheir use as a gene delivery agents cyclodextrins are usedas linking agents or structural modifiers in complex car-rier molecules For example conjugation of cyclodextrinto PEI resulted in lower toxicity and higher transfectionefficiencies119 In addition to the advantages cited abovea cyclodextrin polycation delivery system was reportedto block immune reactions raised against small RNAsthrough a masking effect120121 Importantly studies innon-human primates revealed that cyclodextrin-based car-riers were well tolerated and they do not stimulate signif-icant antibody responses120
AptamersAptamers are nucleic acid-based molecules selectedin vitro according to their capacity to bind target moleculesspecifically and with high affinity The immunogenicity ofaptamers is limited due to chemical modifications min-imizing adverse reactions Moreover nucleic acid natureand small size of aptamers result in improved transport andtissue penetration Since they can be specifically designedaccording to cell or tissue types (eg tumor cell com-ponents) side effects and off-target effects are minimalIn gene therapy applications the nucleic acid nature ofaptamers allows easy conjugation to RNADNA combin-ing targeting advantages with a therapeutic potential122
Alternatively non-covalent adapter linkages might be cre-ated between aptamers and RNA molecules Functionalgroups might be added to the 5prime- or 3prime-termini allowingcovalent or non-covalent conjugation of aptamers to carriernanoparticles123
Inorganic ParticlesInorganic nanoparticals such as carbon nanotubes mag-netic nanoparticles quantum dots and silica are the focusof recent efforts in drug and gene delivery Many of theseparticles actually offer the opportunity to combine imag-ing and therapeutic possibilities in the same particle ren-dering the nanocarrier a valuable ldquotheranosticrdquo device124
Increased surfacevolume ratio of inorganic particles pro-vides an opportunity for surface modifications includingconjugations to drugs oligonucleotides targeting peptidesor other molecules125126 Yet inorganic nanoparticles tendto aggregate and the size of the aggregate might have animpact on its function and biodistribution Such inorganicnanoparticles are hence coated with organic moleculeswhich provide colloid formation in aqueous and physiolog-ical media and stability Nature of the organic coatings hasto be designed for specific purposes but biocompatibilityof the organic molecules themselves andor their degra-dation products are critical for drug delivery purposes126
Chemistry of the coating might influence the half-life inblood and biodistribution as well as the toxicity of inor-ganic nanoparticles and their clearance mechanisms
1760 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Depending on the material they consist of inorganicnanoparticles may possess a number of different propertiessuch as high electron density and strong optical absorption(eg metal particles in particular Au) photoluminescenceor fluorescence (semiconductor quantum dots eg CdSeCdTe CdTeSeZnS) phosphorescence (doped oxide mate-rials eg Y2O3) or magnetic moment (eg iron oxide orcobalt nanoparticles) The shape of the nanoparticle is alsoan important factor influencing its interaction with cellsMany of the above mentioned nanoparticle are sphericalin shape except carbon nanotubes that are tubular
Carbon NanotubesCarbon nanotubes (CNTs) easily cross the plasma mem-brane and translocate directly into the cytoplasm of tar-get cells due to their nanoneedle structure and usingan endocytosis-independent mechanism yet they do notinduce cell death127ndash129 CNTs are classified as single-walled CNTs and multiwalled CNTs Single or multiplegraphine layer(s) might have a length ranging from 50 nmto 100 mm and a diameter of 1 nm to 100 nm Properfunctionalizing of CNTs by covalent or non-covalentstrategies (such as coating with PEG or Tween-20) mayprovide solubility in aqueous solutions and prevent non-specific interactions thus minimizing toxicity observedwith non-functionalized raw particles130131 Modificationsmight also increase biocompatibility and blood circulationhalf-life132133 CNTs have very strong absorption charac-teristics providing an opportunity for photothermal abla-tion therapy in addition to nanocarrier properties
Magnetic NanoparticlesMagnetic nanoparticles are composed of ferromagneticelements such as Ni Co Mn Fe Superparamagneticiron oxide nanoparticles (SPIONS) such as maghemite--Fe2O3 and magnetite-Fe3O4 are one of the most widelyused magnetic particles as nanocarriers due to relativelylow cost of production biocompatability and superpara-magnetic nature134135 SPIONS are approved by FDA forclinical trials They are commonly used as contrast agentsfor magnetic resonance imaging (MRI) SPION crystals(less than 10 nm in diameter) are coated for specificpurposes with organic molecules such as dextran aminodextran BSA PEI dendrimers lipids and trialkoxysi-lanes including aminopropyltriethoxy silane (APTES)Coating chemistry and preparation methods influence over-all hydrodynamic size pharmacokinetics and the contrasttype (dark-T 2 or bright-T 1 agent) Ability to track the fateof nucleic acid carrier magnetic nanoparticles in vivo usingMRI is highly desirable since it provides informationabout the location of the cargo and its biodistribution136
Attachment of ligands provides target specificity andPEGylation may improve biocompatibility and blood half-life These modifications are commonly introduced to SPI-ONs that are used for imaging and therapy purposes Due
to their magnetic nature drug or nucleic acid carrying SPI-ONs can be concentrated at desired diseased sites such astumors and they may be dragged magnetically towards thelesion area136137 Moreover magnetic nanoparticles offerthe possibility of hyperthermia treatment as a result ofmagnetic heating135 Under applied alternating magneticfield SPIONs cause local temperature increase (41ndash42 C)which may be exploited for alternative and efficient cancertherapy Therefore SPIONs are one of the most versatileand multifunctional nanoparticles Consequently SPIONswere used as popular gene delivery vehicles135
Magnetic nanoparticles may be engineered for oligonu-cleotide delivery purposes MRI visible PEI-PEG coatedSPIONs which are tagged with an antibody have beenshown to effectively carry siRNA to cancer cell lines andshowed low toxicity138 SPIONs coated with both thermoresponsive and cationic polymers such as poly[2-(2-methoxyethoxy)ethylmethacrylate]-b-poly-[2-(dimethyl-amino)ethyl methacrylate] were reported to have25ndash100 times better transfection efficiency than branchedPEI 25 kDa when coupled with magnetic targeting139
SPIONs coated with low molecular weight PEI(12ndash2 kDa) which is usually not effective as poly-plexes in transfection were shown succesful in deliveringsiRNA to mouse macrophages (H Yagci Acar WIPOPatent WO2006055447A3) Therefore magnetic nanpar-ticles are under heavy investigation for the developmentof multifunctional nanocarriers for cancer therapy anddiagnosis135
Quantum DotsSemiconductor quantum dots (QDs) are light-emittingnanoparticles of few nanometer in diameter and they havebeen increasingly used as biological imaging and labelingprobes140 Luminescencefluorescence properties of QDsdepend on the crystal size and type Chemical composi-tion of the crystalline semiconductor core determines theband gap of the material therefore the emission wave-length range Within possible spectral window size ofthe crystal determines the specific wavelength of lumines-cencefluorescence for each and every QD due to quan-tum confinement effect Broad absorption of QDs allowexcitation of multiple QDs at a single wavelength andminimal signal mixing due to the narrow emission bandIn addition they are much more resistant to photobleach-ing These two characteristics are the major advantages ofQDs compared to organic fluorophores as imaging probesUtilization of QDs in nucleic acid delivery aims bothimaging and therapy since in vivo localization of cargocan be observed using optical imaging systems141142 Forexample cationic CdTeZnS QDs conjugated with PEGwas demonstrated to form an effective nanoplex with sur-vivin siRNA and successfully transfeced human tonguecancer cells in vitro and provided real time tracking143
However well-established QDs harbour significant toxic-ity due to constituents such as Cd Se Te144 Therefore
J Biomed Nanotechnol 10 1751ndash1783 2014 1761
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
toxicity of these QDs is a drawback for their use in vivoAs an alternative silver (Ag) chalcogenites emerged assafer near-infra red-emitting QDs145146 Ag2S QDs did notinduce cytotoxicity ROS production apoptosis necrosisor DNA damage147 For example Ag2S QDs (coated with2-mercaptopropionic acid) emitting between 750ndash850 nmshowed no cytotoxicity in NIH3T3 cells at even highdoses (600 mgml) along with good cellular imagingpotential148
Gold NanoparticlesGold nanoparticles emerged as popular tools fornanocarrier-mediated gene therapy149 They are easily syn-thesized and biocompatible particles that allow addition offunctional molecules on their surface due to high surface-to-volume ratio114150 A variety of surface changes andfunctional additions were reported including cationic lipidcoating branched PEI addition or functionalization usingcationic quaternary ammonium or cystamine114151152
Indeed cystamine functionalized gold nanoparticles wereshown to effectively bind deliver and release 35 differ-ent miRNA in in vitro studies using neuroblastoma andovarian cancer cell lines153
Silica NanoparticlesSilica-based nanoparticles are inert stable biocompati-ble and biodegradable particles154 They can be renderedhydrophilic hydrophobic anionic or cationic using func-tional surface modifiers through electrostatic interactionsor by formation of any other type covalent bonds (egester amine) Common functionalization strategies to ren-der the molecule cationic and improve nucleic acid bind-ing include grafting of molecules such as PEI PEI-PEGand Poly-L-arginine155 Nucleic acids may also be loadedinside the mesoporous silica particles156 siRNA encapsu-lating mesoporous silica nanoparticles were successfullyused for in vitro and in vivo gene silencing in several stud-ies (For example Ref [156])
RECENT IN VIVO STUDIES USING RNAINTERFERENCE IN CANCER THERAPYThere is an exponential increase in the number of scientificpublications dedicated to gene therapy of diseases usingsmall RNAs and nanoparticles A literature search usingldquonanoparticlerdquo and ldquosiRNA shRNA or miRNArdquo revealedmore than 700 articles published in the last two yearsThis number is roughly equal to the number of all articlespublished in this field until two years ago So the field isexpanding and there seems to form a consensus aroundthe use of nanoparticles as next generation gene therapytools We believe that these high expectations are not onlya consequence of shifting trends in science and technol-ogy The exponential rise in interest in the field of smallRNA carrier nanoparticles is fueled by the advances inthe field of nano materials promising results obtained in
small RNA therapeutics by both academic laboratories andindustry and increasing number of successful clinical tri-als In this section we will summarize results of selectedrecent studies using RNA therapeutics for cancer treatmentin preclinical in vivo experimentsOverview of the works dealing with small RNA treat-
ment of experimental cancers and published within thelast two years were summarized in Table I Although sev-eral studies were performed using lipid-based nanopar-ticles (Liposomes micelles or lipidoids) other particlessuch as polymers organic or inorganic carriers and com-pounds mixtures with functional modifications of vari-able substances were also tested by many research teamswith reasonable success Scheme 4 summarizes the generalstrategy followed in most of these studies
Tumor Types and RNAi TherapyRecent studies in the literature showed that tumors of vari-ous tissue origins could be treated using RNA interferencestrategies (Table I) Fine tuning of nanoparticles throughaddition of functional moieties or modifications alloweddelivery of drugs into almost any kind of tumor tissue withaccompanied therapeutic effects Although several studiesused animal tumor models that resulted from the injectionof cell lines from most commonly seen human cancers(lung breast prostate cervix or ovarian cancer cell lines)animals with kidney urinary bladder head and neckgastric pancreatic melanomas neuroblastomas glioblas-tomas multiple myelomas or sarcomas were also treatedwith RNAinanocarrier strategy81156ndash170 These results givehope about the general use of RNA interference as astrategy to treat cancers of different origins Althoughit is difficult to compare the efficacies of different nucleicacid molecules and their interference effects at this pointsiRNA or microRNAs as well as shRNA vectors wereshown to achieve intratumoral in vivo target gene knock-down and anticancer effects leading to a decrease in tumorsize (For example Refs [156 171]) Since in most studiesin addition to RNAi loaded particles naked nanoparticlesor particles loaded with non-specific control nucleic acidswere also used antitumor effects obtained in these studiesare specific and they may be attributable to small RNAmolecules rather than the particles themselves underliningthe potential of RNA interference in cancer treatmentMajority of recent studies with in vivo models chose
to use human tumor cell line xenografts in immune com-promised mice nude or severe-combined immuno defi-cient SCID mice (Table I) (For example Refs [162 172])Syngeneic transplants and established genetically engi-neered mouse models of cancer were rarely studied in thiscontext167173ndash175 Therefore although antitumor effects andsome of the toxic effects (eg liver toxicity) might berevealed using immune compromised mice hematologicalimmunological and inflammatory side effects of the treat-ment strategies used in recent studies might need to berevisited using immunocompetent mice
1762 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IRec
entstudieswithRNAica
rryingnan
oparticles
forthetrea
tmen
tofex
perim
entalca
nce
rs(P
ublis
hed
within
thelast
twoye
ars)
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGF
Mag
netic
mes
oporou
ssilicana
nopa
rticles
PEIan
dfuso
genicpe
ptide
KALA
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[156
]
siRNA
Polo-likekina
se1(P
LK1)
pH-sen
sitiveca
tioniclip
idYSK05
-MEND
(YSK05
POPEcho
lesterol
=50
2525
)
PEG
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
PLK
1[51]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Bioen
gine
ered
bacterial
outermem
bran
eve
sicles
Hum
anep
idermal
grow
thfactor
rece
ptor
2(H
ER2)-spe
cific
affib
ody
targeting
HCC-195
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
KSP
Dec
reas
edtumor
volume
[81]
siRNA
Luciferase
Dioleoy
lpho
spha
tidic
acid-(DOPA
-)co
ated
nano
-sized
calcium
phos
phate(LCP-II)
DSPE-P
EG-an
dan
isam
idefortargeting
sigm
a-1rece
ptor
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
Xen
ograft
it
ND
Kno
ckdo
wnof
luciferase
[211
]
siRNA
mTERT
N-((2-hyd
roxy
-3-trim
ethy
l-am
mon
ium)propy
l)ch
itosa
nch
lorid
e(H
TCC)na
nopa
rticles
Partic
leload
edwith
paclita
xel
LCC
murinelung
canc
erce
llssy
ngen
eicsc
graft
oral
Noeffect
Kno
ckdo
wnof
mTERT
Dec
reas
edtumor
volume
Syn
ergize
dwith
paclita
xel
[159
]
siRNA
VEGF
Multilay
ered
polyion
complexes
Polyc
ationinterla
yeran
dade
tach
able
PEG
shell
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
[212
]
siRNA
Multid
rug
resistan
ceprotein1
(MRP1)
Nan
opartic
lesas
sembled
vialaye
r-by
laye
rde
positio
nof
siRNA
and
poly-L-arginine
Hya
lurona
n(H
A)co
ating
forHA-C
D44
targeting
MDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
it
Noeffect
Kno
ckdo
wnof
MRP1
Dec
reas
edtumor
volume
[183
]
siRNA
STA
T3-a
Nan
oporou
ssilicon
nano
particles
Argininean
dPEI
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicefat
padxe
nograft
iv
Noeffect
Kno
ckdo
wnof
STA
T3-a
[204
]
siRNA
Luciferase
Lipo
somal
nano
particle
Fou
rtand
emrepe
atsof
human
histon
eH2A
peptideinterven
edby
cathep
sinD
clea
vage
sites
PEG-A
nisa
mide
fortargeting
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
luciferase
[199
]
siRNA
Polo-likekina
se1(P
LK1)
Hya
luronicac
id(H
A)
base
dse
lfass
embling
HA-P
EIP
EG
nano
system
s
Hya
lurona
nforCD44
targeting
B16
F10
amurine
melan
omace
llsA54
9-luchu
man
lung
canc
erce
llsHep
3Bhu
man
liver
canc
erce
llsMDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
graftor
metas
tatic
lung
lesion
sby
IVinjection
it
ND
Kno
ckdo
wnof
PLK
1[160
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1763
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
P-glyco
protein
drug
expo
rter
(P-
gpM
DR1)
Mes
oporou
ssilica
nano
particles
Polye
thylen
eimine
polyethy
lene
glyc
ol(P
EI-PEG)co
polymer
MCF-7M
DR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gpMDR1
Dec
reas
edtumor
volume
Syn
ergy
with
doxo
rubicin
[179
]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Multifun
ctiona
lcarrie
rsy
stem
with
catio
nic
(olig
oethan
amino)am
ide
core
attach
edto
PEG
chain
Folic
acid
fortargeting
Inf7
(Infl
uenz
ape
ptide)
asen
doso
molytic
peptide
coup
ledto
the5prime-end
ofsiRNA
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
itor
iv
ND
Kno
ckdo
wnof
EG5
Dec
reas
edtumor
volume
[161
]
siRNA
Epide
rmal
Growth
Factor
Rec
eptor
(EGFR)
Poly-L-argininean
dde
xtransu
lfate-bas
edna
noco
mplex
FaDuhu
man
pharyn
xsq
uamou
sca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[172
]
siRNA
Cho
line
kina
se(C
hk)
Polye
thylen
imine-
polyethy
lene
glyc
ol(P
EI-PEG)co
grafted
polymer
Con
versionof
nontox
ic5-flu
oroc
ytos
ine(5-FC)to
cytotoxic5-flu
orou
racil
(5-FU)by
activating
bacterialc
ytos
ine
deam
inas
e(bCD)
PC3-PIP
andPC3-Flu
human
pros
tate
canc
erce
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
e[157
]
siRNA
Polo-like
kina
se1
(Plk1)
Cationiclip
idpo
lymer
hybrid
nano
particles
(cationiclip
id(N
N-
bis(2-hy
drox
yethyl)-N-
methy
l-N-(2-
choles
teryloxy
carbon
ylam
inoe
thyl)am
mon
ium
brom
ide
BHEM-C
hol)
andam
phiphilic
polymers(H
ydroph
obic
polylactideco
re)
PEG
shell
BT47
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Plk1
Dec
reas
edtumor
volume
[213
]
siRNA
hTERT
Single-walledca
rbon
nano
tube
s(S
WNTs)
Branc
hedPEIco
njug
ated
DSPE-P
EG20
00-M
aleimide
forco
njug
ationwith
NGR
(Cys
-Asn
-Gly-A
rg-C
ys-)
targetingpe
ptide(rec
ognize
tumor
neov
ascu
lature)
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
hTERT
Dec
reas
edtumor
volume
Syn
ergy
with
photothe
rmal
trea
tmen
t
[139
]
1764 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 2 Major types of nanoparticles used as nucleic acid carriers
therapeutic RNA interference effects Various strategieswere adapted to overcome these negative effects of PEGwhile exploiting its circulatory advantages Cleavage ofPEG-chains upon delivery into the tumor environment wasachieved through addition of tumor-related matrix met-alloproteinase sensitive lipids or peptides51 pH-sensitivelinkers between the PEG moiety and nanocarriers canalso be used to release PEG from the particle in theacidic environment of the endosomes and allow cytosolic
Scheme 3 A representative nanoparticle with functional modifications Various molecules might be added to a nanoparticleto improve its physico-chemical properties and pharmacokinetics (eg PEG) to increase RNADNA binding (eg PEI) to allowbetter targeting (eg antibodies) or tracking (eg fluorophores)
release of small RNAs Modulation of the hydrophobic-ity of the PEGndashnanocarrier conjugate was also testedas a release strategy In lipid-based nanocarriers thelength of the alkyl chain of the PEG-lipid anchor wasshown to determine its affinity for the lipid deliveryvehicle and changing its length modified endosomalescape potential and drug effects52 Cholesterol-anchoredPEG was also shown to improve endosomal escapecapacities52
J Biomed Nanotechnol 10 1751ndash1783 2014 1757
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
LiposomesLiposomes have been tested extensively as gene deliv-ery agents Liposomes are artificial membrane-boundvesicles formed by bilayers of amphipathic lipids Theymight be unilamellar or multilamellar Their biocom-patibility low toxicity and low immunogenicity madethem popular agents for both in vitro and in vivo genedelivery5354 Liposomes are typically made of mix-tures of lipids found in biological membranes or theirderivatives including phosphatidylcholine (PC or DOPC12-Oleoyl-sn-Glycero-3-phosphatidylcholine) phosphatidyl-ethanolamine (PE or DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidylethanolamine) cholesterol and evenceramide53 Although liposomes made of neutral lipids aremore biocompatible than cationic lipids and have betterpharmacokinetics during preparation of gene deliveryvectors they bind less to negatively charged DNA orRNA molecules and have lower entrapment efficiencies55
Therefore despite their more toxic nature cationic lipidsare commonly used as liposome-based transfection agentsCationic lipids posses positively charged headgroupssuch as amines quaternary ammonium salts peptidesaminoacids or guanidiniums which electrostaticly attractand bind to negatively charged phosphate residues innucleic acid backbones The nature of cationic lipid head-groups determines the efficacy of gene delivery Thereforevarious mixtures of lipids with different headgroupsand properties were tested to achieve optimal liposomeformulations for drug andor gene delivery56ndash59
Although liposomes are excellent transfection agentsin vitro some side effects and problems were encoun-tered during in vivo studies56ndash59 These include intracellu-lar instability and failure to release small RNA contentsdose-dependent toxicity and pulmonary inflammation thatcorrelated with the production of reactive oxygen species(ROS) opsonization by serum proteins immunogenic-ity and uptake by the RES components60ndash63 Addition-ally cationic liposome-dependent gene expression changeswere observed during in vitro experiments with someformulations64
In order to minimize such undesired effects special-ized liposomes were produced through addition of vari-ous functional groups PEGylation and crosslinking withinthe bilayer of the liposomes was successfully utilized toimprove stability and decrease side effects65 PEGylationin general improved bioavailability and biocompatibilityas well For example to obtain improved pharmacokinet-ics PEGylated cationic liposomes called ldquosolid nucleicacid lipid particlesrdquo (SNALPs) were created and they weresuccessfully used for siRNA delivery In fact in SNALPsPEG coating neutralized net charge and increased theblood circulation time of the liposomes significantly66ndash72
Moreover fusogenic lipids added to liposome formula-tions improved cellular uptake and endosomal escape33
Most importantly SNALPs were relatively well toler-ated in vivo even in non-human primates3233 The list of
modifiedimproved liposomes performing well in in vivostudies also includes cationic solidndashlipid nanoparticles andcardiolipin-based liposomes3373ndash75 Currently improvedliposomes are one of the most promising tools for genedelivery and patented formulations produced by sev-eral companies were successful enough to reach clinicaltrials31
LipidoidsLipidoids are cationic lipids that are created by the conju-gation of primary or secondary amines to alkyl-acrylatesor alkyl-acrylamides76 They were introduced as novelalternatives to liposome formulations used in gene deliv-ery Changes in the composition lipidoids were shown toimprove their therapeutic properties For example changesin the alkyl chain length of the PEG lipid was reportedto affect PEG deshielding rate and dose kinetics of lipi-doids in the blood76 Moreover cholesterol incorporationwas shown to improve carrier stability Small sized lipi-doids (50ndash60 nm) were successfully used for the deliveryof siRNA into liver cells avoiding engulfment by Kuppfercells76 Lipidoids may also be used for coating inorganicnanoparticles in order to introduce cationic charges77 Lipi-doids have lower toxicity and increased efficacy thereforethey present an alternative to classical liposomes for genedelivery studies
MinicellsMinicells are bacteria-derived non-living anucleatednano-sized vesicles that were used as nano drug carriers78
Inactivation of min genes that control normal division inbacteria such as Salmonella typhimurium result in the for-mation of minicells min gene products ensure that celldivision septum is correctly located to the midpoint ofthe cell In case of min gene product mutations septa-tion defects result in the formation of minicells devoid ofthe chromosomal DNA Therapeutic RNAs may be loadedinto minicells by the introduction of shRNA of interestinto min mutant bacteria and eventually shRNAs segregateinto minicells78 Purified minicells prepared by this methodare pre-packaged with effective copy numbers of the plas-mid For targeting purposes tumor-specific antibodies maybe decorated onto minicells by the exploitation of bac-terial cell surface components such as O-polysaccharideof LPS Minicell-RNAi combinations proved to be effec-tive in experimental cancer treatment79 Other cell derived-vesicles that were tested as nanocarriers include bacterialghosts bacterial outer membranes or mammalian cell-derived exosomes80ndash82
PolyplexesMaterials that self-assemble with nucleic acids intonanocomplexes are called ldquopolyplexesrdquo These complexesgenerally form though the electrostatic interaction of the
1758 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
cationic units of the polymers with the anionic phos-phate groups of the nucleic acids Natural and biocompat-ible (eg chitosan Atelocollagen cyclodextrin) or morefrequently synthetic (eg Polyethylenimine PEI poly-L-lysine PLL poly-dl-lactide-co-glycolide PLGA) poly-mers are used for polyplex formation83ndash86 Flexibility of thesynthetic polymers in terms of chemical nature molecularweight and architecture (linear branched grafted blocky)provide opportunity to balance their toxicity improvenucleic acid binding protection and release efficienciesMoreover surface modifications may be introduced for tar-geting purposes and improved pharmacodynamics Poly-mers such as PLGA also benefit from a biodegradablenature which allows clearance of the nanocarriers in time
PEIPEI is the most widely and most successfully used polyca-tion for polyplexe formation It can be synthesized in lin-ear or branched forms and in variable molecular weights(from 1 kDa to gt 1000 kDa) Higher molecular weightpolymers (70 kDa and above) are very effective in nucleicacid binding but they are significantly toxic Low molec-ular weight forms (2 kDa or less) are less toxic but theyare less effective as transfection agents87 Therefore PEIsat and below 25 kDa with a branched or linear architec-ture are commonly used as gene delivery reagents88ndash91 Thegolden standard gene delivery polymer is branched PEIof 25 kDa which offers a balance between the toxicitynucleic acid bindingprotection and release Abundance ofpositive charges due to protonation under physiologicalconditions allows PEI to spontaneously form complexeswith negatively charged small RNAs and DNAs and pro-tect nucleic acid molecules from nuclease attacks84 More-over buried inside the polymer some off-target effects ofthe small RNAs were shown to be prevented92
The net positive charge of PEI-RNAi complexes alsoallow interactions with the negatively charged polysaccha-rides found on the cell surface93 These interactions arebelieved to be an important factor for the endocytosis ofthe complexes by target cells A key event for the successof gene delivery is the escape of the nucleic acids fromthe endosomal pathway in order to avoid accumulation anddegradation in the lysosomes of the cell93 The escape isthought to be the result of the lsquoproton spongersquo effect wherethe influx of protons and water lead to endosome swellingrupture and release of contents including nucleic acids tothe cytosolPEI-induced toxicity was proposed to be a result of
mitochondrial apoptosis induction by the polymer9495
Moreover PEI itself was shown to cause changes in geneexpression in vivo which might influence biological out-comes of treatment protocols59 PEGylation of the PEIreduces both cytotoxicity of PEI-polyplexes and increaseblood circulation half-life However a critical balanceneed to be achieved since PEGylation decreases the sur-face charge it impacts the binding capacity and cell
internalization of the polyplexes Alternatively short PEIchains attached together with hydrolysable links such asdisulfide and ester may provide initially a high molecu-lar weight PEI system for good nucleic acid condensationand protection but upon dissolution because of intracel-lular redox conditions they may act as a low molecularweight PEI polymers with lower toxicity87 Additionallypluronics that are block copolymers of ethylene glycol-propylene glycol-ethylene glycol can be used instead ofPEG Similar to PEG pluronics were shown to improvethe biocompatibility and bioavailability of the nanocarri-ers but they interact better with the cell membrane due tothe propylene glycol units and enhance cellular uptake ofthe particles87
PLGAPLGA is a biodegradable copolymer of glycolic acid andlactic acid96 It is widely used in biomedical research asan FDA-approved substance PLGA offers several advan-tages The polymer is highly stable biodegradable andallows sustained release During nucleic acid deliveryPLGA is easily taken up by cells through endocytosisand no serious toxicity problems were observed97 PLGAbinds nucleic acids weakly but it might encapsulate themfor drug delivery purposes Indeed PLGA nanoparticleswere used in several studies for delivery of drugs totumors through the EPR effects98 Yet following endocyto-sis PLGA particles do not effectively realease cargo fromendosomes8397 To overcome nucleic acid binding deliv-ery and endosomal release problems the surface of PLGAcan be decorated with various cationic nanoparticles suchas DOTAP PEI or polyamine and may be conjugated topeptides and antibodies99
DendrimersDendrimers are tree-like highly branched generally sym-metrical and three-dimensional macromolecules Theyhave uniform size and molecular weight which increaseswith each new branch (generation) Dendrimers possess ahighly functional outer surface allowing chemical modi-fications and interactions Therefore they may be used asflexible and modifiable gene delivery agents100 Besidesthe ability of dendrimers to encapsulate cargos add to theirpotential as drug carriers101 Dendrimers including poly-amidoamine dendrimers (PAMAM) poly-propylene imine(PPI) dendrimers poly-L-lysine dendrimers triazine den-drimers carbosilane dendrimers poly-glycerol-based den-drimers nanocarbon-based dendrimers and others weretested as RNAi delivery agents PAMAM and PPI den-drimers being the most commonly studied ones It wasshown that introduction of surface-modifications mini-mized toxicity-related problems increased RNAi-bindingand cellular uptake efficacies of the dendrimers102103
Of note in vivo gene expression changes were alsoobserved with drug-free dendrimers104 Therefore well
J Biomed Nanotechnol 10 1751ndash1783 2014 1759
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
controlled experiments are needed before drawing conclu-sions during RNA interference studies
AtelocollagenAtelocollagen is an organic protein-based moleculederived from type I collagen of calf dermis Sinceit is obtained following a pepsin treatment atelocolla-gen is devoid of telopeptides that are responsible forthe immunogenicity of collagen105 Moreover atelocol-lagen has low toxicity it was shown to stabilize RNAmolecules Increased cellular uptake and sustained deliv-ery was observed in in vivo making atelocollagen an idealagent for gene delivery106 Indeed several studies used ate-locollagen with success for the systemic or local deliveryof RNAi in tumor models107ndash109
ChitosanChitosan is obtained through alkaline deacetylation of thepolysaccharide chitin that forms the exoskeleton of crus-taceans some anthropods and insects Chitosan that is usedin biomedical research is a copolymer of N -acetyl-D-glucosamine and D-glucosamine having a positive chargeIn addition to being biodegradable and biocompatible chi-tosan has a low production cost Mucoadhesive propertiesof chitosan allow the penetration of the substance intoepithelial cell layers including the gastrointestinal barri-ers Nucleic acid encapsulation and sustained release wasproved to be possible using chitosan110ndash112 Moreover chi-tosan prolongs transient time in bowel improving par-enteral drug bioavailability113 Nanoparticles of chitosanare taken up into cells through endocytosis to a cer-tain extent To improve gene delivery efficacies PEG ordeoxycholic acid conjugates or modifications includingtrimethylation thiolation galactosylation may be intro-duced to chitosan111 Moreover chitosan-based carrierspossess functional groups that are suitable for conjugationto ligands relevant for targeted tumor delivery Althoughinefficient endosomal escape is a problem encounteredwith chitosan-based carriers some chemically modifiedforms showed improved escape properties114
CyclodextrinsCyclodextrins are natural polymers They are cyclicoligosaccharides of a glucopyranose generated during thebacterial digestion of cellulose Their central cavity ishydrophobic while the outer surface is a hydrophilicand they can create water-soluble molecular complexes115
Native cyclodextrins do not form stable complexeswith nucleic acids But the DNARNA complex for-mation capacities of the molecule can be modulatedand improved through molecular modifications includ-ing changes in functional groups hydrophilic-hydrophobicbalance charge density spacer length and conjugation toother carrier molecules115116 Cyclodextrins are not onlybiocompatible but they have the capacity to decrease
cytotoxicity of other molecules and carriers that are conju-gated to them117 Moreover cyclodextrins increase cellularadsorption and intake of molecules118 So in addition totheir use as a gene delivery agents cyclodextrins are usedas linking agents or structural modifiers in complex car-rier molecules For example conjugation of cyclodextrinto PEI resulted in lower toxicity and higher transfectionefficiencies119 In addition to the advantages cited abovea cyclodextrin polycation delivery system was reportedto block immune reactions raised against small RNAsthrough a masking effect120121 Importantly studies innon-human primates revealed that cyclodextrin-based car-riers were well tolerated and they do not stimulate signif-icant antibody responses120
AptamersAptamers are nucleic acid-based molecules selectedin vitro according to their capacity to bind target moleculesspecifically and with high affinity The immunogenicity ofaptamers is limited due to chemical modifications min-imizing adverse reactions Moreover nucleic acid natureand small size of aptamers result in improved transport andtissue penetration Since they can be specifically designedaccording to cell or tissue types (eg tumor cell com-ponents) side effects and off-target effects are minimalIn gene therapy applications the nucleic acid nature ofaptamers allows easy conjugation to RNADNA combin-ing targeting advantages with a therapeutic potential122
Alternatively non-covalent adapter linkages might be cre-ated between aptamers and RNA molecules Functionalgroups might be added to the 5prime- or 3prime-termini allowingcovalent or non-covalent conjugation of aptamers to carriernanoparticles123
Inorganic ParticlesInorganic nanoparticals such as carbon nanotubes mag-netic nanoparticles quantum dots and silica are the focusof recent efforts in drug and gene delivery Many of theseparticles actually offer the opportunity to combine imag-ing and therapeutic possibilities in the same particle ren-dering the nanocarrier a valuable ldquotheranosticrdquo device124
Increased surfacevolume ratio of inorganic particles pro-vides an opportunity for surface modifications includingconjugations to drugs oligonucleotides targeting peptidesor other molecules125126 Yet inorganic nanoparticles tendto aggregate and the size of the aggregate might have animpact on its function and biodistribution Such inorganicnanoparticles are hence coated with organic moleculeswhich provide colloid formation in aqueous and physiolog-ical media and stability Nature of the organic coatings hasto be designed for specific purposes but biocompatibilityof the organic molecules themselves andor their degra-dation products are critical for drug delivery purposes126
Chemistry of the coating might influence the half-life inblood and biodistribution as well as the toxicity of inor-ganic nanoparticles and their clearance mechanisms
1760 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Depending on the material they consist of inorganicnanoparticles may possess a number of different propertiessuch as high electron density and strong optical absorption(eg metal particles in particular Au) photoluminescenceor fluorescence (semiconductor quantum dots eg CdSeCdTe CdTeSeZnS) phosphorescence (doped oxide mate-rials eg Y2O3) or magnetic moment (eg iron oxide orcobalt nanoparticles) The shape of the nanoparticle is alsoan important factor influencing its interaction with cellsMany of the above mentioned nanoparticle are sphericalin shape except carbon nanotubes that are tubular
Carbon NanotubesCarbon nanotubes (CNTs) easily cross the plasma mem-brane and translocate directly into the cytoplasm of tar-get cells due to their nanoneedle structure and usingan endocytosis-independent mechanism yet they do notinduce cell death127ndash129 CNTs are classified as single-walled CNTs and multiwalled CNTs Single or multiplegraphine layer(s) might have a length ranging from 50 nmto 100 mm and a diameter of 1 nm to 100 nm Properfunctionalizing of CNTs by covalent or non-covalentstrategies (such as coating with PEG or Tween-20) mayprovide solubility in aqueous solutions and prevent non-specific interactions thus minimizing toxicity observedwith non-functionalized raw particles130131 Modificationsmight also increase biocompatibility and blood circulationhalf-life132133 CNTs have very strong absorption charac-teristics providing an opportunity for photothermal abla-tion therapy in addition to nanocarrier properties
Magnetic NanoparticlesMagnetic nanoparticles are composed of ferromagneticelements such as Ni Co Mn Fe Superparamagneticiron oxide nanoparticles (SPIONS) such as maghemite--Fe2O3 and magnetite-Fe3O4 are one of the most widelyused magnetic particles as nanocarriers due to relativelylow cost of production biocompatability and superpara-magnetic nature134135 SPIONS are approved by FDA forclinical trials They are commonly used as contrast agentsfor magnetic resonance imaging (MRI) SPION crystals(less than 10 nm in diameter) are coated for specificpurposes with organic molecules such as dextran aminodextran BSA PEI dendrimers lipids and trialkoxysi-lanes including aminopropyltriethoxy silane (APTES)Coating chemistry and preparation methods influence over-all hydrodynamic size pharmacokinetics and the contrasttype (dark-T 2 or bright-T 1 agent) Ability to track the fateof nucleic acid carrier magnetic nanoparticles in vivo usingMRI is highly desirable since it provides informationabout the location of the cargo and its biodistribution136
Attachment of ligands provides target specificity andPEGylation may improve biocompatibility and blood half-life These modifications are commonly introduced to SPI-ONs that are used for imaging and therapy purposes Due
to their magnetic nature drug or nucleic acid carrying SPI-ONs can be concentrated at desired diseased sites such astumors and they may be dragged magnetically towards thelesion area136137 Moreover magnetic nanoparticles offerthe possibility of hyperthermia treatment as a result ofmagnetic heating135 Under applied alternating magneticfield SPIONs cause local temperature increase (41ndash42 C)which may be exploited for alternative and efficient cancertherapy Therefore SPIONs are one of the most versatileand multifunctional nanoparticles Consequently SPIONswere used as popular gene delivery vehicles135
Magnetic nanoparticles may be engineered for oligonu-cleotide delivery purposes MRI visible PEI-PEG coatedSPIONs which are tagged with an antibody have beenshown to effectively carry siRNA to cancer cell lines andshowed low toxicity138 SPIONs coated with both thermoresponsive and cationic polymers such as poly[2-(2-methoxyethoxy)ethylmethacrylate]-b-poly-[2-(dimethyl-amino)ethyl methacrylate] were reported to have25ndash100 times better transfection efficiency than branchedPEI 25 kDa when coupled with magnetic targeting139
SPIONs coated with low molecular weight PEI(12ndash2 kDa) which is usually not effective as poly-plexes in transfection were shown succesful in deliveringsiRNA to mouse macrophages (H Yagci Acar WIPOPatent WO2006055447A3) Therefore magnetic nanpar-ticles are under heavy investigation for the developmentof multifunctional nanocarriers for cancer therapy anddiagnosis135
Quantum DotsSemiconductor quantum dots (QDs) are light-emittingnanoparticles of few nanometer in diameter and they havebeen increasingly used as biological imaging and labelingprobes140 Luminescencefluorescence properties of QDsdepend on the crystal size and type Chemical composi-tion of the crystalline semiconductor core determines theband gap of the material therefore the emission wave-length range Within possible spectral window size ofthe crystal determines the specific wavelength of lumines-cencefluorescence for each and every QD due to quan-tum confinement effect Broad absorption of QDs allowexcitation of multiple QDs at a single wavelength andminimal signal mixing due to the narrow emission bandIn addition they are much more resistant to photobleach-ing These two characteristics are the major advantages ofQDs compared to organic fluorophores as imaging probesUtilization of QDs in nucleic acid delivery aims bothimaging and therapy since in vivo localization of cargocan be observed using optical imaging systems141142 Forexample cationic CdTeZnS QDs conjugated with PEGwas demonstrated to form an effective nanoplex with sur-vivin siRNA and successfully transfeced human tonguecancer cells in vitro and provided real time tracking143
However well-established QDs harbour significant toxic-ity due to constituents such as Cd Se Te144 Therefore
J Biomed Nanotechnol 10 1751ndash1783 2014 1761
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
toxicity of these QDs is a drawback for their use in vivoAs an alternative silver (Ag) chalcogenites emerged assafer near-infra red-emitting QDs145146 Ag2S QDs did notinduce cytotoxicity ROS production apoptosis necrosisor DNA damage147 For example Ag2S QDs (coated with2-mercaptopropionic acid) emitting between 750ndash850 nmshowed no cytotoxicity in NIH3T3 cells at even highdoses (600 mgml) along with good cellular imagingpotential148
Gold NanoparticlesGold nanoparticles emerged as popular tools fornanocarrier-mediated gene therapy149 They are easily syn-thesized and biocompatible particles that allow addition offunctional molecules on their surface due to high surface-to-volume ratio114150 A variety of surface changes andfunctional additions were reported including cationic lipidcoating branched PEI addition or functionalization usingcationic quaternary ammonium or cystamine114151152
Indeed cystamine functionalized gold nanoparticles wereshown to effectively bind deliver and release 35 differ-ent miRNA in in vitro studies using neuroblastoma andovarian cancer cell lines153
Silica NanoparticlesSilica-based nanoparticles are inert stable biocompati-ble and biodegradable particles154 They can be renderedhydrophilic hydrophobic anionic or cationic using func-tional surface modifiers through electrostatic interactionsor by formation of any other type covalent bonds (egester amine) Common functionalization strategies to ren-der the molecule cationic and improve nucleic acid bind-ing include grafting of molecules such as PEI PEI-PEGand Poly-L-arginine155 Nucleic acids may also be loadedinside the mesoporous silica particles156 siRNA encapsu-lating mesoporous silica nanoparticles were successfullyused for in vitro and in vivo gene silencing in several stud-ies (For example Ref [156])
RECENT IN VIVO STUDIES USING RNAINTERFERENCE IN CANCER THERAPYThere is an exponential increase in the number of scientificpublications dedicated to gene therapy of diseases usingsmall RNAs and nanoparticles A literature search usingldquonanoparticlerdquo and ldquosiRNA shRNA or miRNArdquo revealedmore than 700 articles published in the last two yearsThis number is roughly equal to the number of all articlespublished in this field until two years ago So the field isexpanding and there seems to form a consensus aroundthe use of nanoparticles as next generation gene therapytools We believe that these high expectations are not onlya consequence of shifting trends in science and technol-ogy The exponential rise in interest in the field of smallRNA carrier nanoparticles is fueled by the advances inthe field of nano materials promising results obtained in
small RNA therapeutics by both academic laboratories andindustry and increasing number of successful clinical tri-als In this section we will summarize results of selectedrecent studies using RNA therapeutics for cancer treatmentin preclinical in vivo experimentsOverview of the works dealing with small RNA treat-
ment of experimental cancers and published within thelast two years were summarized in Table I Although sev-eral studies were performed using lipid-based nanopar-ticles (Liposomes micelles or lipidoids) other particlessuch as polymers organic or inorganic carriers and com-pounds mixtures with functional modifications of vari-able substances were also tested by many research teamswith reasonable success Scheme 4 summarizes the generalstrategy followed in most of these studies
Tumor Types and RNAi TherapyRecent studies in the literature showed that tumors of vari-ous tissue origins could be treated using RNA interferencestrategies (Table I) Fine tuning of nanoparticles throughaddition of functional moieties or modifications alloweddelivery of drugs into almost any kind of tumor tissue withaccompanied therapeutic effects Although several studiesused animal tumor models that resulted from the injectionof cell lines from most commonly seen human cancers(lung breast prostate cervix or ovarian cancer cell lines)animals with kidney urinary bladder head and neckgastric pancreatic melanomas neuroblastomas glioblas-tomas multiple myelomas or sarcomas were also treatedwith RNAinanocarrier strategy81156ndash170 These results givehope about the general use of RNA interference as astrategy to treat cancers of different origins Althoughit is difficult to compare the efficacies of different nucleicacid molecules and their interference effects at this pointsiRNA or microRNAs as well as shRNA vectors wereshown to achieve intratumoral in vivo target gene knock-down and anticancer effects leading to a decrease in tumorsize (For example Refs [156 171]) Since in most studiesin addition to RNAi loaded particles naked nanoparticlesor particles loaded with non-specific control nucleic acidswere also used antitumor effects obtained in these studiesare specific and they may be attributable to small RNAmolecules rather than the particles themselves underliningthe potential of RNA interference in cancer treatmentMajority of recent studies with in vivo models chose
to use human tumor cell line xenografts in immune com-promised mice nude or severe-combined immuno defi-cient SCID mice (Table I) (For example Refs [162 172])Syngeneic transplants and established genetically engi-neered mouse models of cancer were rarely studied in thiscontext167173ndash175 Therefore although antitumor effects andsome of the toxic effects (eg liver toxicity) might berevealed using immune compromised mice hematologicalimmunological and inflammatory side effects of the treat-ment strategies used in recent studies might need to berevisited using immunocompetent mice
1762 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IRec
entstudieswithRNAica
rryingnan
oparticles
forthetrea
tmen
tofex
perim
entalca
nce
rs(P
ublis
hed
within
thelast
twoye
ars)
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGF
Mag
netic
mes
oporou
ssilicana
nopa
rticles
PEIan
dfuso
genicpe
ptide
KALA
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[156
]
siRNA
Polo-likekina
se1(P
LK1)
pH-sen
sitiveca
tioniclip
idYSK05
-MEND
(YSK05
POPEcho
lesterol
=50
2525
)
PEG
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
PLK
1[51]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Bioen
gine
ered
bacterial
outermem
bran
eve
sicles
Hum
anep
idermal
grow
thfactor
rece
ptor
2(H
ER2)-spe
cific
affib
ody
targeting
HCC-195
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
KSP
Dec
reas
edtumor
volume
[81]
siRNA
Luciferase
Dioleoy
lpho
spha
tidic
acid-(DOPA
-)co
ated
nano
-sized
calcium
phos
phate(LCP-II)
DSPE-P
EG-an
dan
isam
idefortargeting
sigm
a-1rece
ptor
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
Xen
ograft
it
ND
Kno
ckdo
wnof
luciferase
[211
]
siRNA
mTERT
N-((2-hyd
roxy
-3-trim
ethy
l-am
mon
ium)propy
l)ch
itosa
nch
lorid
e(H
TCC)na
nopa
rticles
Partic
leload
edwith
paclita
xel
LCC
murinelung
canc
erce
llssy
ngen
eicsc
graft
oral
Noeffect
Kno
ckdo
wnof
mTERT
Dec
reas
edtumor
volume
Syn
ergize
dwith
paclita
xel
[159
]
siRNA
VEGF
Multilay
ered
polyion
complexes
Polyc
ationinterla
yeran
dade
tach
able
PEG
shell
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
[212
]
siRNA
Multid
rug
resistan
ceprotein1
(MRP1)
Nan
opartic
lesas
sembled
vialaye
r-by
laye
rde
positio
nof
siRNA
and
poly-L-arginine
Hya
lurona
n(H
A)co
ating
forHA-C
D44
targeting
MDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
it
Noeffect
Kno
ckdo
wnof
MRP1
Dec
reas
edtumor
volume
[183
]
siRNA
STA
T3-a
Nan
oporou
ssilicon
nano
particles
Argininean
dPEI
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicefat
padxe
nograft
iv
Noeffect
Kno
ckdo
wnof
STA
T3-a
[204
]
siRNA
Luciferase
Lipo
somal
nano
particle
Fou
rtand
emrepe
atsof
human
histon
eH2A
peptideinterven
edby
cathep
sinD
clea
vage
sites
PEG-A
nisa
mide
fortargeting
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
luciferase
[199
]
siRNA
Polo-likekina
se1(P
LK1)
Hya
luronicac
id(H
A)
base
dse
lfass
embling
HA-P
EIP
EG
nano
system
s
Hya
lurona
nforCD44
targeting
B16
F10
amurine
melan
omace
llsA54
9-luchu
man
lung
canc
erce
llsHep
3Bhu
man
liver
canc
erce
llsMDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
graftor
metas
tatic
lung
lesion
sby
IVinjection
it
ND
Kno
ckdo
wnof
PLK
1[160
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1763
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
P-glyco
protein
drug
expo
rter
(P-
gpM
DR1)
Mes
oporou
ssilica
nano
particles
Polye
thylen
eimine
polyethy
lene
glyc
ol(P
EI-PEG)co
polymer
MCF-7M
DR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gpMDR1
Dec
reas
edtumor
volume
Syn
ergy
with
doxo
rubicin
[179
]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Multifun
ctiona
lcarrie
rsy
stem
with
catio
nic
(olig
oethan
amino)am
ide
core
attach
edto
PEG
chain
Folic
acid
fortargeting
Inf7
(Infl
uenz
ape
ptide)
asen
doso
molytic
peptide
coup
ledto
the5prime-end
ofsiRNA
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
itor
iv
ND
Kno
ckdo
wnof
EG5
Dec
reas
edtumor
volume
[161
]
siRNA
Epide
rmal
Growth
Factor
Rec
eptor
(EGFR)
Poly-L-argininean
dde
xtransu
lfate-bas
edna
noco
mplex
FaDuhu
man
pharyn
xsq
uamou
sca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[172
]
siRNA
Cho
line
kina
se(C
hk)
Polye
thylen
imine-
polyethy
lene
glyc
ol(P
EI-PEG)co
grafted
polymer
Con
versionof
nontox
ic5-flu
oroc
ytos
ine(5-FC)to
cytotoxic5-flu
orou
racil
(5-FU)by
activating
bacterialc
ytos
ine
deam
inas
e(bCD)
PC3-PIP
andPC3-Flu
human
pros
tate
canc
erce
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
e[157
]
siRNA
Polo-like
kina
se1
(Plk1)
Cationiclip
idpo
lymer
hybrid
nano
particles
(cationiclip
id(N
N-
bis(2-hy
drox
yethyl)-N-
methy
l-N-(2-
choles
teryloxy
carbon
ylam
inoe
thyl)am
mon
ium
brom
ide
BHEM-C
hol)
andam
phiphilic
polymers(H
ydroph
obic
polylactideco
re)
PEG
shell
BT47
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Plk1
Dec
reas
edtumor
volume
[213
]
siRNA
hTERT
Single-walledca
rbon
nano
tube
s(S
WNTs)
Branc
hedPEIco
njug
ated
DSPE-P
EG20
00-M
aleimide
forco
njug
ationwith
NGR
(Cys
-Asn
-Gly-A
rg-C
ys-)
targetingpe
ptide(rec
ognize
tumor
neov
ascu
lature)
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
hTERT
Dec
reas
edtumor
volume
Syn
ergy
with
photothe
rmal
trea
tmen
t
[139
]
1764 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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1776 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
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1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
LiposomesLiposomes have been tested extensively as gene deliv-ery agents Liposomes are artificial membrane-boundvesicles formed by bilayers of amphipathic lipids Theymight be unilamellar or multilamellar Their biocom-patibility low toxicity and low immunogenicity madethem popular agents for both in vitro and in vivo genedelivery5354 Liposomes are typically made of mix-tures of lipids found in biological membranes or theirderivatives including phosphatidylcholine (PC or DOPC12-Oleoyl-sn-Glycero-3-phosphatidylcholine) phosphatidyl-ethanolamine (PE or DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidylethanolamine) cholesterol and evenceramide53 Although liposomes made of neutral lipids aremore biocompatible than cationic lipids and have betterpharmacokinetics during preparation of gene deliveryvectors they bind less to negatively charged DNA orRNA molecules and have lower entrapment efficiencies55
Therefore despite their more toxic nature cationic lipidsare commonly used as liposome-based transfection agentsCationic lipids posses positively charged headgroupssuch as amines quaternary ammonium salts peptidesaminoacids or guanidiniums which electrostaticly attractand bind to negatively charged phosphate residues innucleic acid backbones The nature of cationic lipid head-groups determines the efficacy of gene delivery Thereforevarious mixtures of lipids with different headgroupsand properties were tested to achieve optimal liposomeformulations for drug andor gene delivery56ndash59
Although liposomes are excellent transfection agentsin vitro some side effects and problems were encoun-tered during in vivo studies56ndash59 These include intracellu-lar instability and failure to release small RNA contentsdose-dependent toxicity and pulmonary inflammation thatcorrelated with the production of reactive oxygen species(ROS) opsonization by serum proteins immunogenic-ity and uptake by the RES components60ndash63 Addition-ally cationic liposome-dependent gene expression changeswere observed during in vitro experiments with someformulations64
In order to minimize such undesired effects special-ized liposomes were produced through addition of vari-ous functional groups PEGylation and crosslinking withinthe bilayer of the liposomes was successfully utilized toimprove stability and decrease side effects65 PEGylationin general improved bioavailability and biocompatibilityas well For example to obtain improved pharmacokinet-ics PEGylated cationic liposomes called ldquosolid nucleicacid lipid particlesrdquo (SNALPs) were created and they weresuccessfully used for siRNA delivery In fact in SNALPsPEG coating neutralized net charge and increased theblood circulation time of the liposomes significantly66ndash72
Moreover fusogenic lipids added to liposome formula-tions improved cellular uptake and endosomal escape33
Most importantly SNALPs were relatively well toler-ated in vivo even in non-human primates3233 The list of
modifiedimproved liposomes performing well in in vivostudies also includes cationic solidndashlipid nanoparticles andcardiolipin-based liposomes3373ndash75 Currently improvedliposomes are one of the most promising tools for genedelivery and patented formulations produced by sev-eral companies were successful enough to reach clinicaltrials31
LipidoidsLipidoids are cationic lipids that are created by the conju-gation of primary or secondary amines to alkyl-acrylatesor alkyl-acrylamides76 They were introduced as novelalternatives to liposome formulations used in gene deliv-ery Changes in the composition lipidoids were shown toimprove their therapeutic properties For example changesin the alkyl chain length of the PEG lipid was reportedto affect PEG deshielding rate and dose kinetics of lipi-doids in the blood76 Moreover cholesterol incorporationwas shown to improve carrier stability Small sized lipi-doids (50ndash60 nm) were successfully used for the deliveryof siRNA into liver cells avoiding engulfment by Kuppfercells76 Lipidoids may also be used for coating inorganicnanoparticles in order to introduce cationic charges77 Lipi-doids have lower toxicity and increased efficacy thereforethey present an alternative to classical liposomes for genedelivery studies
MinicellsMinicells are bacteria-derived non-living anucleatednano-sized vesicles that were used as nano drug carriers78
Inactivation of min genes that control normal division inbacteria such as Salmonella typhimurium result in the for-mation of minicells min gene products ensure that celldivision septum is correctly located to the midpoint ofthe cell In case of min gene product mutations septa-tion defects result in the formation of minicells devoid ofthe chromosomal DNA Therapeutic RNAs may be loadedinto minicells by the introduction of shRNA of interestinto min mutant bacteria and eventually shRNAs segregateinto minicells78 Purified minicells prepared by this methodare pre-packaged with effective copy numbers of the plas-mid For targeting purposes tumor-specific antibodies maybe decorated onto minicells by the exploitation of bac-terial cell surface components such as O-polysaccharideof LPS Minicell-RNAi combinations proved to be effec-tive in experimental cancer treatment79 Other cell derived-vesicles that were tested as nanocarriers include bacterialghosts bacterial outer membranes or mammalian cell-derived exosomes80ndash82
PolyplexesMaterials that self-assemble with nucleic acids intonanocomplexes are called ldquopolyplexesrdquo These complexesgenerally form though the electrostatic interaction of the
1758 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
cationic units of the polymers with the anionic phos-phate groups of the nucleic acids Natural and biocompat-ible (eg chitosan Atelocollagen cyclodextrin) or morefrequently synthetic (eg Polyethylenimine PEI poly-L-lysine PLL poly-dl-lactide-co-glycolide PLGA) poly-mers are used for polyplex formation83ndash86 Flexibility of thesynthetic polymers in terms of chemical nature molecularweight and architecture (linear branched grafted blocky)provide opportunity to balance their toxicity improvenucleic acid binding protection and release efficienciesMoreover surface modifications may be introduced for tar-geting purposes and improved pharmacodynamics Poly-mers such as PLGA also benefit from a biodegradablenature which allows clearance of the nanocarriers in time
PEIPEI is the most widely and most successfully used polyca-tion for polyplexe formation It can be synthesized in lin-ear or branched forms and in variable molecular weights(from 1 kDa to gt 1000 kDa) Higher molecular weightpolymers (70 kDa and above) are very effective in nucleicacid binding but they are significantly toxic Low molec-ular weight forms (2 kDa or less) are less toxic but theyare less effective as transfection agents87 Therefore PEIsat and below 25 kDa with a branched or linear architec-ture are commonly used as gene delivery reagents88ndash91 Thegolden standard gene delivery polymer is branched PEIof 25 kDa which offers a balance between the toxicitynucleic acid bindingprotection and release Abundance ofpositive charges due to protonation under physiologicalconditions allows PEI to spontaneously form complexeswith negatively charged small RNAs and DNAs and pro-tect nucleic acid molecules from nuclease attacks84 More-over buried inside the polymer some off-target effects ofthe small RNAs were shown to be prevented92
The net positive charge of PEI-RNAi complexes alsoallow interactions with the negatively charged polysaccha-rides found on the cell surface93 These interactions arebelieved to be an important factor for the endocytosis ofthe complexes by target cells A key event for the successof gene delivery is the escape of the nucleic acids fromthe endosomal pathway in order to avoid accumulation anddegradation in the lysosomes of the cell93 The escape isthought to be the result of the lsquoproton spongersquo effect wherethe influx of protons and water lead to endosome swellingrupture and release of contents including nucleic acids tothe cytosolPEI-induced toxicity was proposed to be a result of
mitochondrial apoptosis induction by the polymer9495
Moreover PEI itself was shown to cause changes in geneexpression in vivo which might influence biological out-comes of treatment protocols59 PEGylation of the PEIreduces both cytotoxicity of PEI-polyplexes and increaseblood circulation half-life However a critical balanceneed to be achieved since PEGylation decreases the sur-face charge it impacts the binding capacity and cell
internalization of the polyplexes Alternatively short PEIchains attached together with hydrolysable links such asdisulfide and ester may provide initially a high molecu-lar weight PEI system for good nucleic acid condensationand protection but upon dissolution because of intracel-lular redox conditions they may act as a low molecularweight PEI polymers with lower toxicity87 Additionallypluronics that are block copolymers of ethylene glycol-propylene glycol-ethylene glycol can be used instead ofPEG Similar to PEG pluronics were shown to improvethe biocompatibility and bioavailability of the nanocarri-ers but they interact better with the cell membrane due tothe propylene glycol units and enhance cellular uptake ofthe particles87
PLGAPLGA is a biodegradable copolymer of glycolic acid andlactic acid96 It is widely used in biomedical research asan FDA-approved substance PLGA offers several advan-tages The polymer is highly stable biodegradable andallows sustained release During nucleic acid deliveryPLGA is easily taken up by cells through endocytosisand no serious toxicity problems were observed97 PLGAbinds nucleic acids weakly but it might encapsulate themfor drug delivery purposes Indeed PLGA nanoparticleswere used in several studies for delivery of drugs totumors through the EPR effects98 Yet following endocyto-sis PLGA particles do not effectively realease cargo fromendosomes8397 To overcome nucleic acid binding deliv-ery and endosomal release problems the surface of PLGAcan be decorated with various cationic nanoparticles suchas DOTAP PEI or polyamine and may be conjugated topeptides and antibodies99
DendrimersDendrimers are tree-like highly branched generally sym-metrical and three-dimensional macromolecules Theyhave uniform size and molecular weight which increaseswith each new branch (generation) Dendrimers possess ahighly functional outer surface allowing chemical modi-fications and interactions Therefore they may be used asflexible and modifiable gene delivery agents100 Besidesthe ability of dendrimers to encapsulate cargos add to theirpotential as drug carriers101 Dendrimers including poly-amidoamine dendrimers (PAMAM) poly-propylene imine(PPI) dendrimers poly-L-lysine dendrimers triazine den-drimers carbosilane dendrimers poly-glycerol-based den-drimers nanocarbon-based dendrimers and others weretested as RNAi delivery agents PAMAM and PPI den-drimers being the most commonly studied ones It wasshown that introduction of surface-modifications mini-mized toxicity-related problems increased RNAi-bindingand cellular uptake efficacies of the dendrimers102103
Of note in vivo gene expression changes were alsoobserved with drug-free dendrimers104 Therefore well
J Biomed Nanotechnol 10 1751ndash1783 2014 1759
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
controlled experiments are needed before drawing conclu-sions during RNA interference studies
AtelocollagenAtelocollagen is an organic protein-based moleculederived from type I collagen of calf dermis Sinceit is obtained following a pepsin treatment atelocolla-gen is devoid of telopeptides that are responsible forthe immunogenicity of collagen105 Moreover atelocol-lagen has low toxicity it was shown to stabilize RNAmolecules Increased cellular uptake and sustained deliv-ery was observed in in vivo making atelocollagen an idealagent for gene delivery106 Indeed several studies used ate-locollagen with success for the systemic or local deliveryof RNAi in tumor models107ndash109
ChitosanChitosan is obtained through alkaline deacetylation of thepolysaccharide chitin that forms the exoskeleton of crus-taceans some anthropods and insects Chitosan that is usedin biomedical research is a copolymer of N -acetyl-D-glucosamine and D-glucosamine having a positive chargeIn addition to being biodegradable and biocompatible chi-tosan has a low production cost Mucoadhesive propertiesof chitosan allow the penetration of the substance intoepithelial cell layers including the gastrointestinal barri-ers Nucleic acid encapsulation and sustained release wasproved to be possible using chitosan110ndash112 Moreover chi-tosan prolongs transient time in bowel improving par-enteral drug bioavailability113 Nanoparticles of chitosanare taken up into cells through endocytosis to a cer-tain extent To improve gene delivery efficacies PEG ordeoxycholic acid conjugates or modifications includingtrimethylation thiolation galactosylation may be intro-duced to chitosan111 Moreover chitosan-based carrierspossess functional groups that are suitable for conjugationto ligands relevant for targeted tumor delivery Althoughinefficient endosomal escape is a problem encounteredwith chitosan-based carriers some chemically modifiedforms showed improved escape properties114
CyclodextrinsCyclodextrins are natural polymers They are cyclicoligosaccharides of a glucopyranose generated during thebacterial digestion of cellulose Their central cavity ishydrophobic while the outer surface is a hydrophilicand they can create water-soluble molecular complexes115
Native cyclodextrins do not form stable complexeswith nucleic acids But the DNARNA complex for-mation capacities of the molecule can be modulatedand improved through molecular modifications includ-ing changes in functional groups hydrophilic-hydrophobicbalance charge density spacer length and conjugation toother carrier molecules115116 Cyclodextrins are not onlybiocompatible but they have the capacity to decrease
cytotoxicity of other molecules and carriers that are conju-gated to them117 Moreover cyclodextrins increase cellularadsorption and intake of molecules118 So in addition totheir use as a gene delivery agents cyclodextrins are usedas linking agents or structural modifiers in complex car-rier molecules For example conjugation of cyclodextrinto PEI resulted in lower toxicity and higher transfectionefficiencies119 In addition to the advantages cited abovea cyclodextrin polycation delivery system was reportedto block immune reactions raised against small RNAsthrough a masking effect120121 Importantly studies innon-human primates revealed that cyclodextrin-based car-riers were well tolerated and they do not stimulate signif-icant antibody responses120
AptamersAptamers are nucleic acid-based molecules selectedin vitro according to their capacity to bind target moleculesspecifically and with high affinity The immunogenicity ofaptamers is limited due to chemical modifications min-imizing adverse reactions Moreover nucleic acid natureand small size of aptamers result in improved transport andtissue penetration Since they can be specifically designedaccording to cell or tissue types (eg tumor cell com-ponents) side effects and off-target effects are minimalIn gene therapy applications the nucleic acid nature ofaptamers allows easy conjugation to RNADNA combin-ing targeting advantages with a therapeutic potential122
Alternatively non-covalent adapter linkages might be cre-ated between aptamers and RNA molecules Functionalgroups might be added to the 5prime- or 3prime-termini allowingcovalent or non-covalent conjugation of aptamers to carriernanoparticles123
Inorganic ParticlesInorganic nanoparticals such as carbon nanotubes mag-netic nanoparticles quantum dots and silica are the focusof recent efforts in drug and gene delivery Many of theseparticles actually offer the opportunity to combine imag-ing and therapeutic possibilities in the same particle ren-dering the nanocarrier a valuable ldquotheranosticrdquo device124
Increased surfacevolume ratio of inorganic particles pro-vides an opportunity for surface modifications includingconjugations to drugs oligonucleotides targeting peptidesor other molecules125126 Yet inorganic nanoparticles tendto aggregate and the size of the aggregate might have animpact on its function and biodistribution Such inorganicnanoparticles are hence coated with organic moleculeswhich provide colloid formation in aqueous and physiolog-ical media and stability Nature of the organic coatings hasto be designed for specific purposes but biocompatibilityof the organic molecules themselves andor their degra-dation products are critical for drug delivery purposes126
Chemistry of the coating might influence the half-life inblood and biodistribution as well as the toxicity of inor-ganic nanoparticles and their clearance mechanisms
1760 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Depending on the material they consist of inorganicnanoparticles may possess a number of different propertiessuch as high electron density and strong optical absorption(eg metal particles in particular Au) photoluminescenceor fluorescence (semiconductor quantum dots eg CdSeCdTe CdTeSeZnS) phosphorescence (doped oxide mate-rials eg Y2O3) or magnetic moment (eg iron oxide orcobalt nanoparticles) The shape of the nanoparticle is alsoan important factor influencing its interaction with cellsMany of the above mentioned nanoparticle are sphericalin shape except carbon nanotubes that are tubular
Carbon NanotubesCarbon nanotubes (CNTs) easily cross the plasma mem-brane and translocate directly into the cytoplasm of tar-get cells due to their nanoneedle structure and usingan endocytosis-independent mechanism yet they do notinduce cell death127ndash129 CNTs are classified as single-walled CNTs and multiwalled CNTs Single or multiplegraphine layer(s) might have a length ranging from 50 nmto 100 mm and a diameter of 1 nm to 100 nm Properfunctionalizing of CNTs by covalent or non-covalentstrategies (such as coating with PEG or Tween-20) mayprovide solubility in aqueous solutions and prevent non-specific interactions thus minimizing toxicity observedwith non-functionalized raw particles130131 Modificationsmight also increase biocompatibility and blood circulationhalf-life132133 CNTs have very strong absorption charac-teristics providing an opportunity for photothermal abla-tion therapy in addition to nanocarrier properties
Magnetic NanoparticlesMagnetic nanoparticles are composed of ferromagneticelements such as Ni Co Mn Fe Superparamagneticiron oxide nanoparticles (SPIONS) such as maghemite--Fe2O3 and magnetite-Fe3O4 are one of the most widelyused magnetic particles as nanocarriers due to relativelylow cost of production biocompatability and superpara-magnetic nature134135 SPIONS are approved by FDA forclinical trials They are commonly used as contrast agentsfor magnetic resonance imaging (MRI) SPION crystals(less than 10 nm in diameter) are coated for specificpurposes with organic molecules such as dextran aminodextran BSA PEI dendrimers lipids and trialkoxysi-lanes including aminopropyltriethoxy silane (APTES)Coating chemistry and preparation methods influence over-all hydrodynamic size pharmacokinetics and the contrasttype (dark-T 2 or bright-T 1 agent) Ability to track the fateof nucleic acid carrier magnetic nanoparticles in vivo usingMRI is highly desirable since it provides informationabout the location of the cargo and its biodistribution136
Attachment of ligands provides target specificity andPEGylation may improve biocompatibility and blood half-life These modifications are commonly introduced to SPI-ONs that are used for imaging and therapy purposes Due
to their magnetic nature drug or nucleic acid carrying SPI-ONs can be concentrated at desired diseased sites such astumors and they may be dragged magnetically towards thelesion area136137 Moreover magnetic nanoparticles offerthe possibility of hyperthermia treatment as a result ofmagnetic heating135 Under applied alternating magneticfield SPIONs cause local temperature increase (41ndash42 C)which may be exploited for alternative and efficient cancertherapy Therefore SPIONs are one of the most versatileand multifunctional nanoparticles Consequently SPIONswere used as popular gene delivery vehicles135
Magnetic nanoparticles may be engineered for oligonu-cleotide delivery purposes MRI visible PEI-PEG coatedSPIONs which are tagged with an antibody have beenshown to effectively carry siRNA to cancer cell lines andshowed low toxicity138 SPIONs coated with both thermoresponsive and cationic polymers such as poly[2-(2-methoxyethoxy)ethylmethacrylate]-b-poly-[2-(dimethyl-amino)ethyl methacrylate] were reported to have25ndash100 times better transfection efficiency than branchedPEI 25 kDa when coupled with magnetic targeting139
SPIONs coated with low molecular weight PEI(12ndash2 kDa) which is usually not effective as poly-plexes in transfection were shown succesful in deliveringsiRNA to mouse macrophages (H Yagci Acar WIPOPatent WO2006055447A3) Therefore magnetic nanpar-ticles are under heavy investigation for the developmentof multifunctional nanocarriers for cancer therapy anddiagnosis135
Quantum DotsSemiconductor quantum dots (QDs) are light-emittingnanoparticles of few nanometer in diameter and they havebeen increasingly used as biological imaging and labelingprobes140 Luminescencefluorescence properties of QDsdepend on the crystal size and type Chemical composi-tion of the crystalline semiconductor core determines theband gap of the material therefore the emission wave-length range Within possible spectral window size ofthe crystal determines the specific wavelength of lumines-cencefluorescence for each and every QD due to quan-tum confinement effect Broad absorption of QDs allowexcitation of multiple QDs at a single wavelength andminimal signal mixing due to the narrow emission bandIn addition they are much more resistant to photobleach-ing These two characteristics are the major advantages ofQDs compared to organic fluorophores as imaging probesUtilization of QDs in nucleic acid delivery aims bothimaging and therapy since in vivo localization of cargocan be observed using optical imaging systems141142 Forexample cationic CdTeZnS QDs conjugated with PEGwas demonstrated to form an effective nanoplex with sur-vivin siRNA and successfully transfeced human tonguecancer cells in vitro and provided real time tracking143
However well-established QDs harbour significant toxic-ity due to constituents such as Cd Se Te144 Therefore
J Biomed Nanotechnol 10 1751ndash1783 2014 1761
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
toxicity of these QDs is a drawback for their use in vivoAs an alternative silver (Ag) chalcogenites emerged assafer near-infra red-emitting QDs145146 Ag2S QDs did notinduce cytotoxicity ROS production apoptosis necrosisor DNA damage147 For example Ag2S QDs (coated with2-mercaptopropionic acid) emitting between 750ndash850 nmshowed no cytotoxicity in NIH3T3 cells at even highdoses (600 mgml) along with good cellular imagingpotential148
Gold NanoparticlesGold nanoparticles emerged as popular tools fornanocarrier-mediated gene therapy149 They are easily syn-thesized and biocompatible particles that allow addition offunctional molecules on their surface due to high surface-to-volume ratio114150 A variety of surface changes andfunctional additions were reported including cationic lipidcoating branched PEI addition or functionalization usingcationic quaternary ammonium or cystamine114151152
Indeed cystamine functionalized gold nanoparticles wereshown to effectively bind deliver and release 35 differ-ent miRNA in in vitro studies using neuroblastoma andovarian cancer cell lines153
Silica NanoparticlesSilica-based nanoparticles are inert stable biocompati-ble and biodegradable particles154 They can be renderedhydrophilic hydrophobic anionic or cationic using func-tional surface modifiers through electrostatic interactionsor by formation of any other type covalent bonds (egester amine) Common functionalization strategies to ren-der the molecule cationic and improve nucleic acid bind-ing include grafting of molecules such as PEI PEI-PEGand Poly-L-arginine155 Nucleic acids may also be loadedinside the mesoporous silica particles156 siRNA encapsu-lating mesoporous silica nanoparticles were successfullyused for in vitro and in vivo gene silencing in several stud-ies (For example Ref [156])
RECENT IN VIVO STUDIES USING RNAINTERFERENCE IN CANCER THERAPYThere is an exponential increase in the number of scientificpublications dedicated to gene therapy of diseases usingsmall RNAs and nanoparticles A literature search usingldquonanoparticlerdquo and ldquosiRNA shRNA or miRNArdquo revealedmore than 700 articles published in the last two yearsThis number is roughly equal to the number of all articlespublished in this field until two years ago So the field isexpanding and there seems to form a consensus aroundthe use of nanoparticles as next generation gene therapytools We believe that these high expectations are not onlya consequence of shifting trends in science and technol-ogy The exponential rise in interest in the field of smallRNA carrier nanoparticles is fueled by the advances inthe field of nano materials promising results obtained in
small RNA therapeutics by both academic laboratories andindustry and increasing number of successful clinical tri-als In this section we will summarize results of selectedrecent studies using RNA therapeutics for cancer treatmentin preclinical in vivo experimentsOverview of the works dealing with small RNA treat-
ment of experimental cancers and published within thelast two years were summarized in Table I Although sev-eral studies were performed using lipid-based nanopar-ticles (Liposomes micelles or lipidoids) other particlessuch as polymers organic or inorganic carriers and com-pounds mixtures with functional modifications of vari-able substances were also tested by many research teamswith reasonable success Scheme 4 summarizes the generalstrategy followed in most of these studies
Tumor Types and RNAi TherapyRecent studies in the literature showed that tumors of vari-ous tissue origins could be treated using RNA interferencestrategies (Table I) Fine tuning of nanoparticles throughaddition of functional moieties or modifications alloweddelivery of drugs into almost any kind of tumor tissue withaccompanied therapeutic effects Although several studiesused animal tumor models that resulted from the injectionof cell lines from most commonly seen human cancers(lung breast prostate cervix or ovarian cancer cell lines)animals with kidney urinary bladder head and neckgastric pancreatic melanomas neuroblastomas glioblas-tomas multiple myelomas or sarcomas were also treatedwith RNAinanocarrier strategy81156ndash170 These results givehope about the general use of RNA interference as astrategy to treat cancers of different origins Althoughit is difficult to compare the efficacies of different nucleicacid molecules and their interference effects at this pointsiRNA or microRNAs as well as shRNA vectors wereshown to achieve intratumoral in vivo target gene knock-down and anticancer effects leading to a decrease in tumorsize (For example Refs [156 171]) Since in most studiesin addition to RNAi loaded particles naked nanoparticlesor particles loaded with non-specific control nucleic acidswere also used antitumor effects obtained in these studiesare specific and they may be attributable to small RNAmolecules rather than the particles themselves underliningthe potential of RNA interference in cancer treatmentMajority of recent studies with in vivo models chose
to use human tumor cell line xenografts in immune com-promised mice nude or severe-combined immuno defi-cient SCID mice (Table I) (For example Refs [162 172])Syngeneic transplants and established genetically engi-neered mouse models of cancer were rarely studied in thiscontext167173ndash175 Therefore although antitumor effects andsome of the toxic effects (eg liver toxicity) might berevealed using immune compromised mice hematologicalimmunological and inflammatory side effects of the treat-ment strategies used in recent studies might need to berevisited using immunocompetent mice
1762 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IRec
entstudieswithRNAica
rryingnan
oparticles
forthetrea
tmen
tofex
perim
entalca
nce
rs(P
ublis
hed
within
thelast
twoye
ars)
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGF
Mag
netic
mes
oporou
ssilicana
nopa
rticles
PEIan
dfuso
genicpe
ptide
KALA
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[156
]
siRNA
Polo-likekina
se1(P
LK1)
pH-sen
sitiveca
tioniclip
idYSK05
-MEND
(YSK05
POPEcho
lesterol
=50
2525
)
PEG
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
PLK
1[51]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Bioen
gine
ered
bacterial
outermem
bran
eve
sicles
Hum
anep
idermal
grow
thfactor
rece
ptor
2(H
ER2)-spe
cific
affib
ody
targeting
HCC-195
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
KSP
Dec
reas
edtumor
volume
[81]
siRNA
Luciferase
Dioleoy
lpho
spha
tidic
acid-(DOPA
-)co
ated
nano
-sized
calcium
phos
phate(LCP-II)
DSPE-P
EG-an
dan
isam
idefortargeting
sigm
a-1rece
ptor
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
Xen
ograft
it
ND
Kno
ckdo
wnof
luciferase
[211
]
siRNA
mTERT
N-((2-hyd
roxy
-3-trim
ethy
l-am
mon
ium)propy
l)ch
itosa
nch
lorid
e(H
TCC)na
nopa
rticles
Partic
leload
edwith
paclita
xel
LCC
murinelung
canc
erce
llssy
ngen
eicsc
graft
oral
Noeffect
Kno
ckdo
wnof
mTERT
Dec
reas
edtumor
volume
Syn
ergize
dwith
paclita
xel
[159
]
siRNA
VEGF
Multilay
ered
polyion
complexes
Polyc
ationinterla
yeran
dade
tach
able
PEG
shell
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
[212
]
siRNA
Multid
rug
resistan
ceprotein1
(MRP1)
Nan
opartic
lesas
sembled
vialaye
r-by
laye
rde
positio
nof
siRNA
and
poly-L-arginine
Hya
lurona
n(H
A)co
ating
forHA-C
D44
targeting
MDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
it
Noeffect
Kno
ckdo
wnof
MRP1
Dec
reas
edtumor
volume
[183
]
siRNA
STA
T3-a
Nan
oporou
ssilicon
nano
particles
Argininean
dPEI
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicefat
padxe
nograft
iv
Noeffect
Kno
ckdo
wnof
STA
T3-a
[204
]
siRNA
Luciferase
Lipo
somal
nano
particle
Fou
rtand
emrepe
atsof
human
histon
eH2A
peptideinterven
edby
cathep
sinD
clea
vage
sites
PEG-A
nisa
mide
fortargeting
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
luciferase
[199
]
siRNA
Polo-likekina
se1(P
LK1)
Hya
luronicac
id(H
A)
base
dse
lfass
embling
HA-P
EIP
EG
nano
system
s
Hya
lurona
nforCD44
targeting
B16
F10
amurine
melan
omace
llsA54
9-luchu
man
lung
canc
erce
llsHep
3Bhu
man
liver
canc
erce
llsMDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
graftor
metas
tatic
lung
lesion
sby
IVinjection
it
ND
Kno
ckdo
wnof
PLK
1[160
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1763
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
P-glyco
protein
drug
expo
rter
(P-
gpM
DR1)
Mes
oporou
ssilica
nano
particles
Polye
thylen
eimine
polyethy
lene
glyc
ol(P
EI-PEG)co
polymer
MCF-7M
DR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gpMDR1
Dec
reas
edtumor
volume
Syn
ergy
with
doxo
rubicin
[179
]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Multifun
ctiona
lcarrie
rsy
stem
with
catio
nic
(olig
oethan
amino)am
ide
core
attach
edto
PEG
chain
Folic
acid
fortargeting
Inf7
(Infl
uenz
ape
ptide)
asen
doso
molytic
peptide
coup
ledto
the5prime-end
ofsiRNA
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
itor
iv
ND
Kno
ckdo
wnof
EG5
Dec
reas
edtumor
volume
[161
]
siRNA
Epide
rmal
Growth
Factor
Rec
eptor
(EGFR)
Poly-L-argininean
dde
xtransu
lfate-bas
edna
noco
mplex
FaDuhu
man
pharyn
xsq
uamou
sca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[172
]
siRNA
Cho
line
kina
se(C
hk)
Polye
thylen
imine-
polyethy
lene
glyc
ol(P
EI-PEG)co
grafted
polymer
Con
versionof
nontox
ic5-flu
oroc
ytos
ine(5-FC)to
cytotoxic5-flu
orou
racil
(5-FU)by
activating
bacterialc
ytos
ine
deam
inas
e(bCD)
PC3-PIP
andPC3-Flu
human
pros
tate
canc
erce
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
e[157
]
siRNA
Polo-like
kina
se1
(Plk1)
Cationiclip
idpo
lymer
hybrid
nano
particles
(cationiclip
id(N
N-
bis(2-hy
drox
yethyl)-N-
methy
l-N-(2-
choles
teryloxy
carbon
ylam
inoe
thyl)am
mon
ium
brom
ide
BHEM-C
hol)
andam
phiphilic
polymers(H
ydroph
obic
polylactideco
re)
PEG
shell
BT47
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Plk1
Dec
reas
edtumor
volume
[213
]
siRNA
hTERT
Single-walledca
rbon
nano
tube
s(S
WNTs)
Branc
hedPEIco
njug
ated
DSPE-P
EG20
00-M
aleimide
forco
njug
ationwith
NGR
(Cys
-Asn
-Gly-A
rg-C
ys-)
targetingpe
ptide(rec
ognize
tumor
neov
ascu
lature)
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
hTERT
Dec
reas
edtumor
volume
Syn
ergy
with
photothe
rmal
trea
tmen
t
[139
]
1764 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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1776 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
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1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
cationic units of the polymers with the anionic phos-phate groups of the nucleic acids Natural and biocompat-ible (eg chitosan Atelocollagen cyclodextrin) or morefrequently synthetic (eg Polyethylenimine PEI poly-L-lysine PLL poly-dl-lactide-co-glycolide PLGA) poly-mers are used for polyplex formation83ndash86 Flexibility of thesynthetic polymers in terms of chemical nature molecularweight and architecture (linear branched grafted blocky)provide opportunity to balance their toxicity improvenucleic acid binding protection and release efficienciesMoreover surface modifications may be introduced for tar-geting purposes and improved pharmacodynamics Poly-mers such as PLGA also benefit from a biodegradablenature which allows clearance of the nanocarriers in time
PEIPEI is the most widely and most successfully used polyca-tion for polyplexe formation It can be synthesized in lin-ear or branched forms and in variable molecular weights(from 1 kDa to gt 1000 kDa) Higher molecular weightpolymers (70 kDa and above) are very effective in nucleicacid binding but they are significantly toxic Low molec-ular weight forms (2 kDa or less) are less toxic but theyare less effective as transfection agents87 Therefore PEIsat and below 25 kDa with a branched or linear architec-ture are commonly used as gene delivery reagents88ndash91 Thegolden standard gene delivery polymer is branched PEIof 25 kDa which offers a balance between the toxicitynucleic acid bindingprotection and release Abundance ofpositive charges due to protonation under physiologicalconditions allows PEI to spontaneously form complexeswith negatively charged small RNAs and DNAs and pro-tect nucleic acid molecules from nuclease attacks84 More-over buried inside the polymer some off-target effects ofthe small RNAs were shown to be prevented92
The net positive charge of PEI-RNAi complexes alsoallow interactions with the negatively charged polysaccha-rides found on the cell surface93 These interactions arebelieved to be an important factor for the endocytosis ofthe complexes by target cells A key event for the successof gene delivery is the escape of the nucleic acids fromthe endosomal pathway in order to avoid accumulation anddegradation in the lysosomes of the cell93 The escape isthought to be the result of the lsquoproton spongersquo effect wherethe influx of protons and water lead to endosome swellingrupture and release of contents including nucleic acids tothe cytosolPEI-induced toxicity was proposed to be a result of
mitochondrial apoptosis induction by the polymer9495
Moreover PEI itself was shown to cause changes in geneexpression in vivo which might influence biological out-comes of treatment protocols59 PEGylation of the PEIreduces both cytotoxicity of PEI-polyplexes and increaseblood circulation half-life However a critical balanceneed to be achieved since PEGylation decreases the sur-face charge it impacts the binding capacity and cell
internalization of the polyplexes Alternatively short PEIchains attached together with hydrolysable links such asdisulfide and ester may provide initially a high molecu-lar weight PEI system for good nucleic acid condensationand protection but upon dissolution because of intracel-lular redox conditions they may act as a low molecularweight PEI polymers with lower toxicity87 Additionallypluronics that are block copolymers of ethylene glycol-propylene glycol-ethylene glycol can be used instead ofPEG Similar to PEG pluronics were shown to improvethe biocompatibility and bioavailability of the nanocarri-ers but they interact better with the cell membrane due tothe propylene glycol units and enhance cellular uptake ofthe particles87
PLGAPLGA is a biodegradable copolymer of glycolic acid andlactic acid96 It is widely used in biomedical research asan FDA-approved substance PLGA offers several advan-tages The polymer is highly stable biodegradable andallows sustained release During nucleic acid deliveryPLGA is easily taken up by cells through endocytosisand no serious toxicity problems were observed97 PLGAbinds nucleic acids weakly but it might encapsulate themfor drug delivery purposes Indeed PLGA nanoparticleswere used in several studies for delivery of drugs totumors through the EPR effects98 Yet following endocyto-sis PLGA particles do not effectively realease cargo fromendosomes8397 To overcome nucleic acid binding deliv-ery and endosomal release problems the surface of PLGAcan be decorated with various cationic nanoparticles suchas DOTAP PEI or polyamine and may be conjugated topeptides and antibodies99
DendrimersDendrimers are tree-like highly branched generally sym-metrical and three-dimensional macromolecules Theyhave uniform size and molecular weight which increaseswith each new branch (generation) Dendrimers possess ahighly functional outer surface allowing chemical modi-fications and interactions Therefore they may be used asflexible and modifiable gene delivery agents100 Besidesthe ability of dendrimers to encapsulate cargos add to theirpotential as drug carriers101 Dendrimers including poly-amidoamine dendrimers (PAMAM) poly-propylene imine(PPI) dendrimers poly-L-lysine dendrimers triazine den-drimers carbosilane dendrimers poly-glycerol-based den-drimers nanocarbon-based dendrimers and others weretested as RNAi delivery agents PAMAM and PPI den-drimers being the most commonly studied ones It wasshown that introduction of surface-modifications mini-mized toxicity-related problems increased RNAi-bindingand cellular uptake efficacies of the dendrimers102103
Of note in vivo gene expression changes were alsoobserved with drug-free dendrimers104 Therefore well
J Biomed Nanotechnol 10 1751ndash1783 2014 1759
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
controlled experiments are needed before drawing conclu-sions during RNA interference studies
AtelocollagenAtelocollagen is an organic protein-based moleculederived from type I collagen of calf dermis Sinceit is obtained following a pepsin treatment atelocolla-gen is devoid of telopeptides that are responsible forthe immunogenicity of collagen105 Moreover atelocol-lagen has low toxicity it was shown to stabilize RNAmolecules Increased cellular uptake and sustained deliv-ery was observed in in vivo making atelocollagen an idealagent for gene delivery106 Indeed several studies used ate-locollagen with success for the systemic or local deliveryof RNAi in tumor models107ndash109
ChitosanChitosan is obtained through alkaline deacetylation of thepolysaccharide chitin that forms the exoskeleton of crus-taceans some anthropods and insects Chitosan that is usedin biomedical research is a copolymer of N -acetyl-D-glucosamine and D-glucosamine having a positive chargeIn addition to being biodegradable and biocompatible chi-tosan has a low production cost Mucoadhesive propertiesof chitosan allow the penetration of the substance intoepithelial cell layers including the gastrointestinal barri-ers Nucleic acid encapsulation and sustained release wasproved to be possible using chitosan110ndash112 Moreover chi-tosan prolongs transient time in bowel improving par-enteral drug bioavailability113 Nanoparticles of chitosanare taken up into cells through endocytosis to a cer-tain extent To improve gene delivery efficacies PEG ordeoxycholic acid conjugates or modifications includingtrimethylation thiolation galactosylation may be intro-duced to chitosan111 Moreover chitosan-based carrierspossess functional groups that are suitable for conjugationto ligands relevant for targeted tumor delivery Althoughinefficient endosomal escape is a problem encounteredwith chitosan-based carriers some chemically modifiedforms showed improved escape properties114
CyclodextrinsCyclodextrins are natural polymers They are cyclicoligosaccharides of a glucopyranose generated during thebacterial digestion of cellulose Their central cavity ishydrophobic while the outer surface is a hydrophilicand they can create water-soluble molecular complexes115
Native cyclodextrins do not form stable complexeswith nucleic acids But the DNARNA complex for-mation capacities of the molecule can be modulatedand improved through molecular modifications includ-ing changes in functional groups hydrophilic-hydrophobicbalance charge density spacer length and conjugation toother carrier molecules115116 Cyclodextrins are not onlybiocompatible but they have the capacity to decrease
cytotoxicity of other molecules and carriers that are conju-gated to them117 Moreover cyclodextrins increase cellularadsorption and intake of molecules118 So in addition totheir use as a gene delivery agents cyclodextrins are usedas linking agents or structural modifiers in complex car-rier molecules For example conjugation of cyclodextrinto PEI resulted in lower toxicity and higher transfectionefficiencies119 In addition to the advantages cited abovea cyclodextrin polycation delivery system was reportedto block immune reactions raised against small RNAsthrough a masking effect120121 Importantly studies innon-human primates revealed that cyclodextrin-based car-riers were well tolerated and they do not stimulate signif-icant antibody responses120
AptamersAptamers are nucleic acid-based molecules selectedin vitro according to their capacity to bind target moleculesspecifically and with high affinity The immunogenicity ofaptamers is limited due to chemical modifications min-imizing adverse reactions Moreover nucleic acid natureand small size of aptamers result in improved transport andtissue penetration Since they can be specifically designedaccording to cell or tissue types (eg tumor cell com-ponents) side effects and off-target effects are minimalIn gene therapy applications the nucleic acid nature ofaptamers allows easy conjugation to RNADNA combin-ing targeting advantages with a therapeutic potential122
Alternatively non-covalent adapter linkages might be cre-ated between aptamers and RNA molecules Functionalgroups might be added to the 5prime- or 3prime-termini allowingcovalent or non-covalent conjugation of aptamers to carriernanoparticles123
Inorganic ParticlesInorganic nanoparticals such as carbon nanotubes mag-netic nanoparticles quantum dots and silica are the focusof recent efforts in drug and gene delivery Many of theseparticles actually offer the opportunity to combine imag-ing and therapeutic possibilities in the same particle ren-dering the nanocarrier a valuable ldquotheranosticrdquo device124
Increased surfacevolume ratio of inorganic particles pro-vides an opportunity for surface modifications includingconjugations to drugs oligonucleotides targeting peptidesor other molecules125126 Yet inorganic nanoparticles tendto aggregate and the size of the aggregate might have animpact on its function and biodistribution Such inorganicnanoparticles are hence coated with organic moleculeswhich provide colloid formation in aqueous and physiolog-ical media and stability Nature of the organic coatings hasto be designed for specific purposes but biocompatibilityof the organic molecules themselves andor their degra-dation products are critical for drug delivery purposes126
Chemistry of the coating might influence the half-life inblood and biodistribution as well as the toxicity of inor-ganic nanoparticles and their clearance mechanisms
1760 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Depending on the material they consist of inorganicnanoparticles may possess a number of different propertiessuch as high electron density and strong optical absorption(eg metal particles in particular Au) photoluminescenceor fluorescence (semiconductor quantum dots eg CdSeCdTe CdTeSeZnS) phosphorescence (doped oxide mate-rials eg Y2O3) or magnetic moment (eg iron oxide orcobalt nanoparticles) The shape of the nanoparticle is alsoan important factor influencing its interaction with cellsMany of the above mentioned nanoparticle are sphericalin shape except carbon nanotubes that are tubular
Carbon NanotubesCarbon nanotubes (CNTs) easily cross the plasma mem-brane and translocate directly into the cytoplasm of tar-get cells due to their nanoneedle structure and usingan endocytosis-independent mechanism yet they do notinduce cell death127ndash129 CNTs are classified as single-walled CNTs and multiwalled CNTs Single or multiplegraphine layer(s) might have a length ranging from 50 nmto 100 mm and a diameter of 1 nm to 100 nm Properfunctionalizing of CNTs by covalent or non-covalentstrategies (such as coating with PEG or Tween-20) mayprovide solubility in aqueous solutions and prevent non-specific interactions thus minimizing toxicity observedwith non-functionalized raw particles130131 Modificationsmight also increase biocompatibility and blood circulationhalf-life132133 CNTs have very strong absorption charac-teristics providing an opportunity for photothermal abla-tion therapy in addition to nanocarrier properties
Magnetic NanoparticlesMagnetic nanoparticles are composed of ferromagneticelements such as Ni Co Mn Fe Superparamagneticiron oxide nanoparticles (SPIONS) such as maghemite--Fe2O3 and magnetite-Fe3O4 are one of the most widelyused magnetic particles as nanocarriers due to relativelylow cost of production biocompatability and superpara-magnetic nature134135 SPIONS are approved by FDA forclinical trials They are commonly used as contrast agentsfor magnetic resonance imaging (MRI) SPION crystals(less than 10 nm in diameter) are coated for specificpurposes with organic molecules such as dextran aminodextran BSA PEI dendrimers lipids and trialkoxysi-lanes including aminopropyltriethoxy silane (APTES)Coating chemistry and preparation methods influence over-all hydrodynamic size pharmacokinetics and the contrasttype (dark-T 2 or bright-T 1 agent) Ability to track the fateof nucleic acid carrier magnetic nanoparticles in vivo usingMRI is highly desirable since it provides informationabout the location of the cargo and its biodistribution136
Attachment of ligands provides target specificity andPEGylation may improve biocompatibility and blood half-life These modifications are commonly introduced to SPI-ONs that are used for imaging and therapy purposes Due
to their magnetic nature drug or nucleic acid carrying SPI-ONs can be concentrated at desired diseased sites such astumors and they may be dragged magnetically towards thelesion area136137 Moreover magnetic nanoparticles offerthe possibility of hyperthermia treatment as a result ofmagnetic heating135 Under applied alternating magneticfield SPIONs cause local temperature increase (41ndash42 C)which may be exploited for alternative and efficient cancertherapy Therefore SPIONs are one of the most versatileand multifunctional nanoparticles Consequently SPIONswere used as popular gene delivery vehicles135
Magnetic nanoparticles may be engineered for oligonu-cleotide delivery purposes MRI visible PEI-PEG coatedSPIONs which are tagged with an antibody have beenshown to effectively carry siRNA to cancer cell lines andshowed low toxicity138 SPIONs coated with both thermoresponsive and cationic polymers such as poly[2-(2-methoxyethoxy)ethylmethacrylate]-b-poly-[2-(dimethyl-amino)ethyl methacrylate] were reported to have25ndash100 times better transfection efficiency than branchedPEI 25 kDa when coupled with magnetic targeting139
SPIONs coated with low molecular weight PEI(12ndash2 kDa) which is usually not effective as poly-plexes in transfection were shown succesful in deliveringsiRNA to mouse macrophages (H Yagci Acar WIPOPatent WO2006055447A3) Therefore magnetic nanpar-ticles are under heavy investigation for the developmentof multifunctional nanocarriers for cancer therapy anddiagnosis135
Quantum DotsSemiconductor quantum dots (QDs) are light-emittingnanoparticles of few nanometer in diameter and they havebeen increasingly used as biological imaging and labelingprobes140 Luminescencefluorescence properties of QDsdepend on the crystal size and type Chemical composi-tion of the crystalline semiconductor core determines theband gap of the material therefore the emission wave-length range Within possible spectral window size ofthe crystal determines the specific wavelength of lumines-cencefluorescence for each and every QD due to quan-tum confinement effect Broad absorption of QDs allowexcitation of multiple QDs at a single wavelength andminimal signal mixing due to the narrow emission bandIn addition they are much more resistant to photobleach-ing These two characteristics are the major advantages ofQDs compared to organic fluorophores as imaging probesUtilization of QDs in nucleic acid delivery aims bothimaging and therapy since in vivo localization of cargocan be observed using optical imaging systems141142 Forexample cationic CdTeZnS QDs conjugated with PEGwas demonstrated to form an effective nanoplex with sur-vivin siRNA and successfully transfeced human tonguecancer cells in vitro and provided real time tracking143
However well-established QDs harbour significant toxic-ity due to constituents such as Cd Se Te144 Therefore
J Biomed Nanotechnol 10 1751ndash1783 2014 1761
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
toxicity of these QDs is a drawback for their use in vivoAs an alternative silver (Ag) chalcogenites emerged assafer near-infra red-emitting QDs145146 Ag2S QDs did notinduce cytotoxicity ROS production apoptosis necrosisor DNA damage147 For example Ag2S QDs (coated with2-mercaptopropionic acid) emitting between 750ndash850 nmshowed no cytotoxicity in NIH3T3 cells at even highdoses (600 mgml) along with good cellular imagingpotential148
Gold NanoparticlesGold nanoparticles emerged as popular tools fornanocarrier-mediated gene therapy149 They are easily syn-thesized and biocompatible particles that allow addition offunctional molecules on their surface due to high surface-to-volume ratio114150 A variety of surface changes andfunctional additions were reported including cationic lipidcoating branched PEI addition or functionalization usingcationic quaternary ammonium or cystamine114151152
Indeed cystamine functionalized gold nanoparticles wereshown to effectively bind deliver and release 35 differ-ent miRNA in in vitro studies using neuroblastoma andovarian cancer cell lines153
Silica NanoparticlesSilica-based nanoparticles are inert stable biocompati-ble and biodegradable particles154 They can be renderedhydrophilic hydrophobic anionic or cationic using func-tional surface modifiers through electrostatic interactionsor by formation of any other type covalent bonds (egester amine) Common functionalization strategies to ren-der the molecule cationic and improve nucleic acid bind-ing include grafting of molecules such as PEI PEI-PEGand Poly-L-arginine155 Nucleic acids may also be loadedinside the mesoporous silica particles156 siRNA encapsu-lating mesoporous silica nanoparticles were successfullyused for in vitro and in vivo gene silencing in several stud-ies (For example Ref [156])
RECENT IN VIVO STUDIES USING RNAINTERFERENCE IN CANCER THERAPYThere is an exponential increase in the number of scientificpublications dedicated to gene therapy of diseases usingsmall RNAs and nanoparticles A literature search usingldquonanoparticlerdquo and ldquosiRNA shRNA or miRNArdquo revealedmore than 700 articles published in the last two yearsThis number is roughly equal to the number of all articlespublished in this field until two years ago So the field isexpanding and there seems to form a consensus aroundthe use of nanoparticles as next generation gene therapytools We believe that these high expectations are not onlya consequence of shifting trends in science and technol-ogy The exponential rise in interest in the field of smallRNA carrier nanoparticles is fueled by the advances inthe field of nano materials promising results obtained in
small RNA therapeutics by both academic laboratories andindustry and increasing number of successful clinical tri-als In this section we will summarize results of selectedrecent studies using RNA therapeutics for cancer treatmentin preclinical in vivo experimentsOverview of the works dealing with small RNA treat-
ment of experimental cancers and published within thelast two years were summarized in Table I Although sev-eral studies were performed using lipid-based nanopar-ticles (Liposomes micelles or lipidoids) other particlessuch as polymers organic or inorganic carriers and com-pounds mixtures with functional modifications of vari-able substances were also tested by many research teamswith reasonable success Scheme 4 summarizes the generalstrategy followed in most of these studies
Tumor Types and RNAi TherapyRecent studies in the literature showed that tumors of vari-ous tissue origins could be treated using RNA interferencestrategies (Table I) Fine tuning of nanoparticles throughaddition of functional moieties or modifications alloweddelivery of drugs into almost any kind of tumor tissue withaccompanied therapeutic effects Although several studiesused animal tumor models that resulted from the injectionof cell lines from most commonly seen human cancers(lung breast prostate cervix or ovarian cancer cell lines)animals with kidney urinary bladder head and neckgastric pancreatic melanomas neuroblastomas glioblas-tomas multiple myelomas or sarcomas were also treatedwith RNAinanocarrier strategy81156ndash170 These results givehope about the general use of RNA interference as astrategy to treat cancers of different origins Althoughit is difficult to compare the efficacies of different nucleicacid molecules and their interference effects at this pointsiRNA or microRNAs as well as shRNA vectors wereshown to achieve intratumoral in vivo target gene knock-down and anticancer effects leading to a decrease in tumorsize (For example Refs [156 171]) Since in most studiesin addition to RNAi loaded particles naked nanoparticlesor particles loaded with non-specific control nucleic acidswere also used antitumor effects obtained in these studiesare specific and they may be attributable to small RNAmolecules rather than the particles themselves underliningthe potential of RNA interference in cancer treatmentMajority of recent studies with in vivo models chose
to use human tumor cell line xenografts in immune com-promised mice nude or severe-combined immuno defi-cient SCID mice (Table I) (For example Refs [162 172])Syngeneic transplants and established genetically engi-neered mouse models of cancer were rarely studied in thiscontext167173ndash175 Therefore although antitumor effects andsome of the toxic effects (eg liver toxicity) might berevealed using immune compromised mice hematologicalimmunological and inflammatory side effects of the treat-ment strategies used in recent studies might need to berevisited using immunocompetent mice
1762 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IRec
entstudieswithRNAica
rryingnan
oparticles
forthetrea
tmen
tofex
perim
entalca
nce
rs(P
ublis
hed
within
thelast
twoye
ars)
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGF
Mag
netic
mes
oporou
ssilicana
nopa
rticles
PEIan
dfuso
genicpe
ptide
KALA
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[156
]
siRNA
Polo-likekina
se1(P
LK1)
pH-sen
sitiveca
tioniclip
idYSK05
-MEND
(YSK05
POPEcho
lesterol
=50
2525
)
PEG
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
PLK
1[51]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Bioen
gine
ered
bacterial
outermem
bran
eve
sicles
Hum
anep
idermal
grow
thfactor
rece
ptor
2(H
ER2)-spe
cific
affib
ody
targeting
HCC-195
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
KSP
Dec
reas
edtumor
volume
[81]
siRNA
Luciferase
Dioleoy
lpho
spha
tidic
acid-(DOPA
-)co
ated
nano
-sized
calcium
phos
phate(LCP-II)
DSPE-P
EG-an
dan
isam
idefortargeting
sigm
a-1rece
ptor
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
Xen
ograft
it
ND
Kno
ckdo
wnof
luciferase
[211
]
siRNA
mTERT
N-((2-hyd
roxy
-3-trim
ethy
l-am
mon
ium)propy
l)ch
itosa
nch
lorid
e(H
TCC)na
nopa
rticles
Partic
leload
edwith
paclita
xel
LCC
murinelung
canc
erce
llssy
ngen
eicsc
graft
oral
Noeffect
Kno
ckdo
wnof
mTERT
Dec
reas
edtumor
volume
Syn
ergize
dwith
paclita
xel
[159
]
siRNA
VEGF
Multilay
ered
polyion
complexes
Polyc
ationinterla
yeran
dade
tach
able
PEG
shell
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
[212
]
siRNA
Multid
rug
resistan
ceprotein1
(MRP1)
Nan
opartic
lesas
sembled
vialaye
r-by
laye
rde
positio
nof
siRNA
and
poly-L-arginine
Hya
lurona
n(H
A)co
ating
forHA-C
D44
targeting
MDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
it
Noeffect
Kno
ckdo
wnof
MRP1
Dec
reas
edtumor
volume
[183
]
siRNA
STA
T3-a
Nan
oporou
ssilicon
nano
particles
Argininean
dPEI
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicefat
padxe
nograft
iv
Noeffect
Kno
ckdo
wnof
STA
T3-a
[204
]
siRNA
Luciferase
Lipo
somal
nano
particle
Fou
rtand
emrepe
atsof
human
histon
eH2A
peptideinterven
edby
cathep
sinD
clea
vage
sites
PEG-A
nisa
mide
fortargeting
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
luciferase
[199
]
siRNA
Polo-likekina
se1(P
LK1)
Hya
luronicac
id(H
A)
base
dse
lfass
embling
HA-P
EIP
EG
nano
system
s
Hya
lurona
nforCD44
targeting
B16
F10
amurine
melan
omace
llsA54
9-luchu
man
lung
canc
erce
llsHep
3Bhu
man
liver
canc
erce
llsMDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
graftor
metas
tatic
lung
lesion
sby
IVinjection
it
ND
Kno
ckdo
wnof
PLK
1[160
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1763
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
P-glyco
protein
drug
expo
rter
(P-
gpM
DR1)
Mes
oporou
ssilica
nano
particles
Polye
thylen
eimine
polyethy
lene
glyc
ol(P
EI-PEG)co
polymer
MCF-7M
DR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gpMDR1
Dec
reas
edtumor
volume
Syn
ergy
with
doxo
rubicin
[179
]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Multifun
ctiona
lcarrie
rsy
stem
with
catio
nic
(olig
oethan
amino)am
ide
core
attach
edto
PEG
chain
Folic
acid
fortargeting
Inf7
(Infl
uenz
ape
ptide)
asen
doso
molytic
peptide
coup
ledto
the5prime-end
ofsiRNA
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
itor
iv
ND
Kno
ckdo
wnof
EG5
Dec
reas
edtumor
volume
[161
]
siRNA
Epide
rmal
Growth
Factor
Rec
eptor
(EGFR)
Poly-L-argininean
dde
xtransu
lfate-bas
edna
noco
mplex
FaDuhu
man
pharyn
xsq
uamou
sca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[172
]
siRNA
Cho
line
kina
se(C
hk)
Polye
thylen
imine-
polyethy
lene
glyc
ol(P
EI-PEG)co
grafted
polymer
Con
versionof
nontox
ic5-flu
oroc
ytos
ine(5-FC)to
cytotoxic5-flu
orou
racil
(5-FU)by
activating
bacterialc
ytos
ine
deam
inas
e(bCD)
PC3-PIP
andPC3-Flu
human
pros
tate
canc
erce
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
e[157
]
siRNA
Polo-like
kina
se1
(Plk1)
Cationiclip
idpo
lymer
hybrid
nano
particles
(cationiclip
id(N
N-
bis(2-hy
drox
yethyl)-N-
methy
l-N-(2-
choles
teryloxy
carbon
ylam
inoe
thyl)am
mon
ium
brom
ide
BHEM-C
hol)
andam
phiphilic
polymers(H
ydroph
obic
polylactideco
re)
PEG
shell
BT47
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Plk1
Dec
reas
edtumor
volume
[213
]
siRNA
hTERT
Single-walledca
rbon
nano
tube
s(S
WNTs)
Branc
hedPEIco
njug
ated
DSPE-P
EG20
00-M
aleimide
forco
njug
ationwith
NGR
(Cys
-Asn
-Gly-A
rg-C
ys-)
targetingpe
ptide(rec
ognize
tumor
neov
ascu
lature)
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
hTERT
Dec
reas
edtumor
volume
Syn
ergy
with
photothe
rmal
trea
tmen
t
[139
]
1764 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
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196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
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202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
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230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
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238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
controlled experiments are needed before drawing conclu-sions during RNA interference studies
AtelocollagenAtelocollagen is an organic protein-based moleculederived from type I collagen of calf dermis Sinceit is obtained following a pepsin treatment atelocolla-gen is devoid of telopeptides that are responsible forthe immunogenicity of collagen105 Moreover atelocol-lagen has low toxicity it was shown to stabilize RNAmolecules Increased cellular uptake and sustained deliv-ery was observed in in vivo making atelocollagen an idealagent for gene delivery106 Indeed several studies used ate-locollagen with success for the systemic or local deliveryof RNAi in tumor models107ndash109
ChitosanChitosan is obtained through alkaline deacetylation of thepolysaccharide chitin that forms the exoskeleton of crus-taceans some anthropods and insects Chitosan that is usedin biomedical research is a copolymer of N -acetyl-D-glucosamine and D-glucosamine having a positive chargeIn addition to being biodegradable and biocompatible chi-tosan has a low production cost Mucoadhesive propertiesof chitosan allow the penetration of the substance intoepithelial cell layers including the gastrointestinal barri-ers Nucleic acid encapsulation and sustained release wasproved to be possible using chitosan110ndash112 Moreover chi-tosan prolongs transient time in bowel improving par-enteral drug bioavailability113 Nanoparticles of chitosanare taken up into cells through endocytosis to a cer-tain extent To improve gene delivery efficacies PEG ordeoxycholic acid conjugates or modifications includingtrimethylation thiolation galactosylation may be intro-duced to chitosan111 Moreover chitosan-based carrierspossess functional groups that are suitable for conjugationto ligands relevant for targeted tumor delivery Althoughinefficient endosomal escape is a problem encounteredwith chitosan-based carriers some chemically modifiedforms showed improved escape properties114
CyclodextrinsCyclodextrins are natural polymers They are cyclicoligosaccharides of a glucopyranose generated during thebacterial digestion of cellulose Their central cavity ishydrophobic while the outer surface is a hydrophilicand they can create water-soluble molecular complexes115
Native cyclodextrins do not form stable complexeswith nucleic acids But the DNARNA complex for-mation capacities of the molecule can be modulatedand improved through molecular modifications includ-ing changes in functional groups hydrophilic-hydrophobicbalance charge density spacer length and conjugation toother carrier molecules115116 Cyclodextrins are not onlybiocompatible but they have the capacity to decrease
cytotoxicity of other molecules and carriers that are conju-gated to them117 Moreover cyclodextrins increase cellularadsorption and intake of molecules118 So in addition totheir use as a gene delivery agents cyclodextrins are usedas linking agents or structural modifiers in complex car-rier molecules For example conjugation of cyclodextrinto PEI resulted in lower toxicity and higher transfectionefficiencies119 In addition to the advantages cited abovea cyclodextrin polycation delivery system was reportedto block immune reactions raised against small RNAsthrough a masking effect120121 Importantly studies innon-human primates revealed that cyclodextrin-based car-riers were well tolerated and they do not stimulate signif-icant antibody responses120
AptamersAptamers are nucleic acid-based molecules selectedin vitro according to their capacity to bind target moleculesspecifically and with high affinity The immunogenicity ofaptamers is limited due to chemical modifications min-imizing adverse reactions Moreover nucleic acid natureand small size of aptamers result in improved transport andtissue penetration Since they can be specifically designedaccording to cell or tissue types (eg tumor cell com-ponents) side effects and off-target effects are minimalIn gene therapy applications the nucleic acid nature ofaptamers allows easy conjugation to RNADNA combin-ing targeting advantages with a therapeutic potential122
Alternatively non-covalent adapter linkages might be cre-ated between aptamers and RNA molecules Functionalgroups might be added to the 5prime- or 3prime-termini allowingcovalent or non-covalent conjugation of aptamers to carriernanoparticles123
Inorganic ParticlesInorganic nanoparticals such as carbon nanotubes mag-netic nanoparticles quantum dots and silica are the focusof recent efforts in drug and gene delivery Many of theseparticles actually offer the opportunity to combine imag-ing and therapeutic possibilities in the same particle ren-dering the nanocarrier a valuable ldquotheranosticrdquo device124
Increased surfacevolume ratio of inorganic particles pro-vides an opportunity for surface modifications includingconjugations to drugs oligonucleotides targeting peptidesor other molecules125126 Yet inorganic nanoparticles tendto aggregate and the size of the aggregate might have animpact on its function and biodistribution Such inorganicnanoparticles are hence coated with organic moleculeswhich provide colloid formation in aqueous and physiolog-ical media and stability Nature of the organic coatings hasto be designed for specific purposes but biocompatibilityof the organic molecules themselves andor their degra-dation products are critical for drug delivery purposes126
Chemistry of the coating might influence the half-life inblood and biodistribution as well as the toxicity of inor-ganic nanoparticles and their clearance mechanisms
1760 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Depending on the material they consist of inorganicnanoparticles may possess a number of different propertiessuch as high electron density and strong optical absorption(eg metal particles in particular Au) photoluminescenceor fluorescence (semiconductor quantum dots eg CdSeCdTe CdTeSeZnS) phosphorescence (doped oxide mate-rials eg Y2O3) or magnetic moment (eg iron oxide orcobalt nanoparticles) The shape of the nanoparticle is alsoan important factor influencing its interaction with cellsMany of the above mentioned nanoparticle are sphericalin shape except carbon nanotubes that are tubular
Carbon NanotubesCarbon nanotubes (CNTs) easily cross the plasma mem-brane and translocate directly into the cytoplasm of tar-get cells due to their nanoneedle structure and usingan endocytosis-independent mechanism yet they do notinduce cell death127ndash129 CNTs are classified as single-walled CNTs and multiwalled CNTs Single or multiplegraphine layer(s) might have a length ranging from 50 nmto 100 mm and a diameter of 1 nm to 100 nm Properfunctionalizing of CNTs by covalent or non-covalentstrategies (such as coating with PEG or Tween-20) mayprovide solubility in aqueous solutions and prevent non-specific interactions thus minimizing toxicity observedwith non-functionalized raw particles130131 Modificationsmight also increase biocompatibility and blood circulationhalf-life132133 CNTs have very strong absorption charac-teristics providing an opportunity for photothermal abla-tion therapy in addition to nanocarrier properties
Magnetic NanoparticlesMagnetic nanoparticles are composed of ferromagneticelements such as Ni Co Mn Fe Superparamagneticiron oxide nanoparticles (SPIONS) such as maghemite--Fe2O3 and magnetite-Fe3O4 are one of the most widelyused magnetic particles as nanocarriers due to relativelylow cost of production biocompatability and superpara-magnetic nature134135 SPIONS are approved by FDA forclinical trials They are commonly used as contrast agentsfor magnetic resonance imaging (MRI) SPION crystals(less than 10 nm in diameter) are coated for specificpurposes with organic molecules such as dextran aminodextran BSA PEI dendrimers lipids and trialkoxysi-lanes including aminopropyltriethoxy silane (APTES)Coating chemistry and preparation methods influence over-all hydrodynamic size pharmacokinetics and the contrasttype (dark-T 2 or bright-T 1 agent) Ability to track the fateof nucleic acid carrier magnetic nanoparticles in vivo usingMRI is highly desirable since it provides informationabout the location of the cargo and its biodistribution136
Attachment of ligands provides target specificity andPEGylation may improve biocompatibility and blood half-life These modifications are commonly introduced to SPI-ONs that are used for imaging and therapy purposes Due
to their magnetic nature drug or nucleic acid carrying SPI-ONs can be concentrated at desired diseased sites such astumors and they may be dragged magnetically towards thelesion area136137 Moreover magnetic nanoparticles offerthe possibility of hyperthermia treatment as a result ofmagnetic heating135 Under applied alternating magneticfield SPIONs cause local temperature increase (41ndash42 C)which may be exploited for alternative and efficient cancertherapy Therefore SPIONs are one of the most versatileand multifunctional nanoparticles Consequently SPIONswere used as popular gene delivery vehicles135
Magnetic nanoparticles may be engineered for oligonu-cleotide delivery purposes MRI visible PEI-PEG coatedSPIONs which are tagged with an antibody have beenshown to effectively carry siRNA to cancer cell lines andshowed low toxicity138 SPIONs coated with both thermoresponsive and cationic polymers such as poly[2-(2-methoxyethoxy)ethylmethacrylate]-b-poly-[2-(dimethyl-amino)ethyl methacrylate] were reported to have25ndash100 times better transfection efficiency than branchedPEI 25 kDa when coupled with magnetic targeting139
SPIONs coated with low molecular weight PEI(12ndash2 kDa) which is usually not effective as poly-plexes in transfection were shown succesful in deliveringsiRNA to mouse macrophages (H Yagci Acar WIPOPatent WO2006055447A3) Therefore magnetic nanpar-ticles are under heavy investigation for the developmentof multifunctional nanocarriers for cancer therapy anddiagnosis135
Quantum DotsSemiconductor quantum dots (QDs) are light-emittingnanoparticles of few nanometer in diameter and they havebeen increasingly used as biological imaging and labelingprobes140 Luminescencefluorescence properties of QDsdepend on the crystal size and type Chemical composi-tion of the crystalline semiconductor core determines theband gap of the material therefore the emission wave-length range Within possible spectral window size ofthe crystal determines the specific wavelength of lumines-cencefluorescence for each and every QD due to quan-tum confinement effect Broad absorption of QDs allowexcitation of multiple QDs at a single wavelength andminimal signal mixing due to the narrow emission bandIn addition they are much more resistant to photobleach-ing These two characteristics are the major advantages ofQDs compared to organic fluorophores as imaging probesUtilization of QDs in nucleic acid delivery aims bothimaging and therapy since in vivo localization of cargocan be observed using optical imaging systems141142 Forexample cationic CdTeZnS QDs conjugated with PEGwas demonstrated to form an effective nanoplex with sur-vivin siRNA and successfully transfeced human tonguecancer cells in vitro and provided real time tracking143
However well-established QDs harbour significant toxic-ity due to constituents such as Cd Se Te144 Therefore
J Biomed Nanotechnol 10 1751ndash1783 2014 1761
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
toxicity of these QDs is a drawback for their use in vivoAs an alternative silver (Ag) chalcogenites emerged assafer near-infra red-emitting QDs145146 Ag2S QDs did notinduce cytotoxicity ROS production apoptosis necrosisor DNA damage147 For example Ag2S QDs (coated with2-mercaptopropionic acid) emitting between 750ndash850 nmshowed no cytotoxicity in NIH3T3 cells at even highdoses (600 mgml) along with good cellular imagingpotential148
Gold NanoparticlesGold nanoparticles emerged as popular tools fornanocarrier-mediated gene therapy149 They are easily syn-thesized and biocompatible particles that allow addition offunctional molecules on their surface due to high surface-to-volume ratio114150 A variety of surface changes andfunctional additions were reported including cationic lipidcoating branched PEI addition or functionalization usingcationic quaternary ammonium or cystamine114151152
Indeed cystamine functionalized gold nanoparticles wereshown to effectively bind deliver and release 35 differ-ent miRNA in in vitro studies using neuroblastoma andovarian cancer cell lines153
Silica NanoparticlesSilica-based nanoparticles are inert stable biocompati-ble and biodegradable particles154 They can be renderedhydrophilic hydrophobic anionic or cationic using func-tional surface modifiers through electrostatic interactionsor by formation of any other type covalent bonds (egester amine) Common functionalization strategies to ren-der the molecule cationic and improve nucleic acid bind-ing include grafting of molecules such as PEI PEI-PEGand Poly-L-arginine155 Nucleic acids may also be loadedinside the mesoporous silica particles156 siRNA encapsu-lating mesoporous silica nanoparticles were successfullyused for in vitro and in vivo gene silencing in several stud-ies (For example Ref [156])
RECENT IN VIVO STUDIES USING RNAINTERFERENCE IN CANCER THERAPYThere is an exponential increase in the number of scientificpublications dedicated to gene therapy of diseases usingsmall RNAs and nanoparticles A literature search usingldquonanoparticlerdquo and ldquosiRNA shRNA or miRNArdquo revealedmore than 700 articles published in the last two yearsThis number is roughly equal to the number of all articlespublished in this field until two years ago So the field isexpanding and there seems to form a consensus aroundthe use of nanoparticles as next generation gene therapytools We believe that these high expectations are not onlya consequence of shifting trends in science and technol-ogy The exponential rise in interest in the field of smallRNA carrier nanoparticles is fueled by the advances inthe field of nano materials promising results obtained in
small RNA therapeutics by both academic laboratories andindustry and increasing number of successful clinical tri-als In this section we will summarize results of selectedrecent studies using RNA therapeutics for cancer treatmentin preclinical in vivo experimentsOverview of the works dealing with small RNA treat-
ment of experimental cancers and published within thelast two years were summarized in Table I Although sev-eral studies were performed using lipid-based nanopar-ticles (Liposomes micelles or lipidoids) other particlessuch as polymers organic or inorganic carriers and com-pounds mixtures with functional modifications of vari-able substances were also tested by many research teamswith reasonable success Scheme 4 summarizes the generalstrategy followed in most of these studies
Tumor Types and RNAi TherapyRecent studies in the literature showed that tumors of vari-ous tissue origins could be treated using RNA interferencestrategies (Table I) Fine tuning of nanoparticles throughaddition of functional moieties or modifications alloweddelivery of drugs into almost any kind of tumor tissue withaccompanied therapeutic effects Although several studiesused animal tumor models that resulted from the injectionof cell lines from most commonly seen human cancers(lung breast prostate cervix or ovarian cancer cell lines)animals with kidney urinary bladder head and neckgastric pancreatic melanomas neuroblastomas glioblas-tomas multiple myelomas or sarcomas were also treatedwith RNAinanocarrier strategy81156ndash170 These results givehope about the general use of RNA interference as astrategy to treat cancers of different origins Althoughit is difficult to compare the efficacies of different nucleicacid molecules and their interference effects at this pointsiRNA or microRNAs as well as shRNA vectors wereshown to achieve intratumoral in vivo target gene knock-down and anticancer effects leading to a decrease in tumorsize (For example Refs [156 171]) Since in most studiesin addition to RNAi loaded particles naked nanoparticlesor particles loaded with non-specific control nucleic acidswere also used antitumor effects obtained in these studiesare specific and they may be attributable to small RNAmolecules rather than the particles themselves underliningthe potential of RNA interference in cancer treatmentMajority of recent studies with in vivo models chose
to use human tumor cell line xenografts in immune com-promised mice nude or severe-combined immuno defi-cient SCID mice (Table I) (For example Refs [162 172])Syngeneic transplants and established genetically engi-neered mouse models of cancer were rarely studied in thiscontext167173ndash175 Therefore although antitumor effects andsome of the toxic effects (eg liver toxicity) might berevealed using immune compromised mice hematologicalimmunological and inflammatory side effects of the treat-ment strategies used in recent studies might need to berevisited using immunocompetent mice
1762 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IRec
entstudieswithRNAica
rryingnan
oparticles
forthetrea
tmen
tofex
perim
entalca
nce
rs(P
ublis
hed
within
thelast
twoye
ars)
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGF
Mag
netic
mes
oporou
ssilicana
nopa
rticles
PEIan
dfuso
genicpe
ptide
KALA
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[156
]
siRNA
Polo-likekina
se1(P
LK1)
pH-sen
sitiveca
tioniclip
idYSK05
-MEND
(YSK05
POPEcho
lesterol
=50
2525
)
PEG
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
PLK
1[51]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Bioen
gine
ered
bacterial
outermem
bran
eve
sicles
Hum
anep
idermal
grow
thfactor
rece
ptor
2(H
ER2)-spe
cific
affib
ody
targeting
HCC-195
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
KSP
Dec
reas
edtumor
volume
[81]
siRNA
Luciferase
Dioleoy
lpho
spha
tidic
acid-(DOPA
-)co
ated
nano
-sized
calcium
phos
phate(LCP-II)
DSPE-P
EG-an
dan
isam
idefortargeting
sigm
a-1rece
ptor
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
Xen
ograft
it
ND
Kno
ckdo
wnof
luciferase
[211
]
siRNA
mTERT
N-((2-hyd
roxy
-3-trim
ethy
l-am
mon
ium)propy
l)ch
itosa
nch
lorid
e(H
TCC)na
nopa
rticles
Partic
leload
edwith
paclita
xel
LCC
murinelung
canc
erce
llssy
ngen
eicsc
graft
oral
Noeffect
Kno
ckdo
wnof
mTERT
Dec
reas
edtumor
volume
Syn
ergize
dwith
paclita
xel
[159
]
siRNA
VEGF
Multilay
ered
polyion
complexes
Polyc
ationinterla
yeran
dade
tach
able
PEG
shell
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
[212
]
siRNA
Multid
rug
resistan
ceprotein1
(MRP1)
Nan
opartic
lesas
sembled
vialaye
r-by
laye
rde
positio
nof
siRNA
and
poly-L-arginine
Hya
lurona
n(H
A)co
ating
forHA-C
D44
targeting
MDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
it
Noeffect
Kno
ckdo
wnof
MRP1
Dec
reas
edtumor
volume
[183
]
siRNA
STA
T3-a
Nan
oporou
ssilicon
nano
particles
Argininean
dPEI
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicefat
padxe
nograft
iv
Noeffect
Kno
ckdo
wnof
STA
T3-a
[204
]
siRNA
Luciferase
Lipo
somal
nano
particle
Fou
rtand
emrepe
atsof
human
histon
eH2A
peptideinterven
edby
cathep
sinD
clea
vage
sites
PEG-A
nisa
mide
fortargeting
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
luciferase
[199
]
siRNA
Polo-likekina
se1(P
LK1)
Hya
luronicac
id(H
A)
base
dse
lfass
embling
HA-P
EIP
EG
nano
system
s
Hya
lurona
nforCD44
targeting
B16
F10
amurine
melan
omace
llsA54
9-luchu
man
lung
canc
erce
llsHep
3Bhu
man
liver
canc
erce
llsMDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
graftor
metas
tatic
lung
lesion
sby
IVinjection
it
ND
Kno
ckdo
wnof
PLK
1[160
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1763
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
P-glyco
protein
drug
expo
rter
(P-
gpM
DR1)
Mes
oporou
ssilica
nano
particles
Polye
thylen
eimine
polyethy
lene
glyc
ol(P
EI-PEG)co
polymer
MCF-7M
DR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gpMDR1
Dec
reas
edtumor
volume
Syn
ergy
with
doxo
rubicin
[179
]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Multifun
ctiona
lcarrie
rsy
stem
with
catio
nic
(olig
oethan
amino)am
ide
core
attach
edto
PEG
chain
Folic
acid
fortargeting
Inf7
(Infl
uenz
ape
ptide)
asen
doso
molytic
peptide
coup
ledto
the5prime-end
ofsiRNA
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
itor
iv
ND
Kno
ckdo
wnof
EG5
Dec
reas
edtumor
volume
[161
]
siRNA
Epide
rmal
Growth
Factor
Rec
eptor
(EGFR)
Poly-L-argininean
dde
xtransu
lfate-bas
edna
noco
mplex
FaDuhu
man
pharyn
xsq
uamou
sca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[172
]
siRNA
Cho
line
kina
se(C
hk)
Polye
thylen
imine-
polyethy
lene
glyc
ol(P
EI-PEG)co
grafted
polymer
Con
versionof
nontox
ic5-flu
oroc
ytos
ine(5-FC)to
cytotoxic5-flu
orou
racil
(5-FU)by
activating
bacterialc
ytos
ine
deam
inas
e(bCD)
PC3-PIP
andPC3-Flu
human
pros
tate
canc
erce
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
e[157
]
siRNA
Polo-like
kina
se1
(Plk1)
Cationiclip
idpo
lymer
hybrid
nano
particles
(cationiclip
id(N
N-
bis(2-hy
drox
yethyl)-N-
methy
l-N-(2-
choles
teryloxy
carbon
ylam
inoe
thyl)am
mon
ium
brom
ide
BHEM-C
hol)
andam
phiphilic
polymers(H
ydroph
obic
polylactideco
re)
PEG
shell
BT47
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Plk1
Dec
reas
edtumor
volume
[213
]
siRNA
hTERT
Single-walledca
rbon
nano
tube
s(S
WNTs)
Branc
hedPEIco
njug
ated
DSPE-P
EG20
00-M
aleimide
forco
njug
ationwith
NGR
(Cys
-Asn
-Gly-A
rg-C
ys-)
targetingpe
ptide(rec
ognize
tumor
neov
ascu
lature)
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
hTERT
Dec
reas
edtumor
volume
Syn
ergy
with
photothe
rmal
trea
tmen
t
[139
]
1764 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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cer J Clin 64 9 (2014)2 M J Espiritu A C Collier and J P Bingham A 21st-century
approach to age-old problems The ascension of biologics in clini-cal therapeutics Drug Discov Today (2014)
3 R L Schilsky Personalized medicine in oncology The future isnow Nat Rev Drug Discov 9 363 (2010)
4 M N Patel M D Halling-Brown J E Tym P Workman andB Al-Lazikani Objective assessment of cancer genes for drug dis-covery Nat Rev Drug Discov 12 35 (2013)
5 D Hanahan and R A Weinberg Hallmarks of cancer The nextgeneration Cell 144 646 (2011)
6 N F Sun Z A Liu W B Huang A L Tian and S Y Hu Theresearch of nanoparticles as gene vector for tumor gene therapyCrit Rev Oncol Hematol 89 352 (2013)
1776 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
7 M Rothe U Modlich and A Schambach Biosafety challenges foruse of lentiviral vectors in gene therapy Curr Gene Ther 13 453(2013)
8 D R Corey RNA learns from antisense Nat Chem Biol 3 8(2007)
9 V N Kim MicroRNA biogenesis Coordinated cropping and dic-ing Nat Rev Mol Cell Biol 6 376 (2005)
10 D E Golden V R Gerbasi and E J Sontheimer An inside jobfor siRNAs Mol Cell 31 309 (2008)
11 M Ghildiyal and P D Zamore Small silencing RNAs An expand-ing universe Nat Rev Genet 10 94 (2009)
12 D H Kim M A Behlke S D Rose M S Chang S Choiand J J Rossi Synthetic dsRNA Dicer substrates enhance RNAipotency and efficacy Nat Biotechnol 23 222 (2005)
13 Y Maida M Yasukawa M Furuuchi T Lassmann R PossematoN Okamoto V Kasim Y Hayashizaki W C Hahn and K Masu-tomi An RNA-dependent RNA polymerase formed by TERT andthe RMRP RNA Nature 461 230 (2009)
14 N R Smalheiser The search for endogenous siRNAs in the mam-malian brain Exp Neurol 235 455 (2012)
15 K A Tekirdag G Korkmaz D G Ozturk R Agami andD Gozuacik MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5 Autophagy 9 374(2013)
16 G Korkmaz K A Tekirdag D G Ozturk A Kosar O USezerman and D Gozuacik MIR376A Is a Regulator ofStarvation-Induced Autophagy PLoS One 8 e82556 (2013)
17 D Castanotto and J J Rossi The promises and pitfalls of RNA-interference-based therapeutics Nature 457 426 (2009)
18 E Iorns C J Lord N Turner and A Ashworth Utilizing RNAinterference to enhance cancer drug discovery Nat Rev Drug Dis-cov 6 556 (2007)
19 M A Behlke Chemical modification of siRNAs for in vivo useOligonucleotides 18 305 (2008)
20 S D Rose D H Kim M Amarzguioui J D Heidel M ACollingwood M E Davis J J Rossi and M A Behlke Func-tional polarity is introduced by Dicer processing of short substrateRNAs Nucleic Acids Res 33 4140 (2005)
21 K Nishina T Unno Y Uno T Kubodera T KanouchiH Mizusawa and T Yokota Efficient in vivo delivery of siRNAto the liver by conjugation of alpha-tocopherol Mol Ther 16 734(2008)
22 F Czauderna M Fechtner S Dames H Aygun A Klippel G JPronk K Giese and J Kaufmann Structural variations and sta-bilising modifications of synthetic siRNAs in mammalian cellsNucleic Acids Res 31 2705 (2003)
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24 F V Rivas N H Tolia J J Song J P Aragon J Liu G JHannon and L Joshua-Tor Purified Argonaute2 and an siRNAform recombinant human RISC Nat Struct Mol Biol 12 340(2005)
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28 D Bumcrot M Manoharan V Koteliansky and D W Sah RNAitherapeutics A potential new class of pharmaceutical drugs NatChem Biol 2 711 (2006)
29 A S Peek and M A Behlke Design of active small interferingRNAs Curr Opin Mol Ther 9 110 (2007)
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33 D V Morrissey J A Lockridge L Shaw K Blanchard K JensenW Breen K Hartsough L Machemer S Radka V JadhavN Vaish S Zinnen C Vargeese K Bowman C S Shaffer L BJeffs A Judge I MacLachlan and B Polisky Potent and persis-tent in vivo anti-HBV activity of chemically modified siRNAs NatBiotechnol 23 1002 (2005)
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35 A Akinc A Zumbuehl M Goldberg E S Leshchiner V BusiniN Hossain S A Bacallado D N Nguyen J Fuller R AlvarezA Borodovsky T Borland R Constien A de Fougerolles J RDorkin K Narayanannair Jayaprakash M Jayaraman M JohnV Koteliansky M Manoharan L Nechev J Qin T RacieD Raitcheva K G Rajeev D W Sah J Soutschek I ToudjarskaH P Vornlocher T S Zimmermann R Langer and D G Ander-son A combinatorial library of lipid-like materials for delivery ofRNAi therapeutics Nat Biotechnol 26 561 (2008)
36 S C Semple A Akinc J Chen A P Sandhu B L Mui C KCho D W Sah D Stebbing E J Crosley E Yaworski I MHafez J R Dorkin J Qin K Lam K G Rajeev K F WongL B Jeffs L Nechev M L Eisenhardt M Jayaraman M KazemM A Maier M Srinivasulu M J Weinstein Q Chen R AlvarezS A Barros S De S K Klimuk T Borland V Kosovrasti W LCantley Y K Tam M Manoharan M A Ciufolini M A TracyA de Fougerolles I MacLachlan P R Cullis T D Madden andM J Hope Rational design of cationic lipids for siRNA deliveryNat Biotechnol 28 172 (2010)
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40 Y Matsumura and H Maeda A new concept for macromoleculartherapeutics in cancer chemotherapy Mechanism of tumoritropicaccumulation of proteins and the antitumor agent smancs CancerRes 46 6387 (1986)
41 T Ishimoto Y Takei Y Yuzawa K Hanai S Nagahara Y TarumiS Matsuo and K Kadomatsu Downregulation of monocytechemoattractant protein-1 involving short interfering RNA atten-uates hapten-induced contact hypersensitivity Mol Ther 16 387(2008)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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43 E Kawata E Ashihara S Kimura K Takenaka K SatoR Tanaka A Yokota Y Kamitsuji M Takeuchi J KurodaF Tanaka T Yoshikawa and T Maekawa Administration of PLK-1 small interfering RNA with atelocollagen prevents the growth ofliver metastases of lung cancer Mol Cancer Ther 7 2904 (2008)
44 H Maeda J Wu T Sawa Y Matsumura and K Hori Tumorvascular permeability and the EPR effect in macromolecular thera-peutics A review J Control Release 65 271 (2000)
45 H Hatakeyama H Akita and H Harashima The polyethyleneg-lycol dilemma Advantage and disadvantage of PEGylation of lipo-somes for systemic genes and nucleic acids delivery to tumorsBiol Pharm Bull 36 892 (2013)
46 F Iversen C Yang F Dagnaes-Hansen D H Schaffert J Kjemsand S Gao Optimized siRNA-PEG conjugates for extended bloodcirculation and reduced urine excretion in mice Theranostics 3 201(2013)
47 A Malek O Merkel L Fink F Czubayko T Kissel andA Aigner In vivo pharmacokinetics tissue distribution and under-lying mechanisms of various PEI(-PEG)siRNA complexes Toxi-col Appl Pharmacol 236 97 (2009)
48 S D Li S Chono and L Huang Efficient gene silencingin metastatic tumor by siRNA formulated in surface-modifiednanoparticles J Control Release 126 77 (2008)
49 K Remaut B Lucas K Braeckmans J Demeester and S C DeSmedt Pegylation of liposomes favours the endosomal degradationof the delivered phosphodiester oligonucleotides J Control Release117 256 (2007)
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51 Y Sato H Hatakeyama Y Sakurai M Hyodo H Akita andH Harashima A pH-sensitive cationic lipid facilitates the deliveryof liposomal siRNA and gene silencing activity in vitro and in vivoJ Control Release 163 267 (2012)
52 K Kusumoto H Akita A El-Sayed and H Harashima Effect ofthe anchor in polyethylene glycol-lipids on the transfection activityof PEGylated cationic liposomes encapsulating DNA Biol PharmBull 35 445 (2012)
53 H M Aliabadi B Landry C Sun T Tang and H UludagSupramolecular assemblies in functional siRNA delivery Where dowe stand Biomaterials 33 2546 (2012)
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55 S Y Wu and N A McMillan Lipidic systems for in vivo siRNAdelivery AAPS J 11 639 (2009)
56 H Tian S Liu J Zhang S Zhang L Cheng C Li X ZhangL Dai P Fan L Dai N Yan R Wang Y Wei and H DengEnhancement of Cisplatin sensitivity in lung cancer xenografts byliposome-mediated delivery of the plasmid expressing small hairpinRNA targeting survivin J Biomed Nanotechnol 8 633 (2012)
57 I R Gilmore S P Fox A J Hollins M Sohail andS Akhtar The design and exogenous delivery of siRNA for post-transcriptional gene silencing J Drug Target 12 315 (2004)
58 I R Gilmore S P Fox A J Hollins and S Akhtar Deliverystrategies for siRNA-mediated gene silencing Curr Drug Deliv3 147 (2006)
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silencing activity and specificity Adv Drug Deliv Rev 59 164(2007)
60 B Ozpolat A K Sood and G Lopez-Berestein Nanomedicinebased approaches for the delivery of siRNA in cancer J InternMed 267 44 (2010)
61 S Dokka D Toledo X Shi V Castranova and Y RojanasakulOxygen radical-mediated pulmonary toxicity induced by somecationic liposomes Pharm Res 17 521 (2000)
62 S Spagnou A D Miller and M Keller Lipidic carriers of siRNADifferences in the formulation cellular uptake and delivery withplasmid DNA Biochemistry (Mosc) 43 13348 (2004)
63 H Lv S Zhang B Wang S Cui and J Yan Toxicity of cationiclipids and cationic polymers in gene delivery J Control Release114 100 (2006)
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65 P Liu H Yu Y Sun M Zhu and Y Duan A mPEG-PLGA-b-PLLcopolymer carrier for adriamycin and siRNA delivery Biomaterials33 4403 (2012)
66 F Alexis E Pridgen L K Molnar and O C Farokhzad Factorsaffecting the clearance and biodistribution of polymeric nanoparti-cles Mol Pharm 5 505 (2008)
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68 J Heyes L Palmer K Bremner and I MacLachlan Cationic lipidsaturation influences intracellular delivery of encapsulated nucleicacids J Control Release 107 276 (2005)
69 O Meyer D Kirpotin K Hong B Sternberg J W Park M CWoodle and D Papahadjopoulos Cationic liposomes coated withpolyethylene glycol as carriers for oligonucleotides J Biol Chem273 15621 (1998)
70 M A Tran R J Watts and G P Robertson Use of liposomesas drug delivery vehicles for treatment of melanoma Pigment CellMelanoma Res 22 388 (2009)
71 C N Landen Jr A Chavez-Reyes C Bucana R Schmandt M TDeavers G Lopez-Berestein and A K Sood Therapeutic EphA2gene targeting in vivo using neutral liposomal small interferingRNA delivery Cancer Res 65 6910 (2005)
72 Z Ma J Li F He A Wilson B Pitt and S Li Cationic lipidsenhance siRNA-mediated interferon response in mice BiochemBiophys Res Commun 330 755 (2005)
73 J Jin K H Bae H Yang S J Lee H Kim Y Kim K M JooS W Seo T G Park and D H Nam In vivo specific delivery of c-Met siRNA to glioblastoma using cationic solid lipid nanoparticlesBioconjug Chem 22 2568 (2011)
74 P Y Chien J Wang D Carbonaro S Lei B Miller S SheikhS M Ali M U Ahmad and I Ahmad Novel cationic cardiolipinanalogue-based liposome for efficient DNA and small interferingRNA delivery in vitro and in vivo Cancer Gene Ther 12 321(2005)
75 A Pal A Ahmad S Khan I Sakabe C Zhang U N Kasidand I Ahmad Systemic delivery of RafsiRNA using cationic car-diolipin liposomes silences Raf-1 expression and inhibits tumorgrowth in xenograft model of human prostate cancer Int J Oncol26 1087 (2005)
76 A Akinc M Goldberg J Qin J R Dorkin C Gamba-VitaloM Maier K N Jayaprakash M Jayaraman K G RajeevM Manoharan V Koteliansky I Rohl E S Leshchiner R Langerand D G Anderson Development of lipidoid-siRNA formulationsfor systemic delivery to the liver Mol Ther 17 872 (2009)
77 S Jiang A A Eltoukhy K T Love R Langer and D GAnderson Lipidoid-coated iron oxide nanoparticles for efficientDNA and siRNA delivery Nano Lett 13 1059 (2013)
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
78 J A MacDiarmid and H Brahmbhatt Minicells Versatile vectorsfor targeted drug or sishRNA cancer therapy Curr Opin Biotech-nol 22 909 (2011)
79 J A MacDiarmid N B Amaro-Mugridge J Madrid-WeissI Sedliarou S Wetzel K Kochar V N Brahmbhatt L PhillipsS T Pattison C Petti B Stillman R M Graham andH Brahmbhatt Sequential treatment of drug-resistant tumors withtargeted minicells containing siRNA or a cytotoxic drug NatBiotechnol 27 643 (2009)
80 C G Millan C I Colino Gandarillas M L Sayalero Marineroand J M Lanao Cell-based drug-delivery platforms Ther Deliv3 25 (2012)
81 V Gujrati S Kim S H Kim J J Min H E Choy S C Kimand S Jon Bioengineered bacterial outer membrane vesicles ascell-specific drug-delivery vehicles for cancer therapy ACS Nano8 1525 (2014)
82 L Alvarez-Erviti Y Seow H Yin C Betts S Lakhal and M JWood Delivery of siRNA to the mouse brain by systemic injectionof targeted exosomes Nat Biotechnol 29 341 (2011)
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84 Y Wang Z Li Y Han L H Liang and A Ji Nanoparticle-based delivery system for application of siRNA in vivo Curr DrugMetab 11 182 (2010)
85 K A Howard Delivery of RNA interference therapeutics usingpolycation-based nanoparticles Adv Drug Deliv Rev 61 710(2009)
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87 L Zhang Z Chen and Y Li Dual-degradable disulfide-containingPEI-PluronicDNA polyplexes Transfection efficiency and balanc-ing protection and DNA release Int J Nanomedicine 8 3689(2013)
88 Y K Kim C S Cho M H Cho and H L Jiang Poly(esteramine) synthesized from trimethylolpropane triacrylate and sper-mine as an efficient siRNA carrier J Nanosci Nanotechnol13 5692 (2013)
89 R Kircheis L Wightman and E Wagner Design and gene deliv-ery activity of modified polyethylenimines Adv Drug Deliv Rev53 341 (2001)
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Hartmann T Stoger and T H Kissel Polymer-related off-targeteffects in non-viral siRNA delivery Biomaterials 32 2388 (2011)
93 D J Gary N Puri and Y Y Won Polymer-based siRNA deliv-ery Perspectives on the fundamental and phenomenological dis-tinctions from polymer-based DNA delivery J Control Release121 64 (2007)
94 S M Moghimi P Symonds J C Murray A C HunterG Debska and A Szewczyk A two-stage poly(ethylenimine)-mediated cytotoxicity Implications for gene transfertherapy MolTher 11 990 (2005)
95 A C Hunter and S M Moghimi Cationic carriers of genetic mate-rial and cell death A mitochondrial tale Biochim Biophys Acta1797 1203 (2010)
96 K A Woodrow Y Cu C J Booth J K Saucier-Sawyer M JWood and W M Saltzman Intravaginal gene silencing usingbiodegradable polymer nanoparticles densely loaded with small-interfering RNA Nat Mater 8 526 (2009)
97 K Singha R Namgung and W J Kim Polymers in small-interfering RNA delivery Nucleic Acid Ther 21 133 (2011)
98 S Acharya and S K Sahoo PLGA nanoparticles containing var-ious anticancer agents and tumour delivery by EPR effect AdvDrug Deliv Rev 63 170 (2011)
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101 J Wu W Huang and Z He Dendrimers as carriers for siRNAdelivery and gene silencing A review Scientific World Journal2013 630654 (2013)
102 M L Patil M Zhang S Betigeri O Taratula H He andT Minko Surface-modified and internally cationic polyami-doamine dendrimers for efficient siRNA delivery Bioconjug Chem19 1396 (2008)
103 M L Patil M Zhang O Taratula O B Garbuzenko H He andT Minko Internally cationic polyamidoamine PAMAM-OH den-drimers for siRNA delivery Effect of the degree of quaternizationand cancer targeting Biomacromolecules 10 258 (2009)
104 A J Hollins Y Omidi I F Benter and S Akhtar Toxicoge-nomics of drug delivery systems Exploiting delivery system-induced changes in target gene expression to enhance siRNAactivity J Drug Target 15 83 (2007)
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106 T Ochiya K Honma F Takeshita and S NagaharaAtelocollagen-mediated drug discovery technology Expert OpinDrug Discov 2 159 (2007)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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127 D Pantarotto R Singh D McCarthy M Erhardt J P BriandM Prato K Kostarelos and A Bianco Functionalized carbonnanotubes for plasmid DNA gene delivery Angew Chem Int EdEngl 43 5242 (2004)
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130 A A Shvedova E R Kisin D Porter P Schulte V E KaganB Fadeel and V Castranova Mechanisms of pulmonary toxicityand medical applications of carbon nanotubes Two faces of JanusPharmacol Ther 121 192 (2009)
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137 Y S Cho T J Yoon E S Jang K Soo Hong S YoungLee O Ran Kim C Park Y J Kim G C Yi and K ChangCetuximab-conjugated magneto-fluorescent silica nanoparticles for
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141 M Ogris G Walker T Blessing R Kircheis M Wolschek andE Wagner Tumor-targeted gene therapy Strategies for the prepa-ration of ligand-polyethylene glycol-polyethylenimineDNA com-plexes J Control Release 91 173 (2003)
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143 J Zhao X Qiu Z Wang J Pan J Chen and J Han Applica-tion of quantum dots as vectors in targeted survivin gene siRNAdelivery Onco Targets Ther 6 303 (2013)
144 Y Su Y He H Lu L Sai Q Li W Li L Wang P ShenQ Huang and C Fan The cytotoxicity of cadmium based aqueousphasemdashsynthesized quantum dots and its modulation by surfacecoating Biomaterials 30 19 (2009)
145 H Y Yang Y W Zhao Z Y Zhang H M Xiong and S N YuOne-pot synthesis of water-dispersible Ag2S quantum dots withbright fluorescent emission in the second near-infrared windowNanotechnology 24 055706 (2013)
146 G Hong J T Robinson Y Zhang S Diao A L AntarisQ Wang and H Dai In vivo fluorescence imaging with Ag2Squantum dots in the second near-infrared region Angew Chem IntEd Engl 51 9818 (2012)
147 Y Zhang G Hong G Chen F Li H Dai and Q Wang Ag2Squantum dot A bright and biocompatible fluorescent nanoprobe inthe second near-infrared window ACS Nano 6 3695 (2012)
148 I Hocaoglu M N Ccedilizmeciyan R Erdem C Ozen A KurtA Sennaroglu and H Y Acar Development of highly luminescentand cytocompatible near-IR-emitting aqueous Ag2S quantum dotsJ Mater Chem 22 14674 (2012)
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1780 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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166 M A Rahman A R Amin X Wang J E Zuckerman C HChoi B Zhou D Wang S Nannapaneni L Koenig Z ChenZ G Chen Y Yen M E Davis and D M Shin Systemic deliveryof siRNA nanoparticles targeting RRM2 suppresses head and necktumor growth J Control Release 159 384 (2012)
167 J Guo J R Ogier S Desgranges R Darcy and C OrsquoDriscollAnisamide-targeted cyclodextrin nanoparticles for siRNA deliveryto prostate tumours in mice Biomaterials 33 7775 (2012)
168 M Shen F Gong P Pang K Zhu X Meng C Wu J WangH Shan and X Shuai An MRI-visible non-viral vector for tar-geted Bcl-2 siRNA delivery to neuroblastoma Int J Nanomedicine7 3319 (2012)
169 D Lin Q Jiang Q Cheng Y Huang P Huang S Han S GuoZ Liang and A Dong Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and invivo siRNA delivery Acta Biomater 9 7746 (2013)
170 L Zou X Song T Yi S Li H Deng X Chen Z Li Y BaiQ Zhong Y Wei and X Zhao Administration of PLGA nanopar-ticles carrying shRNA against focal adhesion kinase and CD44results in enhanced antitumor effects against ovarian cancer CancerGene Ther 20 242 (2013)
171 T Yin P Wang J Li R Zheng B Zheng D Cheng R Li J Laiand X Shuai Ultrasound-sensitive siRNA-loaded nanobubblesformed by hetero-assembly of polymeric micelles and liposomesand their therapeutic effect in gliomas Biomaterials 34 4532(2013)
172 H J Cho S Chong S J Chung C K Shim and D D Kim Poly-L-arginine and dextran sulfate-based nanocomplex for epidermalgrowth factor receptor (EGFR) siRNA delivery Its application forhead and neck cancer treatment Pharm Res 29 1007 (2012)
173 F Abedini H Hosseinkhani M Ismail A J Domb A R OmarP P Chong P D Hong D S Yu and I Y Farber Cationizeddextran nanoparticle-encapsulated CXCR4-siRNA enhanced corre-lation between CXCR4 expression and serum alkaline phosphatasein a mouse model of colorectal cancer Int J Nanomedicine 7 4159(2012)
174 F Yang W Huang Y Li S Liu M Jin Y Wang L Jia andZ Gao Anti-tumor effects in mice induced by survivin-targetedsiRNA delivered through polysaccharide nanoparticles Biomateri-als 34 5689 (2013)
175 L Chen Y Ding Y Wang X Liu R Babu W Ravis and W YanCodelivery of zoledronic acid and doublestranded RNA from corendashshell nanoparticles Int J Nanomedicine 8 137 (2013)
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178 J Shen H Sun P Xu Q Yin Z Zhang S Wang H Yu and Y LiSimultaneous inhibition of metastasis and growth of breast cancerby co-delivery of twist shRNA and paclitaxel using pluronic P85-PEITPGS complex nanoparticles Biomaterials 34 1581 (2013)
179 H Meng W X Mai H Zhang M Xue T Xia S Lin X WangY Zhao Z Ji J I Zink and A E Nel Codelivery of an optimaldrugsiRNA combination using mesoporous silica nanoparticles toovercome drug resistance in breast cancer in vitro and in vivo ACSNano 7 994 (2013)
180 C Zheng M Zheng P Gong J Deng H Yi P Zhang Y ZhangP Liu Y Ma and L Cai Polypeptide cationic micelles mediatedco-delivery of docetaxel and siRNA for synergistic tumor therapyBiomaterials 34 3431 (2013)
181 Q Hu W Li X Hu J Shen X Jin J Zhou G Tang and P KChu Synergistic treatment of ovarian cancer by co-delivery of sur-vivin shRNA and paclitaxel via supramolecular micellar assemblyBiomaterials 33 6580 (2012)
182 Y H Yu E Kim D E Park G Shim S Lee Y B KimC W Kim and Y K Oh Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA Eur J Pharm Biopharm 80 268(2012)
183 Z J Deng S W Morton E Ben-Akiva E C Dreaden K EShopsowitz and P T Hammond Layer-by-layer nanoparticles forsystemic codelivery of an anticancer drug and siRNA for potentialtriple-negative breast cancer treatment ACS Nano 7 9571 (2013)
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186 R J Christie Y Matsumoto K Miyata T Nomoto S FukushimaK Osada J Halnaut F Pittella H J Kim N Nishiyama and
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
187 S Ganesh A K Iyer F Gattacceca D V Morrissey and M MAmiji In vivo biodistribution of siRNA and cisplatin adminis-tered using CD44-targeted hyaluronic acid nanoparticles J ControlRelease 172 699 (2013)
188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Depending on the material they consist of inorganicnanoparticles may possess a number of different propertiessuch as high electron density and strong optical absorption(eg metal particles in particular Au) photoluminescenceor fluorescence (semiconductor quantum dots eg CdSeCdTe CdTeSeZnS) phosphorescence (doped oxide mate-rials eg Y2O3) or magnetic moment (eg iron oxide orcobalt nanoparticles) The shape of the nanoparticle is alsoan important factor influencing its interaction with cellsMany of the above mentioned nanoparticle are sphericalin shape except carbon nanotubes that are tubular
Carbon NanotubesCarbon nanotubes (CNTs) easily cross the plasma mem-brane and translocate directly into the cytoplasm of tar-get cells due to their nanoneedle structure and usingan endocytosis-independent mechanism yet they do notinduce cell death127ndash129 CNTs are classified as single-walled CNTs and multiwalled CNTs Single or multiplegraphine layer(s) might have a length ranging from 50 nmto 100 mm and a diameter of 1 nm to 100 nm Properfunctionalizing of CNTs by covalent or non-covalentstrategies (such as coating with PEG or Tween-20) mayprovide solubility in aqueous solutions and prevent non-specific interactions thus minimizing toxicity observedwith non-functionalized raw particles130131 Modificationsmight also increase biocompatibility and blood circulationhalf-life132133 CNTs have very strong absorption charac-teristics providing an opportunity for photothermal abla-tion therapy in addition to nanocarrier properties
Magnetic NanoparticlesMagnetic nanoparticles are composed of ferromagneticelements such as Ni Co Mn Fe Superparamagneticiron oxide nanoparticles (SPIONS) such as maghemite--Fe2O3 and magnetite-Fe3O4 are one of the most widelyused magnetic particles as nanocarriers due to relativelylow cost of production biocompatability and superpara-magnetic nature134135 SPIONS are approved by FDA forclinical trials They are commonly used as contrast agentsfor magnetic resonance imaging (MRI) SPION crystals(less than 10 nm in diameter) are coated for specificpurposes with organic molecules such as dextran aminodextran BSA PEI dendrimers lipids and trialkoxysi-lanes including aminopropyltriethoxy silane (APTES)Coating chemistry and preparation methods influence over-all hydrodynamic size pharmacokinetics and the contrasttype (dark-T 2 or bright-T 1 agent) Ability to track the fateof nucleic acid carrier magnetic nanoparticles in vivo usingMRI is highly desirable since it provides informationabout the location of the cargo and its biodistribution136
Attachment of ligands provides target specificity andPEGylation may improve biocompatibility and blood half-life These modifications are commonly introduced to SPI-ONs that are used for imaging and therapy purposes Due
to their magnetic nature drug or nucleic acid carrying SPI-ONs can be concentrated at desired diseased sites such astumors and they may be dragged magnetically towards thelesion area136137 Moreover magnetic nanoparticles offerthe possibility of hyperthermia treatment as a result ofmagnetic heating135 Under applied alternating magneticfield SPIONs cause local temperature increase (41ndash42 C)which may be exploited for alternative and efficient cancertherapy Therefore SPIONs are one of the most versatileand multifunctional nanoparticles Consequently SPIONswere used as popular gene delivery vehicles135
Magnetic nanoparticles may be engineered for oligonu-cleotide delivery purposes MRI visible PEI-PEG coatedSPIONs which are tagged with an antibody have beenshown to effectively carry siRNA to cancer cell lines andshowed low toxicity138 SPIONs coated with both thermoresponsive and cationic polymers such as poly[2-(2-methoxyethoxy)ethylmethacrylate]-b-poly-[2-(dimethyl-amino)ethyl methacrylate] were reported to have25ndash100 times better transfection efficiency than branchedPEI 25 kDa when coupled with magnetic targeting139
SPIONs coated with low molecular weight PEI(12ndash2 kDa) which is usually not effective as poly-plexes in transfection were shown succesful in deliveringsiRNA to mouse macrophages (H Yagci Acar WIPOPatent WO2006055447A3) Therefore magnetic nanpar-ticles are under heavy investigation for the developmentof multifunctional nanocarriers for cancer therapy anddiagnosis135
Quantum DotsSemiconductor quantum dots (QDs) are light-emittingnanoparticles of few nanometer in diameter and they havebeen increasingly used as biological imaging and labelingprobes140 Luminescencefluorescence properties of QDsdepend on the crystal size and type Chemical composi-tion of the crystalline semiconductor core determines theband gap of the material therefore the emission wave-length range Within possible spectral window size ofthe crystal determines the specific wavelength of lumines-cencefluorescence for each and every QD due to quan-tum confinement effect Broad absorption of QDs allowexcitation of multiple QDs at a single wavelength andminimal signal mixing due to the narrow emission bandIn addition they are much more resistant to photobleach-ing These two characteristics are the major advantages ofQDs compared to organic fluorophores as imaging probesUtilization of QDs in nucleic acid delivery aims bothimaging and therapy since in vivo localization of cargocan be observed using optical imaging systems141142 Forexample cationic CdTeZnS QDs conjugated with PEGwas demonstrated to form an effective nanoplex with sur-vivin siRNA and successfully transfeced human tonguecancer cells in vitro and provided real time tracking143
However well-established QDs harbour significant toxic-ity due to constituents such as Cd Se Te144 Therefore
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
toxicity of these QDs is a drawback for their use in vivoAs an alternative silver (Ag) chalcogenites emerged assafer near-infra red-emitting QDs145146 Ag2S QDs did notinduce cytotoxicity ROS production apoptosis necrosisor DNA damage147 For example Ag2S QDs (coated with2-mercaptopropionic acid) emitting between 750ndash850 nmshowed no cytotoxicity in NIH3T3 cells at even highdoses (600 mgml) along with good cellular imagingpotential148
Gold NanoparticlesGold nanoparticles emerged as popular tools fornanocarrier-mediated gene therapy149 They are easily syn-thesized and biocompatible particles that allow addition offunctional molecules on their surface due to high surface-to-volume ratio114150 A variety of surface changes andfunctional additions were reported including cationic lipidcoating branched PEI addition or functionalization usingcationic quaternary ammonium or cystamine114151152
Indeed cystamine functionalized gold nanoparticles wereshown to effectively bind deliver and release 35 differ-ent miRNA in in vitro studies using neuroblastoma andovarian cancer cell lines153
Silica NanoparticlesSilica-based nanoparticles are inert stable biocompati-ble and biodegradable particles154 They can be renderedhydrophilic hydrophobic anionic or cationic using func-tional surface modifiers through electrostatic interactionsor by formation of any other type covalent bonds (egester amine) Common functionalization strategies to ren-der the molecule cationic and improve nucleic acid bind-ing include grafting of molecules such as PEI PEI-PEGand Poly-L-arginine155 Nucleic acids may also be loadedinside the mesoporous silica particles156 siRNA encapsu-lating mesoporous silica nanoparticles were successfullyused for in vitro and in vivo gene silencing in several stud-ies (For example Ref [156])
RECENT IN VIVO STUDIES USING RNAINTERFERENCE IN CANCER THERAPYThere is an exponential increase in the number of scientificpublications dedicated to gene therapy of diseases usingsmall RNAs and nanoparticles A literature search usingldquonanoparticlerdquo and ldquosiRNA shRNA or miRNArdquo revealedmore than 700 articles published in the last two yearsThis number is roughly equal to the number of all articlespublished in this field until two years ago So the field isexpanding and there seems to form a consensus aroundthe use of nanoparticles as next generation gene therapytools We believe that these high expectations are not onlya consequence of shifting trends in science and technol-ogy The exponential rise in interest in the field of smallRNA carrier nanoparticles is fueled by the advances inthe field of nano materials promising results obtained in
small RNA therapeutics by both academic laboratories andindustry and increasing number of successful clinical tri-als In this section we will summarize results of selectedrecent studies using RNA therapeutics for cancer treatmentin preclinical in vivo experimentsOverview of the works dealing with small RNA treat-
ment of experimental cancers and published within thelast two years were summarized in Table I Although sev-eral studies were performed using lipid-based nanopar-ticles (Liposomes micelles or lipidoids) other particlessuch as polymers organic or inorganic carriers and com-pounds mixtures with functional modifications of vari-able substances were also tested by many research teamswith reasonable success Scheme 4 summarizes the generalstrategy followed in most of these studies
Tumor Types and RNAi TherapyRecent studies in the literature showed that tumors of vari-ous tissue origins could be treated using RNA interferencestrategies (Table I) Fine tuning of nanoparticles throughaddition of functional moieties or modifications alloweddelivery of drugs into almost any kind of tumor tissue withaccompanied therapeutic effects Although several studiesused animal tumor models that resulted from the injectionof cell lines from most commonly seen human cancers(lung breast prostate cervix or ovarian cancer cell lines)animals with kidney urinary bladder head and neckgastric pancreatic melanomas neuroblastomas glioblas-tomas multiple myelomas or sarcomas were also treatedwith RNAinanocarrier strategy81156ndash170 These results givehope about the general use of RNA interference as astrategy to treat cancers of different origins Althoughit is difficult to compare the efficacies of different nucleicacid molecules and their interference effects at this pointsiRNA or microRNAs as well as shRNA vectors wereshown to achieve intratumoral in vivo target gene knock-down and anticancer effects leading to a decrease in tumorsize (For example Refs [156 171]) Since in most studiesin addition to RNAi loaded particles naked nanoparticlesor particles loaded with non-specific control nucleic acidswere also used antitumor effects obtained in these studiesare specific and they may be attributable to small RNAmolecules rather than the particles themselves underliningthe potential of RNA interference in cancer treatmentMajority of recent studies with in vivo models chose
to use human tumor cell line xenografts in immune com-promised mice nude or severe-combined immuno defi-cient SCID mice (Table I) (For example Refs [162 172])Syngeneic transplants and established genetically engi-neered mouse models of cancer were rarely studied in thiscontext167173ndash175 Therefore although antitumor effects andsome of the toxic effects (eg liver toxicity) might berevealed using immune compromised mice hematologicalimmunological and inflammatory side effects of the treat-ment strategies used in recent studies might need to berevisited using immunocompetent mice
1762 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IRec
entstudieswithRNAica
rryingnan
oparticles
forthetrea
tmen
tofex
perim
entalca
nce
rs(P
ublis
hed
within
thelast
twoye
ars)
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGF
Mag
netic
mes
oporou
ssilicana
nopa
rticles
PEIan
dfuso
genicpe
ptide
KALA
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[156
]
siRNA
Polo-likekina
se1(P
LK1)
pH-sen
sitiveca
tioniclip
idYSK05
-MEND
(YSK05
POPEcho
lesterol
=50
2525
)
PEG
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
PLK
1[51]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Bioen
gine
ered
bacterial
outermem
bran
eve
sicles
Hum
anep
idermal
grow
thfactor
rece
ptor
2(H
ER2)-spe
cific
affib
ody
targeting
HCC-195
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
KSP
Dec
reas
edtumor
volume
[81]
siRNA
Luciferase
Dioleoy
lpho
spha
tidic
acid-(DOPA
-)co
ated
nano
-sized
calcium
phos
phate(LCP-II)
DSPE-P
EG-an
dan
isam
idefortargeting
sigm
a-1rece
ptor
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
Xen
ograft
it
ND
Kno
ckdo
wnof
luciferase
[211
]
siRNA
mTERT
N-((2-hyd
roxy
-3-trim
ethy
l-am
mon
ium)propy
l)ch
itosa
nch
lorid
e(H
TCC)na
nopa
rticles
Partic
leload
edwith
paclita
xel
LCC
murinelung
canc
erce
llssy
ngen
eicsc
graft
oral
Noeffect
Kno
ckdo
wnof
mTERT
Dec
reas
edtumor
volume
Syn
ergize
dwith
paclita
xel
[159
]
siRNA
VEGF
Multilay
ered
polyion
complexes
Polyc
ationinterla
yeran
dade
tach
able
PEG
shell
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
[212
]
siRNA
Multid
rug
resistan
ceprotein1
(MRP1)
Nan
opartic
lesas
sembled
vialaye
r-by
laye
rde
positio
nof
siRNA
and
poly-L-arginine
Hya
lurona
n(H
A)co
ating
forHA-C
D44
targeting
MDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
it
Noeffect
Kno
ckdo
wnof
MRP1
Dec
reas
edtumor
volume
[183
]
siRNA
STA
T3-a
Nan
oporou
ssilicon
nano
particles
Argininean
dPEI
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicefat
padxe
nograft
iv
Noeffect
Kno
ckdo
wnof
STA
T3-a
[204
]
siRNA
Luciferase
Lipo
somal
nano
particle
Fou
rtand
emrepe
atsof
human
histon
eH2A
peptideinterven
edby
cathep
sinD
clea
vage
sites
PEG-A
nisa
mide
fortargeting
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
luciferase
[199
]
siRNA
Polo-likekina
se1(P
LK1)
Hya
luronicac
id(H
A)
base
dse
lfass
embling
HA-P
EIP
EG
nano
system
s
Hya
lurona
nforCD44
targeting
B16
F10
amurine
melan
omace
llsA54
9-luchu
man
lung
canc
erce
llsHep
3Bhu
man
liver
canc
erce
llsMDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
graftor
metas
tatic
lung
lesion
sby
IVinjection
it
ND
Kno
ckdo
wnof
PLK
1[160
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1763
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
P-glyco
protein
drug
expo
rter
(P-
gpM
DR1)
Mes
oporou
ssilica
nano
particles
Polye
thylen
eimine
polyethy
lene
glyc
ol(P
EI-PEG)co
polymer
MCF-7M
DR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gpMDR1
Dec
reas
edtumor
volume
Syn
ergy
with
doxo
rubicin
[179
]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Multifun
ctiona
lcarrie
rsy
stem
with
catio
nic
(olig
oethan
amino)am
ide
core
attach
edto
PEG
chain
Folic
acid
fortargeting
Inf7
(Infl
uenz
ape
ptide)
asen
doso
molytic
peptide
coup
ledto
the5prime-end
ofsiRNA
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
itor
iv
ND
Kno
ckdo
wnof
EG5
Dec
reas
edtumor
volume
[161
]
siRNA
Epide
rmal
Growth
Factor
Rec
eptor
(EGFR)
Poly-L-argininean
dde
xtransu
lfate-bas
edna
noco
mplex
FaDuhu
man
pharyn
xsq
uamou
sca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[172
]
siRNA
Cho
line
kina
se(C
hk)
Polye
thylen
imine-
polyethy
lene
glyc
ol(P
EI-PEG)co
grafted
polymer
Con
versionof
nontox
ic5-flu
oroc
ytos
ine(5-FC)to
cytotoxic5-flu
orou
racil
(5-FU)by
activating
bacterialc
ytos
ine
deam
inas
e(bCD)
PC3-PIP
andPC3-Flu
human
pros
tate
canc
erce
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
e[157
]
siRNA
Polo-like
kina
se1
(Plk1)
Cationiclip
idpo
lymer
hybrid
nano
particles
(cationiclip
id(N
N-
bis(2-hy
drox
yethyl)-N-
methy
l-N-(2-
choles
teryloxy
carbon
ylam
inoe
thyl)am
mon
ium
brom
ide
BHEM-C
hol)
andam
phiphilic
polymers(H
ydroph
obic
polylactideco
re)
PEG
shell
BT47
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Plk1
Dec
reas
edtumor
volume
[213
]
siRNA
hTERT
Single-walledca
rbon
nano
tube
s(S
WNTs)
Branc
hedPEIco
njug
ated
DSPE-P
EG20
00-M
aleimide
forco
njug
ationwith
NGR
(Cys
-Asn
-Gly-A
rg-C
ys-)
targetingpe
ptide(rec
ognize
tumor
neov
ascu
lature)
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
hTERT
Dec
reas
edtumor
volume
Syn
ergy
with
photothe
rmal
trea
tmen
t
[139
]
1764 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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1776 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
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1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
toxicity of these QDs is a drawback for their use in vivoAs an alternative silver (Ag) chalcogenites emerged assafer near-infra red-emitting QDs145146 Ag2S QDs did notinduce cytotoxicity ROS production apoptosis necrosisor DNA damage147 For example Ag2S QDs (coated with2-mercaptopropionic acid) emitting between 750ndash850 nmshowed no cytotoxicity in NIH3T3 cells at even highdoses (600 mgml) along with good cellular imagingpotential148
Gold NanoparticlesGold nanoparticles emerged as popular tools fornanocarrier-mediated gene therapy149 They are easily syn-thesized and biocompatible particles that allow addition offunctional molecules on their surface due to high surface-to-volume ratio114150 A variety of surface changes andfunctional additions were reported including cationic lipidcoating branched PEI addition or functionalization usingcationic quaternary ammonium or cystamine114151152
Indeed cystamine functionalized gold nanoparticles wereshown to effectively bind deliver and release 35 differ-ent miRNA in in vitro studies using neuroblastoma andovarian cancer cell lines153
Silica NanoparticlesSilica-based nanoparticles are inert stable biocompati-ble and biodegradable particles154 They can be renderedhydrophilic hydrophobic anionic or cationic using func-tional surface modifiers through electrostatic interactionsor by formation of any other type covalent bonds (egester amine) Common functionalization strategies to ren-der the molecule cationic and improve nucleic acid bind-ing include grafting of molecules such as PEI PEI-PEGand Poly-L-arginine155 Nucleic acids may also be loadedinside the mesoporous silica particles156 siRNA encapsu-lating mesoporous silica nanoparticles were successfullyused for in vitro and in vivo gene silencing in several stud-ies (For example Ref [156])
RECENT IN VIVO STUDIES USING RNAINTERFERENCE IN CANCER THERAPYThere is an exponential increase in the number of scientificpublications dedicated to gene therapy of diseases usingsmall RNAs and nanoparticles A literature search usingldquonanoparticlerdquo and ldquosiRNA shRNA or miRNArdquo revealedmore than 700 articles published in the last two yearsThis number is roughly equal to the number of all articlespublished in this field until two years ago So the field isexpanding and there seems to form a consensus aroundthe use of nanoparticles as next generation gene therapytools We believe that these high expectations are not onlya consequence of shifting trends in science and technol-ogy The exponential rise in interest in the field of smallRNA carrier nanoparticles is fueled by the advances inthe field of nano materials promising results obtained in
small RNA therapeutics by both academic laboratories andindustry and increasing number of successful clinical tri-als In this section we will summarize results of selectedrecent studies using RNA therapeutics for cancer treatmentin preclinical in vivo experimentsOverview of the works dealing with small RNA treat-
ment of experimental cancers and published within thelast two years were summarized in Table I Although sev-eral studies were performed using lipid-based nanopar-ticles (Liposomes micelles or lipidoids) other particlessuch as polymers organic or inorganic carriers and com-pounds mixtures with functional modifications of vari-able substances were also tested by many research teamswith reasonable success Scheme 4 summarizes the generalstrategy followed in most of these studies
Tumor Types and RNAi TherapyRecent studies in the literature showed that tumors of vari-ous tissue origins could be treated using RNA interferencestrategies (Table I) Fine tuning of nanoparticles throughaddition of functional moieties or modifications alloweddelivery of drugs into almost any kind of tumor tissue withaccompanied therapeutic effects Although several studiesused animal tumor models that resulted from the injectionof cell lines from most commonly seen human cancers(lung breast prostate cervix or ovarian cancer cell lines)animals with kidney urinary bladder head and neckgastric pancreatic melanomas neuroblastomas glioblas-tomas multiple myelomas or sarcomas were also treatedwith RNAinanocarrier strategy81156ndash170 These results givehope about the general use of RNA interference as astrategy to treat cancers of different origins Althoughit is difficult to compare the efficacies of different nucleicacid molecules and their interference effects at this pointsiRNA or microRNAs as well as shRNA vectors wereshown to achieve intratumoral in vivo target gene knock-down and anticancer effects leading to a decrease in tumorsize (For example Refs [156 171]) Since in most studiesin addition to RNAi loaded particles naked nanoparticlesor particles loaded with non-specific control nucleic acidswere also used antitumor effects obtained in these studiesare specific and they may be attributable to small RNAmolecules rather than the particles themselves underliningthe potential of RNA interference in cancer treatmentMajority of recent studies with in vivo models chose
to use human tumor cell line xenografts in immune com-promised mice nude or severe-combined immuno defi-cient SCID mice (Table I) (For example Refs [162 172])Syngeneic transplants and established genetically engi-neered mouse models of cancer were rarely studied in thiscontext167173ndash175 Therefore although antitumor effects andsome of the toxic effects (eg liver toxicity) might berevealed using immune compromised mice hematologicalimmunological and inflammatory side effects of the treat-ment strategies used in recent studies might need to berevisited using immunocompetent mice
1762 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IRec
entstudieswithRNAica
rryingnan
oparticles
forthetrea
tmen
tofex
perim
entalca
nce
rs(P
ublis
hed
within
thelast
twoye
ars)
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGF
Mag
netic
mes
oporou
ssilicana
nopa
rticles
PEIan
dfuso
genicpe
ptide
KALA
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[156
]
siRNA
Polo-likekina
se1(P
LK1)
pH-sen
sitiveca
tioniclip
idYSK05
-MEND
(YSK05
POPEcho
lesterol
=50
2525
)
PEG
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
PLK
1[51]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Bioen
gine
ered
bacterial
outermem
bran
eve
sicles
Hum
anep
idermal
grow
thfactor
rece
ptor
2(H
ER2)-spe
cific
affib
ody
targeting
HCC-195
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
KSP
Dec
reas
edtumor
volume
[81]
siRNA
Luciferase
Dioleoy
lpho
spha
tidic
acid-(DOPA
-)co
ated
nano
-sized
calcium
phos
phate(LCP-II)
DSPE-P
EG-an
dan
isam
idefortargeting
sigm
a-1rece
ptor
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
Xen
ograft
it
ND
Kno
ckdo
wnof
luciferase
[211
]
siRNA
mTERT
N-((2-hyd
roxy
-3-trim
ethy
l-am
mon
ium)propy
l)ch
itosa
nch
lorid
e(H
TCC)na
nopa
rticles
Partic
leload
edwith
paclita
xel
LCC
murinelung
canc
erce
llssy
ngen
eicsc
graft
oral
Noeffect
Kno
ckdo
wnof
mTERT
Dec
reas
edtumor
volume
Syn
ergize
dwith
paclita
xel
[159
]
siRNA
VEGF
Multilay
ered
polyion
complexes
Polyc
ationinterla
yeran
dade
tach
able
PEG
shell
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
[212
]
siRNA
Multid
rug
resistan
ceprotein1
(MRP1)
Nan
opartic
lesas
sembled
vialaye
r-by
laye
rde
positio
nof
siRNA
and
poly-L-arginine
Hya
lurona
n(H
A)co
ating
forHA-C
D44
targeting
MDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
it
Noeffect
Kno
ckdo
wnof
MRP1
Dec
reas
edtumor
volume
[183
]
siRNA
STA
T3-a
Nan
oporou
ssilicon
nano
particles
Argininean
dPEI
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicefat
padxe
nograft
iv
Noeffect
Kno
ckdo
wnof
STA
T3-a
[204
]
siRNA
Luciferase
Lipo
somal
nano
particle
Fou
rtand
emrepe
atsof
human
histon
eH2A
peptideinterven
edby
cathep
sinD
clea
vage
sites
PEG-A
nisa
mide
fortargeting
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
luciferase
[199
]
siRNA
Polo-likekina
se1(P
LK1)
Hya
luronicac
id(H
A)
base
dse
lfass
embling
HA-P
EIP
EG
nano
system
s
Hya
lurona
nforCD44
targeting
B16
F10
amurine
melan
omace
llsA54
9-luchu
man
lung
canc
erce
llsHep
3Bhu
man
liver
canc
erce
llsMDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
graftor
metas
tatic
lung
lesion
sby
IVinjection
it
ND
Kno
ckdo
wnof
PLK
1[160
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1763
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
P-glyco
protein
drug
expo
rter
(P-
gpM
DR1)
Mes
oporou
ssilica
nano
particles
Polye
thylen
eimine
polyethy
lene
glyc
ol(P
EI-PEG)co
polymer
MCF-7M
DR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gpMDR1
Dec
reas
edtumor
volume
Syn
ergy
with
doxo
rubicin
[179
]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Multifun
ctiona
lcarrie
rsy
stem
with
catio
nic
(olig
oethan
amino)am
ide
core
attach
edto
PEG
chain
Folic
acid
fortargeting
Inf7
(Infl
uenz
ape
ptide)
asen
doso
molytic
peptide
coup
ledto
the5prime-end
ofsiRNA
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
itor
iv
ND
Kno
ckdo
wnof
EG5
Dec
reas
edtumor
volume
[161
]
siRNA
Epide
rmal
Growth
Factor
Rec
eptor
(EGFR)
Poly-L-argininean
dde
xtransu
lfate-bas
edna
noco
mplex
FaDuhu
man
pharyn
xsq
uamou
sca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[172
]
siRNA
Cho
line
kina
se(C
hk)
Polye
thylen
imine-
polyethy
lene
glyc
ol(P
EI-PEG)co
grafted
polymer
Con
versionof
nontox
ic5-flu
oroc
ytos
ine(5-FC)to
cytotoxic5-flu
orou
racil
(5-FU)by
activating
bacterialc
ytos
ine
deam
inas
e(bCD)
PC3-PIP
andPC3-Flu
human
pros
tate
canc
erce
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
e[157
]
siRNA
Polo-like
kina
se1
(Plk1)
Cationiclip
idpo
lymer
hybrid
nano
particles
(cationiclip
id(N
N-
bis(2-hy
drox
yethyl)-N-
methy
l-N-(2-
choles
teryloxy
carbon
ylam
inoe
thyl)am
mon
ium
brom
ide
BHEM-C
hol)
andam
phiphilic
polymers(H
ydroph
obic
polylactideco
re)
PEG
shell
BT47
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Plk1
Dec
reas
edtumor
volume
[213
]
siRNA
hTERT
Single-walledca
rbon
nano
tube
s(S
WNTs)
Branc
hedPEIco
njug
ated
DSPE-P
EG20
00-M
aleimide
forco
njug
ationwith
NGR
(Cys
-Asn
-Gly-A
rg-C
ys-)
targetingpe
ptide(rec
ognize
tumor
neov
ascu
lature)
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
hTERT
Dec
reas
edtumor
volume
Syn
ergy
with
photothe
rmal
trea
tmen
t
[139
]
1764 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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cer J Clin 64 9 (2014)2 M J Espiritu A C Collier and J P Bingham A 21st-century
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4 M N Patel M D Halling-Brown J E Tym P Workman andB Al-Lazikani Objective assessment of cancer genes for drug dis-covery Nat Rev Drug Discov 12 35 (2013)
5 D Hanahan and R A Weinberg Hallmarks of cancer The nextgeneration Cell 144 646 (2011)
6 N F Sun Z A Liu W B Huang A L Tian and S Y Hu Theresearch of nanoparticles as gene vector for tumor gene therapyCrit Rev Oncol Hematol 89 352 (2013)
1776 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
7 M Rothe U Modlich and A Schambach Biosafety challenges foruse of lentiviral vectors in gene therapy Curr Gene Ther 13 453(2013)
8 D R Corey RNA learns from antisense Nat Chem Biol 3 8(2007)
9 V N Kim MicroRNA biogenesis Coordinated cropping and dic-ing Nat Rev Mol Cell Biol 6 376 (2005)
10 D E Golden V R Gerbasi and E J Sontheimer An inside jobfor siRNAs Mol Cell 31 309 (2008)
11 M Ghildiyal and P D Zamore Small silencing RNAs An expand-ing universe Nat Rev Genet 10 94 (2009)
12 D H Kim M A Behlke S D Rose M S Chang S Choiand J J Rossi Synthetic dsRNA Dicer substrates enhance RNAipotency and efficacy Nat Biotechnol 23 222 (2005)
13 Y Maida M Yasukawa M Furuuchi T Lassmann R PossematoN Okamoto V Kasim Y Hayashizaki W C Hahn and K Masu-tomi An RNA-dependent RNA polymerase formed by TERT andthe RMRP RNA Nature 461 230 (2009)
14 N R Smalheiser The search for endogenous siRNAs in the mam-malian brain Exp Neurol 235 455 (2012)
15 K A Tekirdag G Korkmaz D G Ozturk R Agami andD Gozuacik MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5 Autophagy 9 374(2013)
16 G Korkmaz K A Tekirdag D G Ozturk A Kosar O USezerman and D Gozuacik MIR376A Is a Regulator ofStarvation-Induced Autophagy PLoS One 8 e82556 (2013)
17 D Castanotto and J J Rossi The promises and pitfalls of RNA-interference-based therapeutics Nature 457 426 (2009)
18 E Iorns C J Lord N Turner and A Ashworth Utilizing RNAinterference to enhance cancer drug discovery Nat Rev Drug Dis-cov 6 556 (2007)
19 M A Behlke Chemical modification of siRNAs for in vivo useOligonucleotides 18 305 (2008)
20 S D Rose D H Kim M Amarzguioui J D Heidel M ACollingwood M E Davis J J Rossi and M A Behlke Func-tional polarity is introduced by Dicer processing of short substrateRNAs Nucleic Acids Res 33 4140 (2005)
21 K Nishina T Unno Y Uno T Kubodera T KanouchiH Mizusawa and T Yokota Efficient in vivo delivery of siRNAto the liver by conjugation of alpha-tocopherol Mol Ther 16 734(2008)
22 F Czauderna M Fechtner S Dames H Aygun A Klippel G JPronk K Giese and J Kaufmann Structural variations and sta-bilising modifications of synthetic siRNAs in mammalian cellsNucleic Acids Res 31 2705 (2003)
23 B A Kraynack and B F Baker Small interfering RNAs contain-ing full 2prime-O-methylribonucleotide-modified sense strands displayArgonaute2eIF2C2-dependent activity RNA 12 163 (2006)
24 F V Rivas N H Tolia J J Song J P Aragon J Liu G JHannon and L Joshua-Tor Purified Argonaute2 and an siRNAform recombinant human RISC Nat Struct Mol Biol 12 340(2005)
25 V Hornung M Guenthner-Biller C Bourquin A AblasserM Schlee S Uematsu A Noronha M Manoharan S AkiraA de Fougerolles S Endres and G Hartmann Sequence-specificpotent induction of IFN-alpha by short interfering RNA in plasma-cytoid dendritic cells through TLR7 Nat Med 11 263 (2005)
26 A D Judge G Bola A C Lee and I MacLachlan Design ofnoninflammatory synthetic siRNA mediating potent gene silencingin vivo Mol Ther 13 494 (2006)
27 A L Jackson J Burchard D Leake A Reynolds J SchelterJ Guo J M Johnson L Lim J Karpilow K NicholsW Marshall A Khvorova and P S Linsley Position-specificchemical modification of siRNAs reduces ldquooff-targetrdquo transcriptsilencing RNA 12 1197 (2006)
28 D Bumcrot M Manoharan V Koteliansky and D W Sah RNAitherapeutics A potential new class of pharmaceutical drugs NatChem Biol 2 711 (2006)
29 A S Peek and M A Behlke Design of active small interferingRNAs Curr Opin Mol Ther 9 110 (2007)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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174 F Yang W Huang Y Li S Liu M Jin Y Wang L Jia andZ Gao Anti-tumor effects in mice induced by survivin-targetedsiRNA delivered through polysaccharide nanoparticles Biomateri-als 34 5689 (2013)
175 L Chen Y Ding Y Wang X Liu R Babu W Ravis and W YanCodelivery of zoledronic acid and doublestranded RNA from corendashshell nanoparticles Int J Nanomedicine 8 137 (2013)
176 H Jagani J V Rao V R Palanimuthu R C Hariharapura andS Gang A nanoformulation of siRNA and its role in cancer ther-apy In vitro and in vivo evaluation Cell Mol Biol Lett 18 120(2013)
177 L A Tobin Y Xie M Tsokos S I Chung A A Merz M AArnold G Li H L Malech and K F Kwong Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of can-cer cell internalization in vivo Biomaterials 34 2980 (2013)
178 J Shen H Sun P Xu Q Yin Z Zhang S Wang H Yu and Y LiSimultaneous inhibition of metastasis and growth of breast cancerby co-delivery of twist shRNA and paclitaxel using pluronic P85-PEITPGS complex nanoparticles Biomaterials 34 1581 (2013)
179 H Meng W X Mai H Zhang M Xue T Xia S Lin X WangY Zhao Z Ji J I Zink and A E Nel Codelivery of an optimaldrugsiRNA combination using mesoporous silica nanoparticles toovercome drug resistance in breast cancer in vitro and in vivo ACSNano 7 994 (2013)
180 C Zheng M Zheng P Gong J Deng H Yi P Zhang Y ZhangP Liu Y Ma and L Cai Polypeptide cationic micelles mediatedco-delivery of docetaxel and siRNA for synergistic tumor therapyBiomaterials 34 3431 (2013)
181 Q Hu W Li X Hu J Shen X Jin J Zhou G Tang and P KChu Synergistic treatment of ovarian cancer by co-delivery of sur-vivin shRNA and paclitaxel via supramolecular micellar assemblyBiomaterials 33 6580 (2012)
182 Y H Yu E Kim D E Park G Shim S Lee Y B KimC W Kim and Y K Oh Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA Eur J Pharm Biopharm 80 268(2012)
183 Z J Deng S W Morton E Ben-Akiva E C Dreaden K EShopsowitz and P T Hammond Layer-by-layer nanoparticles forsystemic codelivery of an anticancer drug and siRNA for potentialtriple-negative breast cancer treatment ACS Nano 7 9571 (2013)
184 X Q Liu M H Xiong X T Shu R Z Tang and J WangTherapeutic delivery of siRNA silencing HIF-1 alpha with micellarnanoparticles inhibits hypoxic tumor growth Mol Pharm 9 2863(2012)
185 J Xiao X Duan Q Yin Z Miao H Yu C Chen Z ZhangJ Wang and Y Li The inhibition of metastasis and growth ofbreast cancer by blocking the NF-kappaB signaling pathway usingbioreducible PEI-basedp65 shRNA complex nanoparticles Bioma-terials 34 5381 (2013)
186 R J Christie Y Matsumoto K Miyata T Nomoto S FukushimaK Osada J Halnaut F Pittella H J Kim N Nishiyama and
J Biomed Nanotechnol 10 1751ndash1783 2014 1781
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
187 S Ganesh A K Iyer F Gattacceca D V Morrissey and M MAmiji In vivo biodistribution of siRNA and cisplatin adminis-tered using CD44-targeted hyaluronic acid nanoparticles J ControlRelease 172 699 (2013)
188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IRec
entstudieswithRNAica
rryingnan
oparticles
forthetrea
tmen
tofex
perim
entalca
nce
rs(P
ublis
hed
within
thelast
twoye
ars)
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGF
Mag
netic
mes
oporou
ssilicana
nopa
rticles
PEIan
dfuso
genicpe
ptide
KALA
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[156
]
siRNA
Polo-likekina
se1(P
LK1)
pH-sen
sitiveca
tioniclip
idYSK05
-MEND
(YSK05
POPEcho
lesterol
=50
2525
)
PEG
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
PLK
1[51]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Bioen
gine
ered
bacterial
outermem
bran
eve
sicles
Hum
anep
idermal
grow
thfactor
rece
ptor
2(H
ER2)-spe
cific
affib
ody
targeting
HCC-195
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
KSP
Dec
reas
edtumor
volume
[81]
siRNA
Luciferase
Dioleoy
lpho
spha
tidic
acid-(DOPA
-)co
ated
nano
-sized
calcium
phos
phate(LCP-II)
DSPE-P
EG-an
dan
isam
idefortargeting
sigm
a-1rece
ptor
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
Xen
ograft
it
ND
Kno
ckdo
wnof
luciferase
[211
]
siRNA
mTERT
N-((2-hyd
roxy
-3-trim
ethy
l-am
mon
ium)propy
l)ch
itosa
nch
lorid
e(H
TCC)na
nopa
rticles
Partic
leload
edwith
paclita
xel
LCC
murinelung
canc
erce
llssy
ngen
eicsc
graft
oral
Noeffect
Kno
ckdo
wnof
mTERT
Dec
reas
edtumor
volume
Syn
ergize
dwith
paclita
xel
[159
]
siRNA
VEGF
Multilay
ered
polyion
complexes
Polyc
ationinterla
yeran
dade
tach
able
PEG
shell
OS-R
C2hu
man
rena
lca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
[212
]
siRNA
Multid
rug
resistan
ceprotein1
(MRP1)
Nan
opartic
lesas
sembled
vialaye
r-by
laye
rde
positio
nof
siRNA
and
poly-L-arginine
Hya
lurona
n(H
A)co
ating
forHA-C
D44
targeting
MDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
it
Noeffect
Kno
ckdo
wnof
MRP1
Dec
reas
edtumor
volume
[183
]
siRNA
STA
T3-a
Nan
oporou
ssilicon
nano
particles
Argininean
dPEI
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicefat
padxe
nograft
iv
Noeffect
Kno
ckdo
wnof
STA
T3-a
[204
]
siRNA
Luciferase
Lipo
somal
nano
particle
Fou
rtand
emrepe
atsof
human
histon
eH2A
peptideinterven
edby
cathep
sinD
clea
vage
sites
PEG-A
nisa
mide
fortargeting
NCI-H-460
human
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
luciferase
[199
]
siRNA
Polo-likekina
se1(P
LK1)
Hya
luronicac
id(H
A)
base
dse
lfass
embling
HA-P
EIP
EG
nano
system
s
Hya
lurona
nforCD44
targeting
B16
F10
amurine
melan
omace
llsA54
9-luchu
man
lung
canc
erce
llsHep
3Bhu
man
liver
canc
erce
llsMDA-M
B-468
human
brea
stca
ncer
cells
Nud
emicesc
graftor
metas
tatic
lung
lesion
sby
IVinjection
it
ND
Kno
ckdo
wnof
PLK
1[160
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1763
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
P-glyco
protein
drug
expo
rter
(P-
gpM
DR1)
Mes
oporou
ssilica
nano
particles
Polye
thylen
eimine
polyethy
lene
glyc
ol(P
EI-PEG)co
polymer
MCF-7M
DR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gpMDR1
Dec
reas
edtumor
volume
Syn
ergy
with
doxo
rubicin
[179
]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Multifun
ctiona
lcarrie
rsy
stem
with
catio
nic
(olig
oethan
amino)am
ide
core
attach
edto
PEG
chain
Folic
acid
fortargeting
Inf7
(Infl
uenz
ape
ptide)
asen
doso
molytic
peptide
coup
ledto
the5prime-end
ofsiRNA
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
itor
iv
ND
Kno
ckdo
wnof
EG5
Dec
reas
edtumor
volume
[161
]
siRNA
Epide
rmal
Growth
Factor
Rec
eptor
(EGFR)
Poly-L-argininean
dde
xtransu
lfate-bas
edna
noco
mplex
FaDuhu
man
pharyn
xsq
uamou
sca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[172
]
siRNA
Cho
line
kina
se(C
hk)
Polye
thylen
imine-
polyethy
lene
glyc
ol(P
EI-PEG)co
grafted
polymer
Con
versionof
nontox
ic5-flu
oroc
ytos
ine(5-FC)to
cytotoxic5-flu
orou
racil
(5-FU)by
activating
bacterialc
ytos
ine
deam
inas
e(bCD)
PC3-PIP
andPC3-Flu
human
pros
tate
canc
erce
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
e[157
]
siRNA
Polo-like
kina
se1
(Plk1)
Cationiclip
idpo
lymer
hybrid
nano
particles
(cationiclip
id(N
N-
bis(2-hy
drox
yethyl)-N-
methy
l-N-(2-
choles
teryloxy
carbon
ylam
inoe
thyl)am
mon
ium
brom
ide
BHEM-C
hol)
andam
phiphilic
polymers(H
ydroph
obic
polylactideco
re)
PEG
shell
BT47
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Plk1
Dec
reas
edtumor
volume
[213
]
siRNA
hTERT
Single-walledca
rbon
nano
tube
s(S
WNTs)
Branc
hedPEIco
njug
ated
DSPE-P
EG20
00-M
aleimide
forco
njug
ationwith
NGR
(Cys
-Asn
-Gly-A
rg-C
ys-)
targetingpe
ptide(rec
ognize
tumor
neov
ascu
lature)
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
hTERT
Dec
reas
edtumor
volume
Syn
ergy
with
photothe
rmal
trea
tmen
t
[139
]
1764 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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148 I Hocaoglu M N Ccedilizmeciyan R Erdem C Ozen A KurtA Sennaroglu and H Y Acar Development of highly luminescentand cytocompatible near-IR-emitting aqueous Ag2S quantum dotsJ Mater Chem 22 14674 (2012)
149 P R Chandran P Appadurai K Rathinasamy and N SandhyaraniEnhanced cytotoxic effect of doxorubicin loaded multifunctionalgold nanoparticle for targeted cancer drug delivery J NanopharmDrug Delivery 1 289 (2013)
150 P R Chandran P Appadurai K Rathinasamy and N SandhyaraniEnhanced cytotoxic effect of doxorubicin loaded multifunctionalgold nanoparticle for targeted cancer drug delivery J NanopharmDrug Delivery 1 289 (2013)
151 N L Rosi D A Giljohann C S Thaxton A K Lytton-JeanM S Han and C A Mirkin Oligonucleotide-modified goldnanoparticles for intracellular gene regulation Science 312 1027(2006)
152 W H Kong K H Bae S D Jo J S Kim and T G Park Cationiclipid-coated gold nanoparticles as efficient and non-cytotoxic intra-cellular siRNA delivery vehicles Pharm Res 29 362 (2012)
153 R Ghosh L C Singh J M Shohet and P H Gunaratne A goldnanoparticle platform for the delivery of functional microRNAs intocancer cells Biomaterials 34 807 (2013)
154 A Bitar N M Ahmad H Fessi and A Elaissari Silica-basednanoparticles for biomedical applications Drug Discov Today17 1147 (2012)
1780 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
155 H Lee D Sung M Veerapandian K Yun and S W Seo PEGy-lated polyethyleneimine grafted silica nanoparticles Enhanced cel-lular uptake and efficient siRNA delivery Anal Bioanal Chem400 535 (2011)
156 X Li Y Chen M Wang Y Ma W Xia and H Gu A mesoporoussilica nanoparticlendashPEIndashfusogenic peptide system for siRNA deliv-ery in cancer therapy Biomaterials 34 1391 (2013)
157 Z Chen M F Penet S Nimmagadda C Li S R Banerjee P TWinnard Jr D Artemov K Glunde M G Pomper and Z MBhujwalla PSMA-targeted theranostic nanoplex for prostate cancertherapy ACS Nano 6 7752 (2012)
158 F Haque D Shu Y Shu L S Shlyakhtenko P G RychahouB M Evers and P Guo Ultrastable synergistic tetravalent RNAnanoparticles for targeting to cancers Nano Today 7 245 (2012)
159 W Wei P P Lv X M Chen Z G Yue Q Fu S Y Liu H Yueand G H Ma Codelivery of mTERT siRNA and paclitaxel bychitosan-based nanoparticles promoted synergistic tumor suppres-sion Biomaterials 34 3912 (2013)
160 S Ganesh A K Iyer D V Morrissey and M M AmijiHyaluronic acid based self-assembling nanosystems for CD44 tar-get mediated siRNA delivery to solid tumors Biomaterials 34 3489(2013)
161 C Dohmen D Edinger T Frohlich L Schreiner U LacheltC Troiber J Radler P Hadwiger H P Vornlocher and E WagnerNanosized multifunctional polyplexes for receptor-mediated siRNAdelivery ACS Nano 6 5198 (2012)
162 S A Jensen E S Day C H Ko L A Hurley J P LucianoF M Kouri T J Merkel A J Luthi P C Patel J I Cutler W LDaniel A W Scott M W Rotz T J Meade D A GiljohannC A Mirkin and A H Stegh Spherical nucleic acid nanoparticleconjugates as an RNAi-based therapy for glioblastoma Sci TranslMed 5 209ra152 (2013)
163 H Arima A Yoshimatsu H Ikeda A Ohyama K MotoyamaT Higashi A Tsuchiya T Niidome Y Katayama K Hattoriand T Takeuchi Folate-PEG-appended dendrimer conjugate withalpha-cyclodextrin as a novel cancer cell-selective siRNA deliverycarrier Mol Pharm 9 2591 (2012)
164 J Wei T Cheang B Tang H Xia Z Xing Z Chen Y FangW Chen A Xu S Wang and J Luo The inhibition of humanbladder cancer growth by calcium carbonateCaIP6 nanocompositeparticles delivering AIB1 siRNA Biomaterials 34 1246 (2013)
165 T Kanazawa K Sugawara K Tanaka S Horiuchi Y Takashimaand H Okada Suppression of tumor growth by systemic delivery ofanti-VEGF siRNA with cell-penetrating peptide-modified MPEG-PCL nanomicelles Eur J Pharm Biopharm 81 470 (2012)
166 M A Rahman A R Amin X Wang J E Zuckerman C HChoi B Zhou D Wang S Nannapaneni L Koenig Z ChenZ G Chen Y Yen M E Davis and D M Shin Systemic deliveryof siRNA nanoparticles targeting RRM2 suppresses head and necktumor growth J Control Release 159 384 (2012)
167 J Guo J R Ogier S Desgranges R Darcy and C OrsquoDriscollAnisamide-targeted cyclodextrin nanoparticles for siRNA deliveryto prostate tumours in mice Biomaterials 33 7775 (2012)
168 M Shen F Gong P Pang K Zhu X Meng C Wu J WangH Shan and X Shuai An MRI-visible non-viral vector for tar-geted Bcl-2 siRNA delivery to neuroblastoma Int J Nanomedicine7 3319 (2012)
169 D Lin Q Jiang Q Cheng Y Huang P Huang S Han S GuoZ Liang and A Dong Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and invivo siRNA delivery Acta Biomater 9 7746 (2013)
170 L Zou X Song T Yi S Li H Deng X Chen Z Li Y BaiQ Zhong Y Wei and X Zhao Administration of PLGA nanopar-ticles carrying shRNA against focal adhesion kinase and CD44results in enhanced antitumor effects against ovarian cancer CancerGene Ther 20 242 (2013)
171 T Yin P Wang J Li R Zheng B Zheng D Cheng R Li J Laiand X Shuai Ultrasound-sensitive siRNA-loaded nanobubblesformed by hetero-assembly of polymeric micelles and liposomesand their therapeutic effect in gliomas Biomaterials 34 4532(2013)
172 H J Cho S Chong S J Chung C K Shim and D D Kim Poly-L-arginine and dextran sulfate-based nanocomplex for epidermalgrowth factor receptor (EGFR) siRNA delivery Its application forhead and neck cancer treatment Pharm Res 29 1007 (2012)
173 F Abedini H Hosseinkhani M Ismail A J Domb A R OmarP P Chong P D Hong D S Yu and I Y Farber Cationizeddextran nanoparticle-encapsulated CXCR4-siRNA enhanced corre-lation between CXCR4 expression and serum alkaline phosphatasein a mouse model of colorectal cancer Int J Nanomedicine 7 4159(2012)
174 F Yang W Huang Y Li S Liu M Jin Y Wang L Jia andZ Gao Anti-tumor effects in mice induced by survivin-targetedsiRNA delivered through polysaccharide nanoparticles Biomateri-als 34 5689 (2013)
175 L Chen Y Ding Y Wang X Liu R Babu W Ravis and W YanCodelivery of zoledronic acid and doublestranded RNA from corendashshell nanoparticles Int J Nanomedicine 8 137 (2013)
176 H Jagani J V Rao V R Palanimuthu R C Hariharapura andS Gang A nanoformulation of siRNA and its role in cancer ther-apy In vitro and in vivo evaluation Cell Mol Biol Lett 18 120(2013)
177 L A Tobin Y Xie M Tsokos S I Chung A A Merz M AArnold G Li H L Malech and K F Kwong Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of can-cer cell internalization in vivo Biomaterials 34 2980 (2013)
178 J Shen H Sun P Xu Q Yin Z Zhang S Wang H Yu and Y LiSimultaneous inhibition of metastasis and growth of breast cancerby co-delivery of twist shRNA and paclitaxel using pluronic P85-PEITPGS complex nanoparticles Biomaterials 34 1581 (2013)
179 H Meng W X Mai H Zhang M Xue T Xia S Lin X WangY Zhao Z Ji J I Zink and A E Nel Codelivery of an optimaldrugsiRNA combination using mesoporous silica nanoparticles toovercome drug resistance in breast cancer in vitro and in vivo ACSNano 7 994 (2013)
180 C Zheng M Zheng P Gong J Deng H Yi P Zhang Y ZhangP Liu Y Ma and L Cai Polypeptide cationic micelles mediatedco-delivery of docetaxel and siRNA for synergistic tumor therapyBiomaterials 34 3431 (2013)
181 Q Hu W Li X Hu J Shen X Jin J Zhou G Tang and P KChu Synergistic treatment of ovarian cancer by co-delivery of sur-vivin shRNA and paclitaxel via supramolecular micellar assemblyBiomaterials 33 6580 (2012)
182 Y H Yu E Kim D E Park G Shim S Lee Y B KimC W Kim and Y K Oh Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA Eur J Pharm Biopharm 80 268(2012)
183 Z J Deng S W Morton E Ben-Akiva E C Dreaden K EShopsowitz and P T Hammond Layer-by-layer nanoparticles forsystemic codelivery of an anticancer drug and siRNA for potentialtriple-negative breast cancer treatment ACS Nano 7 9571 (2013)
184 X Q Liu M H Xiong X T Shu R Z Tang and J WangTherapeutic delivery of siRNA silencing HIF-1 alpha with micellarnanoparticles inhibits hypoxic tumor growth Mol Pharm 9 2863(2012)
185 J Xiao X Duan Q Yin Z Miao H Yu C Chen Z ZhangJ Wang and Y Li The inhibition of metastasis and growth ofbreast cancer by blocking the NF-kappaB signaling pathway usingbioreducible PEI-basedp65 shRNA complex nanoparticles Bioma-terials 34 5381 (2013)
186 R J Christie Y Matsumoto K Miyata T Nomoto S FukushimaK Osada J Halnaut F Pittella H J Kim N Nishiyama and
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
187 S Ganesh A K Iyer F Gattacceca D V Morrissey and M MAmiji In vivo biodistribution of siRNA and cisplatin adminis-tered using CD44-targeted hyaluronic acid nanoparticles J ControlRelease 172 699 (2013)
188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
P-glyco
protein
drug
expo
rter
(P-
gpM
DR1)
Mes
oporou
ssilica
nano
particles
Polye
thylen
eimine
polyethy
lene
glyc
ol(P
EI-PEG)co
polymer
MCF-7M
DR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gpMDR1
Dec
reas
edtumor
volume
Syn
ergy
with
doxo
rubicin
[179
]
siRNA
Kines
insp
indle
protein
(KSPEG5)
Multifun
ctiona
lcarrie
rsy
stem
with
catio
nic
(olig
oethan
amino)am
ide
core
attach
edto
PEG
chain
Folic
acid
fortargeting
Inf7
(Infl
uenz
ape
ptide)
asen
doso
molytic
peptide
coup
ledto
the5prime-end
ofsiRNA
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
itor
iv
ND
Kno
ckdo
wnof
EG5
Dec
reas
edtumor
volume
[161
]
siRNA
Epide
rmal
Growth
Factor
Rec
eptor
(EGFR)
Poly-L-argininean
dde
xtransu
lfate-bas
edna
noco
mplex
FaDuhu
man
pharyn
xsq
uamou
sca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[172
]
siRNA
Cho
line
kina
se(C
hk)
Polye
thylen
imine-
polyethy
lene
glyc
ol(P
EI-PEG)co
grafted
polymer
Con
versionof
nontox
ic5-flu
oroc
ytos
ine(5-FC)to
cytotoxic5-flu
orou
racil
(5-FU)by
activating
bacterialc
ytos
ine
deam
inas
e(bCD)
PC3-PIP
andPC3-Flu
human
pros
tate
canc
erce
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
e[157
]
siRNA
Polo-like
kina
se1
(Plk1)
Cationiclip
idpo
lymer
hybrid
nano
particles
(cationiclip
id(N
N-
bis(2-hy
drox
yethyl)-N-
methy
l-N-(2-
choles
teryloxy
carbon
ylam
inoe
thyl)am
mon
ium
brom
ide
BHEM-C
hol)
andam
phiphilic
polymers(H
ydroph
obic
polylactideco
re)
PEG
shell
BT47
4hu
man
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Plk1
Dec
reas
edtumor
volume
[213
]
siRNA
hTERT
Single-walledca
rbon
nano
tube
s(S
WNTs)
Branc
hedPEIco
njug
ated
DSPE-P
EG20
00-M
aleimide
forco
njug
ationwith
NGR
(Cys
-Asn
-Gly-A
rg-C
ys-)
targetingpe
ptide(rec
ognize
tumor
neov
ascu
lature)
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
hTERT
Dec
reas
edtumor
volume
Syn
ergy
with
photothe
rmal
trea
tmen
t
[139
]
1764 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Copyright American Scientific Publishers
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152 W H Kong K H Bae S D Jo J S Kim and T G Park Cationiclipid-coated gold nanoparticles as efficient and non-cytotoxic intra-cellular siRNA delivery vehicles Pharm Res 29 362 (2012)
153 R Ghosh L C Singh J M Shohet and P H Gunaratne A goldnanoparticle platform for the delivery of functional microRNAs intocancer cells Biomaterials 34 807 (2013)
154 A Bitar N M Ahmad H Fessi and A Elaissari Silica-basednanoparticles for biomedical applications Drug Discov Today17 1147 (2012)
1780 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
155 H Lee D Sung M Veerapandian K Yun and S W Seo PEGy-lated polyethyleneimine grafted silica nanoparticles Enhanced cel-lular uptake and efficient siRNA delivery Anal Bioanal Chem400 535 (2011)
156 X Li Y Chen M Wang Y Ma W Xia and H Gu A mesoporoussilica nanoparticlendashPEIndashfusogenic peptide system for siRNA deliv-ery in cancer therapy Biomaterials 34 1391 (2013)
157 Z Chen M F Penet S Nimmagadda C Li S R Banerjee P TWinnard Jr D Artemov K Glunde M G Pomper and Z MBhujwalla PSMA-targeted theranostic nanoplex for prostate cancertherapy ACS Nano 6 7752 (2012)
158 F Haque D Shu Y Shu L S Shlyakhtenko P G RychahouB M Evers and P Guo Ultrastable synergistic tetravalent RNAnanoparticles for targeting to cancers Nano Today 7 245 (2012)
159 W Wei P P Lv X M Chen Z G Yue Q Fu S Y Liu H Yueand G H Ma Codelivery of mTERT siRNA and paclitaxel bychitosan-based nanoparticles promoted synergistic tumor suppres-sion Biomaterials 34 3912 (2013)
160 S Ganesh A K Iyer D V Morrissey and M M AmijiHyaluronic acid based self-assembling nanosystems for CD44 tar-get mediated siRNA delivery to solid tumors Biomaterials 34 3489(2013)
161 C Dohmen D Edinger T Frohlich L Schreiner U LacheltC Troiber J Radler P Hadwiger H P Vornlocher and E WagnerNanosized multifunctional polyplexes for receptor-mediated siRNAdelivery ACS Nano 6 5198 (2012)
162 S A Jensen E S Day C H Ko L A Hurley J P LucianoF M Kouri T J Merkel A J Luthi P C Patel J I Cutler W LDaniel A W Scott M W Rotz T J Meade D A GiljohannC A Mirkin and A H Stegh Spherical nucleic acid nanoparticleconjugates as an RNAi-based therapy for glioblastoma Sci TranslMed 5 209ra152 (2013)
163 H Arima A Yoshimatsu H Ikeda A Ohyama K MotoyamaT Higashi A Tsuchiya T Niidome Y Katayama K Hattoriand T Takeuchi Folate-PEG-appended dendrimer conjugate withalpha-cyclodextrin as a novel cancer cell-selective siRNA deliverycarrier Mol Pharm 9 2591 (2012)
164 J Wei T Cheang B Tang H Xia Z Xing Z Chen Y FangW Chen A Xu S Wang and J Luo The inhibition of humanbladder cancer growth by calcium carbonateCaIP6 nanocompositeparticles delivering AIB1 siRNA Biomaterials 34 1246 (2013)
165 T Kanazawa K Sugawara K Tanaka S Horiuchi Y Takashimaand H Okada Suppression of tumor growth by systemic delivery ofanti-VEGF siRNA with cell-penetrating peptide-modified MPEG-PCL nanomicelles Eur J Pharm Biopharm 81 470 (2012)
166 M A Rahman A R Amin X Wang J E Zuckerman C HChoi B Zhou D Wang S Nannapaneni L Koenig Z ChenZ G Chen Y Yen M E Davis and D M Shin Systemic deliveryof siRNA nanoparticles targeting RRM2 suppresses head and necktumor growth J Control Release 159 384 (2012)
167 J Guo J R Ogier S Desgranges R Darcy and C OrsquoDriscollAnisamide-targeted cyclodextrin nanoparticles for siRNA deliveryto prostate tumours in mice Biomaterials 33 7775 (2012)
168 M Shen F Gong P Pang K Zhu X Meng C Wu J WangH Shan and X Shuai An MRI-visible non-viral vector for tar-geted Bcl-2 siRNA delivery to neuroblastoma Int J Nanomedicine7 3319 (2012)
169 D Lin Q Jiang Q Cheng Y Huang P Huang S Han S GuoZ Liang and A Dong Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and invivo siRNA delivery Acta Biomater 9 7746 (2013)
170 L Zou X Song T Yi S Li H Deng X Chen Z Li Y BaiQ Zhong Y Wei and X Zhao Administration of PLGA nanopar-ticles carrying shRNA against focal adhesion kinase and CD44results in enhanced antitumor effects against ovarian cancer CancerGene Ther 20 242 (2013)
171 T Yin P Wang J Li R Zheng B Zheng D Cheng R Li J Laiand X Shuai Ultrasound-sensitive siRNA-loaded nanobubblesformed by hetero-assembly of polymeric micelles and liposomesand their therapeutic effect in gliomas Biomaterials 34 4532(2013)
172 H J Cho S Chong S J Chung C K Shim and D D Kim Poly-L-arginine and dextran sulfate-based nanocomplex for epidermalgrowth factor receptor (EGFR) siRNA delivery Its application forhead and neck cancer treatment Pharm Res 29 1007 (2012)
173 F Abedini H Hosseinkhani M Ismail A J Domb A R OmarP P Chong P D Hong D S Yu and I Y Farber Cationizeddextran nanoparticle-encapsulated CXCR4-siRNA enhanced corre-lation between CXCR4 expression and serum alkaline phosphatasein a mouse model of colorectal cancer Int J Nanomedicine 7 4159(2012)
174 F Yang W Huang Y Li S Liu M Jin Y Wang L Jia andZ Gao Anti-tumor effects in mice induced by survivin-targetedsiRNA delivered through polysaccharide nanoparticles Biomateri-als 34 5689 (2013)
175 L Chen Y Ding Y Wang X Liu R Babu W Ravis and W YanCodelivery of zoledronic acid and doublestranded RNA from corendashshell nanoparticles Int J Nanomedicine 8 137 (2013)
176 H Jagani J V Rao V R Palanimuthu R C Hariharapura andS Gang A nanoformulation of siRNA and its role in cancer ther-apy In vitro and in vivo evaluation Cell Mol Biol Lett 18 120(2013)
177 L A Tobin Y Xie M Tsokos S I Chung A A Merz M AArnold G Li H L Malech and K F Kwong Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of can-cer cell internalization in vivo Biomaterials 34 2980 (2013)
178 J Shen H Sun P Xu Q Yin Z Zhang S Wang H Yu and Y LiSimultaneous inhibition of metastasis and growth of breast cancerby co-delivery of twist shRNA and paclitaxel using pluronic P85-PEITPGS complex nanoparticles Biomaterials 34 1581 (2013)
179 H Meng W X Mai H Zhang M Xue T Xia S Lin X WangY Zhao Z Ji J I Zink and A E Nel Codelivery of an optimaldrugsiRNA combination using mesoporous silica nanoparticles toovercome drug resistance in breast cancer in vitro and in vivo ACSNano 7 994 (2013)
180 C Zheng M Zheng P Gong J Deng H Yi P Zhang Y ZhangP Liu Y Ma and L Cai Polypeptide cationic micelles mediatedco-delivery of docetaxel and siRNA for synergistic tumor therapyBiomaterials 34 3431 (2013)
181 Q Hu W Li X Hu J Shen X Jin J Zhou G Tang and P KChu Synergistic treatment of ovarian cancer by co-delivery of sur-vivin shRNA and paclitaxel via supramolecular micellar assemblyBiomaterials 33 6580 (2012)
182 Y H Yu E Kim D E Park G Shim S Lee Y B KimC W Kim and Y K Oh Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA Eur J Pharm Biopharm 80 268(2012)
183 Z J Deng S W Morton E Ben-Akiva E C Dreaden K EShopsowitz and P T Hammond Layer-by-layer nanoparticles forsystemic codelivery of an anticancer drug and siRNA for potentialtriple-negative breast cancer treatment ACS Nano 7 9571 (2013)
184 X Q Liu M H Xiong X T Shu R Z Tang and J WangTherapeutic delivery of siRNA silencing HIF-1 alpha with micellarnanoparticles inhibits hypoxic tumor growth Mol Pharm 9 2863(2012)
185 J Xiao X Duan Q Yin Z Miao H Yu C Chen Z ZhangJ Wang and Y Li The inhibition of metastasis and growth ofbreast cancer by blocking the NF-kappaB signaling pathway usingbioreducible PEI-basedp65 shRNA complex nanoparticles Bioma-terials 34 5381 (2013)
186 R J Christie Y Matsumoto K Miyata T Nomoto S FukushimaK Osada J Halnaut F Pittella H J Kim N Nishiyama and
J Biomed Nanotechnol 10 1751ndash1783 2014 1781
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
187 S Ganesh A K Iyer F Gattacceca D V Morrissey and M MAmiji In vivo biodistribution of siRNA and cisplatin adminis-tered using CD44-targeted hyaluronic acid nanoparticles J ControlRelease 172 699 (2013)
188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
VEGFR2
Targeted
polymeric
micelles
Poly(ethy
lene
glyc
ol)-bloc
k-po
ly(L-ly
sine
)(P
EGb-PLL
)co
mprising
lysine
amines
mod
ified
with
2-im
inothiolan
e(2IT)an
dthecy
clo-Arg-G
ly-A
sp(cRGD)pe
ptideon
the
PEG
term
inus
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
Hep
atotox
icty
compa
reto
controls
Kno
ckdo
wnof
VEGFR2
Dec
reas
edtumor
volume
[186
]
siRNA
Luciferase
Tetrav
alen
tRNA
nano
particles(lu
ciferase
siRNAsu
rvivin
siRNA
malac
hite
gree
n(M
G)
bind
ingap
tamer
and
folate
labe
ledRNA)
Aptam
eran
dfolate
labe
ling
allowed
targetin
KB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[158
]
siRNA
APRIL
and
miR-145
Neg
ativelip
idoid
nano
particle
(98N
12-5(1)
mPEG20
00-C
12C
14lip
idan
dch
oles
terol)
Not
releva
ntDMH
(dim
ethy
l-hy
draz
ine)-
indu
ced
colorectal
tumorsin
ICR
mice
enem
aNoeffect
Deliveryto
tumor
tissu
e[205
]
siRNA
Bcl2L
12Goldna
nopa
rticles
PEGylation
Glio
blas
toma
Multiform
SCID
micesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
BcL
2L12
[162
]
shRNA
Survivin
Amph
iphilic
copo
lymer
poly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diac
rylate--
tetrae
thylen
epen
tamine]
andpo
lyca
prolac
tone
(PBD-P
CL)
Hyd
roph
obic
chem
othe
rape
utic
drug
s(D
oxorub
icin)load
edin
core
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
combina
tion
therap
y
Kno
ckdo
wnP-gp
Dec
reas
edtumor
volume
[214
]
siRNA
EWSFli-1
Biotin
ylated
poly(is
obutyl-
cyan
oacrylate)
nano
particles
Biotin
ylated
with
orwith
out
anti-glyc
oprotein
cd99
antib
ody
A67
3hu
man
Ewingrsquossa
rcom
ace
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EWSFli-1
Dec
reas
edtumor
volume
[190
]
siRNA
Survivin
Pep
tide-co
upledch
itosa
nna
nopa
rticles
(TAT
-g-C
S)
TATpe
ptide
(GCGGGYGRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
MCF-7
human
brea
stca
ncer
cells
4T1murine
mam
mary
carcinom
ace
lls
Syn
gene
icsc
graft
it
ND
Dec
reas
edtumor
volume
[174
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1765
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
REFERENCES1 R Siegel J Ma Z Zou and A Jemal Cancer statistics CA Can-
cer J Clin 64 9 (2014)2 M J Espiritu A C Collier and J P Bingham A 21st-century
approach to age-old problems The ascension of biologics in clini-cal therapeutics Drug Discov Today (2014)
3 R L Schilsky Personalized medicine in oncology The future isnow Nat Rev Drug Discov 9 363 (2010)
4 M N Patel M D Halling-Brown J E Tym P Workman andB Al-Lazikani Objective assessment of cancer genes for drug dis-covery Nat Rev Drug Discov 12 35 (2013)
5 D Hanahan and R A Weinberg Hallmarks of cancer The nextgeneration Cell 144 646 (2011)
6 N F Sun Z A Liu W B Huang A L Tian and S Y Hu Theresearch of nanoparticles as gene vector for tumor gene therapyCrit Rev Oncol Hematol 89 352 (2013)
1776 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
7 M Rothe U Modlich and A Schambach Biosafety challenges foruse of lentiviral vectors in gene therapy Curr Gene Ther 13 453(2013)
8 D R Corey RNA learns from antisense Nat Chem Biol 3 8(2007)
9 V N Kim MicroRNA biogenesis Coordinated cropping and dic-ing Nat Rev Mol Cell Biol 6 376 (2005)
10 D E Golden V R Gerbasi and E J Sontheimer An inside jobfor siRNAs Mol Cell 31 309 (2008)
11 M Ghildiyal and P D Zamore Small silencing RNAs An expand-ing universe Nat Rev Genet 10 94 (2009)
12 D H Kim M A Behlke S D Rose M S Chang S Choiand J J Rossi Synthetic dsRNA Dicer substrates enhance RNAipotency and efficacy Nat Biotechnol 23 222 (2005)
13 Y Maida M Yasukawa M Furuuchi T Lassmann R PossematoN Okamoto V Kasim Y Hayashizaki W C Hahn and K Masu-tomi An RNA-dependent RNA polymerase formed by TERT andthe RMRP RNA Nature 461 230 (2009)
14 N R Smalheiser The search for endogenous siRNAs in the mam-malian brain Exp Neurol 235 455 (2012)
15 K A Tekirdag G Korkmaz D G Ozturk R Agami andD Gozuacik MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5 Autophagy 9 374(2013)
16 G Korkmaz K A Tekirdag D G Ozturk A Kosar O USezerman and D Gozuacik MIR376A Is a Regulator ofStarvation-Induced Autophagy PLoS One 8 e82556 (2013)
17 D Castanotto and J J Rossi The promises and pitfalls of RNA-interference-based therapeutics Nature 457 426 (2009)
18 E Iorns C J Lord N Turner and A Ashworth Utilizing RNAinterference to enhance cancer drug discovery Nat Rev Drug Dis-cov 6 556 (2007)
19 M A Behlke Chemical modification of siRNAs for in vivo useOligonucleotides 18 305 (2008)
20 S D Rose D H Kim M Amarzguioui J D Heidel M ACollingwood M E Davis J J Rossi and M A Behlke Func-tional polarity is introduced by Dicer processing of short substrateRNAs Nucleic Acids Res 33 4140 (2005)
21 K Nishina T Unno Y Uno T Kubodera T KanouchiH Mizusawa and T Yokota Efficient in vivo delivery of siRNAto the liver by conjugation of alpha-tocopherol Mol Ther 16 734(2008)
22 F Czauderna M Fechtner S Dames H Aygun A Klippel G JPronk K Giese and J Kaufmann Structural variations and sta-bilising modifications of synthetic siRNAs in mammalian cellsNucleic Acids Res 31 2705 (2003)
23 B A Kraynack and B F Baker Small interfering RNAs contain-ing full 2prime-O-methylribonucleotide-modified sense strands displayArgonaute2eIF2C2-dependent activity RNA 12 163 (2006)
24 F V Rivas N H Tolia J J Song J P Aragon J Liu G JHannon and L Joshua-Tor Purified Argonaute2 and an siRNAform recombinant human RISC Nat Struct Mol Biol 12 340(2005)
25 V Hornung M Guenthner-Biller C Bourquin A AblasserM Schlee S Uematsu A Noronha M Manoharan S AkiraA de Fougerolles S Endres and G Hartmann Sequence-specificpotent induction of IFN-alpha by short interfering RNA in plasma-cytoid dendritic cells through TLR7 Nat Med 11 263 (2005)
26 A D Judge G Bola A C Lee and I MacLachlan Design ofnoninflammatory synthetic siRNA mediating potent gene silencingin vivo Mol Ther 13 494 (2006)
27 A L Jackson J Burchard D Leake A Reynolds J SchelterJ Guo J M Johnson L Lim J Karpilow K NicholsW Marshall A Khvorova and P S Linsley Position-specificchemical modification of siRNAs reduces ldquooff-targetrdquo transcriptsilencing RNA 12 1197 (2006)
28 D Bumcrot M Manoharan V Koteliansky and D W Sah RNAitherapeutics A potential new class of pharmaceutical drugs NatChem Biol 2 711 (2006)
29 A S Peek and M A Behlke Design of active small interferingRNAs Curr Opin Mol Ther 9 110 (2007)
30 Y Pei and T Tuschl On the art of identifying effective and specificsiRNAs Nat Methods 3 670 (2006)
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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174 F Yang W Huang Y Li S Liu M Jin Y Wang L Jia andZ Gao Anti-tumor effects in mice induced by survivin-targetedsiRNA delivered through polysaccharide nanoparticles Biomateri-als 34 5689 (2013)
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176 H Jagani J V Rao V R Palanimuthu R C Hariharapura andS Gang A nanoformulation of siRNA and its role in cancer ther-apy In vitro and in vivo evaluation Cell Mol Biol Lett 18 120(2013)
177 L A Tobin Y Xie M Tsokos S I Chung A A Merz M AArnold G Li H L Malech and K F Kwong Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of can-cer cell internalization in vivo Biomaterials 34 2980 (2013)
178 J Shen H Sun P Xu Q Yin Z Zhang S Wang H Yu and Y LiSimultaneous inhibition of metastasis and growth of breast cancerby co-delivery of twist shRNA and paclitaxel using pluronic P85-PEITPGS complex nanoparticles Biomaterials 34 1581 (2013)
179 H Meng W X Mai H Zhang M Xue T Xia S Lin X WangY Zhao Z Ji J I Zink and A E Nel Codelivery of an optimaldrugsiRNA combination using mesoporous silica nanoparticles toovercome drug resistance in breast cancer in vitro and in vivo ACSNano 7 994 (2013)
180 C Zheng M Zheng P Gong J Deng H Yi P Zhang Y ZhangP Liu Y Ma and L Cai Polypeptide cationic micelles mediatedco-delivery of docetaxel and siRNA for synergistic tumor therapyBiomaterials 34 3431 (2013)
181 Q Hu W Li X Hu J Shen X Jin J Zhou G Tang and P KChu Synergistic treatment of ovarian cancer by co-delivery of sur-vivin shRNA and paclitaxel via supramolecular micellar assemblyBiomaterials 33 6580 (2012)
182 Y H Yu E Kim D E Park G Shim S Lee Y B KimC W Kim and Y K Oh Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA Eur J Pharm Biopharm 80 268(2012)
183 Z J Deng S W Morton E Ben-Akiva E C Dreaden K EShopsowitz and P T Hammond Layer-by-layer nanoparticles forsystemic codelivery of an anticancer drug and siRNA for potentialtriple-negative breast cancer treatment ACS Nano 7 9571 (2013)
184 X Q Liu M H Xiong X T Shu R Z Tang and J WangTherapeutic delivery of siRNA silencing HIF-1 alpha with micellarnanoparticles inhibits hypoxic tumor growth Mol Pharm 9 2863(2012)
185 J Xiao X Duan Q Yin Z Miao H Yu C Chen Z ZhangJ Wang and Y Li The inhibition of metastasis and growth ofbreast cancer by blocking the NF-kappaB signaling pathway usingbioreducible PEI-basedp65 shRNA complex nanoparticles Bioma-terials 34 5381 (2013)
186 R J Christie Y Matsumoto K Miyata T Nomoto S FukushimaK Osada J Halnaut F Pittella H J Kim N Nishiyama and
J Biomed Nanotechnol 10 1751ndash1783 2014 1781
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
187 S Ganesh A K Iyer F Gattacceca D V Morrissey and M MAmiji In vivo biodistribution of siRNA and cisplatin adminis-tered using CD44-targeted hyaluronic acid nanoparticles J ControlRelease 172 699 (2013)
188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
polo-like
kina
se1
(PLK
1)
PEGylated
polyca
prolac
tone
(PCL)
graftedwith
disu
lfide
linke
dpo
ly(2-
dimethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Cleav
ageof
thedisu
lfide
linka
gesfacilitates
endo
somal
esca
pe
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[169
]
siRNA
GFP
orLu
ciferase
2Dim
ethy
laminoe
thyl
metha
crylate(D
MAEMA)
star
polymers
MiaPaC
ahu
man
panc
reatic
canc
erce
llH46
0no
nsmalllun
gca
ncer
cells
Nud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
GFP
andLu
ciferase
[215
]
shRNA
p65
Twee
n85
-s-s-P
EI2K
(TSP)
biored
ucible
nano
particles
Twee
n85
improv
estab
ility
incirculationsy
stem
and
uptake
byinteractingwith
low-den
sity
lipop
rotein
rece
ptorDisulfid
ebo
ndredu
cedin
tumor
environm
entan
dreleas
esh
RNA
MDA-M
B-435
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[185
]
siRNA
Luciferase
andPlk1
Mes
oporou
ssilica
nano
particlesdisu
lfide
bond
cros
s-lin
kedto
poly(2-dim
ethy
laminoe
thyl
metha
crylate)
(PDMAEMA)
Disulfid
ebo
ndsredu
ctionin
cells
clea
vedPDMAEMA
andtrigge
redsiRNA
releas
e
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
etumor
volume
[216
]
siRNA
Anti-a
poptos
isge
nesirtuin
2(S
IRT2)
Ultras
ound
sens
itive
nano
bubb
leswith
poly(ethylen
eglyc
ol)-b-
poly(B
enzy
loxy
carbon
yl-L-
Lysine
)dibloc
kco
polymer
(mPEG-b-P
CBLL
ys)siRNA
micelles
Low
freq
uenc
yultras
ound
enha
nces
canc
erce
llup
take
throug
hca
vitatio
neffects
Rat
C6Glio
mace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[171
]
shRNA
Foc
alad
hesion
kina
se(FAK)an
dCD44
PolyDL-la
ctide-co
-glyco
lide
acid
(PLG
A)na
nopa
rticles
Ova
rianca
ncer
cells
Nud
emicesc
xeno
graft
ip
Noeffect
Kno
ckdo
wnof
both
FAK
andCD44
Dec
reas
edtumor
volume
[170
]
siRNA
Eph
A2
Nan
opartic
le-in
-micropa
rticle
multis
tage
vector
(MSV)
deliverysy
stem
Hem
isph
erical
porous
silicon
particlesload
edwith
DOPC
nano
lipos
ome-siRNA
Silico
npa
rticlesse
ttleat
tumor
vasc
ulaturean
dlip
osom
alsiRNA
releas
edwhe
npo
rous
silicon
degrad
es
SKOV3ip2
and
Hey
A8-MDR
human
ovarian
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[188
]
1766 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
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rypt
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oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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1776 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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79 J A MacDiarmid N B Amaro-Mugridge J Madrid-WeissI Sedliarou S Wetzel K Kochar V N Brahmbhatt L PhillipsS T Pattison C Petti B Stillman R M Graham andH Brahmbhatt Sequential treatment of drug-resistant tumors withtargeted minicells containing siRNA or a cytotoxic drug NatBiotechnol 27 643 (2009)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
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1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Bcl-2
Polyp
eptid
emicelle
nano
particles
Poly(ethy
lene
glyc
ol)-b-poly(L-ly
sine
)-b-
poly(L-le
ucine)
(PEG-b-P
LL-b-P
LLeu
)
Partic
leco
mbine
dwith
Doc
etax
elMCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
Dec
reas
edtumor
volume
[180
]
siRNA
MDM2
pH-res
pons
ivedibloc
kco
polymer
ofpo
ly(m
etha
cryloy
loxy
ethy
lph
osph
orylch
oline)-block
poly(diisop
ropa
nolamine
ethy
lmetha
crylate)
(PMPC-b-P
DPA
)
PDPA
hydrph
obic
atne
utral
pHbu
thy
drop
hilic
atac
idic
pHan
dfacilitates
PMPC
nano
particle
intrac
ellular
uptake
p53mutan
tH20
09hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MDM2
Dec
reas
edtumor
volume
[200
]
dsRNA
p21
Lipido
iden
caps
ulated
nano
particle
(LNP)
PC-3
human
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Dec
reas
edtumor
volume
[217
]
siRNA
Infla
mmatory
cytokine
sCationiclip
id-coa
tedca
lcium
phos
phatena
nopa
rticles
(LCP)
Cationiclip
id-coa
tingan
dco
mbina
tionwith
zeledron
icac
id
B16
BL6
mou
semelan
omace
llsSyn
gene
icsc
graft
pt
Cytok
ine
indu
ction
Dec
reas
edtumor
volume
[175
]
miR-34a
E2F
3Bcl-2
c-myc
and
cyclin
D1
Cyc
lode
xtrin
-PEIco
njug
ate
Con
juga
tewith
CC9
(CRGDKGPDC)
peptide-pe
netrating
bifunc
tiona
lpep
tide
PANC-1
human
panc
reatic
canc
erce
ll29
3Thu
man
embryo
nickidn
eyce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-34
leve
lDec
reas
edtumor
volume
[193
]
siRNA
EGFP
Dex
tran
conjug
ates
Com
plex
with
catio
nic
polyelec
trolytes
LPEIan
dfolate
fortargeting
MDA-M
B-435
human
brea
stca
ncer
cells
Helahu
man
cervix
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
GFP
[218
]
siRNA
Bcl-2
Chitosa
nna
nopa
rticles
Helahu
man
cervix
carcinom
ace
llsSwissAlbino
micesc
xeno
graft
it
ND
Kno
ckdo
wnof
Bcl-2Syn
ergise
dwith
chem
othe
rapy
[176
]
shRNA
Twist
Pluronic
P85
-PEI)D
-a-Toc
ophe
ryl
PEG10
00su
ccinate(TPGS)
complex
nano
particles
(PTPNs)
Com
bina
tionwith
Pac
litax
el4T
1murinemam
mary
carcinom
ace
llsNud
emice
Syn
geniec
sc
graft
iv
ND
Dec
reas
edtumor
volume
[178
]
siRNA
Luciferase
Cationiclip
osom
alna
nopa
rticles
Con
juga
tionto
PEG20
0for
long
erha
lf-life
MDA-M
B-435
brea
stca
ncer
cells
Rag
-2m
Mice
sc
andip
xe
nograft
iv
ND
Kno
ckdo
wnof
Luciferase
[219
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1767
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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cer J Clin 64 9 (2014)2 M J Espiritu A C Collier and J P Bingham A 21st-century
approach to age-old problems The ascension of biologics in clini-cal therapeutics Drug Discov Today (2014)
3 R L Schilsky Personalized medicine in oncology The future isnow Nat Rev Drug Discov 9 363 (2010)
4 M N Patel M D Halling-Brown J E Tym P Workman andB Al-Lazikani Objective assessment of cancer genes for drug dis-covery Nat Rev Drug Discov 12 35 (2013)
5 D Hanahan and R A Weinberg Hallmarks of cancer The nextgeneration Cell 144 646 (2011)
6 N F Sun Z A Liu W B Huang A L Tian and S Y Hu Theresearch of nanoparticles as gene vector for tumor gene therapyCrit Rev Oncol Hematol 89 352 (2013)
1776 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
7 M Rothe U Modlich and A Schambach Biosafety challenges foruse of lentiviral vectors in gene therapy Curr Gene Ther 13 453(2013)
8 D R Corey RNA learns from antisense Nat Chem Biol 3 8(2007)
9 V N Kim MicroRNA biogenesis Coordinated cropping and dic-ing Nat Rev Mol Cell Biol 6 376 (2005)
10 D E Golden V R Gerbasi and E J Sontheimer An inside jobfor siRNAs Mol Cell 31 309 (2008)
11 M Ghildiyal and P D Zamore Small silencing RNAs An expand-ing universe Nat Rev Genet 10 94 (2009)
12 D H Kim M A Behlke S D Rose M S Chang S Choiand J J Rossi Synthetic dsRNA Dicer substrates enhance RNAipotency and efficacy Nat Biotechnol 23 222 (2005)
13 Y Maida M Yasukawa M Furuuchi T Lassmann R PossematoN Okamoto V Kasim Y Hayashizaki W C Hahn and K Masu-tomi An RNA-dependent RNA polymerase formed by TERT andthe RMRP RNA Nature 461 230 (2009)
14 N R Smalheiser The search for endogenous siRNAs in the mam-malian brain Exp Neurol 235 455 (2012)
15 K A Tekirdag G Korkmaz D G Ozturk R Agami andD Gozuacik MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5 Autophagy 9 374(2013)
16 G Korkmaz K A Tekirdag D G Ozturk A Kosar O USezerman and D Gozuacik MIR376A Is a Regulator ofStarvation-Induced Autophagy PLoS One 8 e82556 (2013)
17 D Castanotto and J J Rossi The promises and pitfalls of RNA-interference-based therapeutics Nature 457 426 (2009)
18 E Iorns C J Lord N Turner and A Ashworth Utilizing RNAinterference to enhance cancer drug discovery Nat Rev Drug Dis-cov 6 556 (2007)
19 M A Behlke Chemical modification of siRNAs for in vivo useOligonucleotides 18 305 (2008)
20 S D Rose D H Kim M Amarzguioui J D Heidel M ACollingwood M E Davis J J Rossi and M A Behlke Func-tional polarity is introduced by Dicer processing of short substrateRNAs Nucleic Acids Res 33 4140 (2005)
21 K Nishina T Unno Y Uno T Kubodera T KanouchiH Mizusawa and T Yokota Efficient in vivo delivery of siRNAto the liver by conjugation of alpha-tocopherol Mol Ther 16 734(2008)
22 F Czauderna M Fechtner S Dames H Aygun A Klippel G JPronk K Giese and J Kaufmann Structural variations and sta-bilising modifications of synthetic siRNAs in mammalian cellsNucleic Acids Res 31 2705 (2003)
23 B A Kraynack and B F Baker Small interfering RNAs contain-ing full 2prime-O-methylribonucleotide-modified sense strands displayArgonaute2eIF2C2-dependent activity RNA 12 163 (2006)
24 F V Rivas N H Tolia J J Song J P Aragon J Liu G JHannon and L Joshua-Tor Purified Argonaute2 and an siRNAform recombinant human RISC Nat Struct Mol Biol 12 340(2005)
25 V Hornung M Guenthner-Biller C Bourquin A AblasserM Schlee S Uematsu A Noronha M Manoharan S AkiraA de Fougerolles S Endres and G Hartmann Sequence-specificpotent induction of IFN-alpha by short interfering RNA in plasma-cytoid dendritic cells through TLR7 Nat Med 11 263 (2005)
26 A D Judge G Bola A C Lee and I MacLachlan Design ofnoninflammatory synthetic siRNA mediating potent gene silencingin vivo Mol Ther 13 494 (2006)
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28 D Bumcrot M Manoharan V Koteliansky and D W Sah RNAitherapeutics A potential new class of pharmaceutical drugs NatChem Biol 2 711 (2006)
29 A S Peek and M A Behlke Design of active small interferingRNAs Curr Opin Mol Ther 9 110 (2007)
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33 D V Morrissey J A Lockridge L Shaw K Blanchard K JensenW Breen K Hartsough L Machemer S Radka V JadhavN Vaish S Zinnen C Vargeese K Bowman C S Shaffer L BJeffs A Judge I MacLachlan and B Polisky Potent and persis-tent in vivo anti-HBV activity of chemically modified siRNAs NatBiotechnol 23 1002 (2005)
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35 A Akinc A Zumbuehl M Goldberg E S Leshchiner V BusiniN Hossain S A Bacallado D N Nguyen J Fuller R AlvarezA Borodovsky T Borland R Constien A de Fougerolles J RDorkin K Narayanannair Jayaprakash M Jayaraman M JohnV Koteliansky M Manoharan L Nechev J Qin T RacieD Raitcheva K G Rajeev D W Sah J Soutschek I ToudjarskaH P Vornlocher T S Zimmermann R Langer and D G Ander-son A combinatorial library of lipid-like materials for delivery ofRNAi therapeutics Nat Biotechnol 26 561 (2008)
36 S C Semple A Akinc J Chen A P Sandhu B L Mui C KCho D W Sah D Stebbing E J Crosley E Yaworski I MHafez J R Dorkin J Qin K Lam K G Rajeev K F WongL B Jeffs L Nechev M L Eisenhardt M Jayaraman M KazemM A Maier M Srinivasulu M J Weinstein Q Chen R AlvarezS A Barros S De S K Klimuk T Borland V Kosovrasti W LCantley Y K Tam M Manoharan M A Ciufolini M A TracyA de Fougerolles I MacLachlan P R Cullis T D Madden andM J Hope Rational design of cationic lipids for siRNA deliveryNat Biotechnol 28 172 (2010)
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40 Y Matsumura and H Maeda A new concept for macromoleculartherapeutics in cancer chemotherapy Mechanism of tumoritropicaccumulation of proteins and the antitumor agent smancs CancerRes 46 6387 (1986)
41 T Ishimoto Y Takei Y Yuzawa K Hanai S Nagahara Y TarumiS Matsuo and K Kadomatsu Downregulation of monocytechemoattractant protein-1 involving short interfering RNA atten-uates hapten-induced contact hypersensitivity Mol Ther 16 387(2008)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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43 E Kawata E Ashihara S Kimura K Takenaka K SatoR Tanaka A Yokota Y Kamitsuji M Takeuchi J KurodaF Tanaka T Yoshikawa and T Maekawa Administration of PLK-1 small interfering RNA with atelocollagen prevents the growth ofliver metastases of lung cancer Mol Cancer Ther 7 2904 (2008)
44 H Maeda J Wu T Sawa Y Matsumura and K Hori Tumorvascular permeability and the EPR effect in macromolecular thera-peutics A review J Control Release 65 271 (2000)
45 H Hatakeyama H Akita and H Harashima The polyethyleneg-lycol dilemma Advantage and disadvantage of PEGylation of lipo-somes for systemic genes and nucleic acids delivery to tumorsBiol Pharm Bull 36 892 (2013)
46 F Iversen C Yang F Dagnaes-Hansen D H Schaffert J Kjemsand S Gao Optimized siRNA-PEG conjugates for extended bloodcirculation and reduced urine excretion in mice Theranostics 3 201(2013)
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48 S D Li S Chono and L Huang Efficient gene silencingin metastatic tumor by siRNA formulated in surface-modifiednanoparticles J Control Release 126 77 (2008)
49 K Remaut B Lucas K Braeckmans J Demeester and S C DeSmedt Pegylation of liposomes favours the endosomal degradationof the delivered phosphodiester oligonucleotides J Control Release117 256 (2007)
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51 Y Sato H Hatakeyama Y Sakurai M Hyodo H Akita andH Harashima A pH-sensitive cationic lipid facilitates the deliveryof liposomal siRNA and gene silencing activity in vitro and in vivoJ Control Release 163 267 (2012)
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56 H Tian S Liu J Zhang S Zhang L Cheng C Li X ZhangL Dai P Fan L Dai N Yan R Wang Y Wei and H DengEnhancement of Cisplatin sensitivity in lung cancer xenografts byliposome-mediated delivery of the plasmid expressing small hairpinRNA targeting survivin J Biomed Nanotechnol 8 633 (2012)
57 I R Gilmore S P Fox A J Hollins M Sohail andS Akhtar The design and exogenous delivery of siRNA for post-transcriptional gene silencing J Drug Target 12 315 (2004)
58 I R Gilmore S P Fox A J Hollins and S Akhtar Deliverystrategies for siRNA-mediated gene silencing Curr Drug Deliv3 147 (2006)
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60 B Ozpolat A K Sood and G Lopez-Berestein Nanomedicinebased approaches for the delivery of siRNA in cancer J InternMed 267 44 (2010)
61 S Dokka D Toledo X Shi V Castranova and Y RojanasakulOxygen radical-mediated pulmonary toxicity induced by somecationic liposomes Pharm Res 17 521 (2000)
62 S Spagnou A D Miller and M Keller Lipidic carriers of siRNADifferences in the formulation cellular uptake and delivery withplasmid DNA Biochemistry (Mosc) 43 13348 (2004)
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65 P Liu H Yu Y Sun M Zhu and Y Duan A mPEG-PLGA-b-PLLcopolymer carrier for adriamycin and siRNA delivery Biomaterials33 4403 (2012)
66 F Alexis E Pridgen L K Molnar and O C Farokhzad Factorsaffecting the clearance and biodistribution of polymeric nanoparti-cles Mol Pharm 5 505 (2008)
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69 O Meyer D Kirpotin K Hong B Sternberg J W Park M CWoodle and D Papahadjopoulos Cationic liposomes coated withpolyethylene glycol as carriers for oligonucleotides J Biol Chem273 15621 (1998)
70 M A Tran R J Watts and G P Robertson Use of liposomesas drug delivery vehicles for treatment of melanoma Pigment CellMelanoma Res 22 388 (2009)
71 C N Landen Jr A Chavez-Reyes C Bucana R Schmandt M TDeavers G Lopez-Berestein and A K Sood Therapeutic EphA2gene targeting in vivo using neutral liposomal small interferingRNA delivery Cancer Res 65 6910 (2005)
72 Z Ma J Li F He A Wilson B Pitt and S Li Cationic lipidsenhance siRNA-mediated interferon response in mice BiochemBiophys Res Commun 330 755 (2005)
73 J Jin K H Bae H Yang S J Lee H Kim Y Kim K M JooS W Seo T G Park and D H Nam In vivo specific delivery of c-Met siRNA to glioblastoma using cationic solid lipid nanoparticlesBioconjug Chem 22 2568 (2011)
74 P Y Chien J Wang D Carbonaro S Lei B Miller S SheikhS M Ali M U Ahmad and I Ahmad Novel cationic cardiolipinanalogue-based liposome for efficient DNA and small interferingRNA delivery in vitro and in vivo Cancer Gene Ther 12 321(2005)
75 A Pal A Ahmad S Khan I Sakabe C Zhang U N Kasidand I Ahmad Systemic delivery of RafsiRNA using cationic car-diolipin liposomes silences Raf-1 expression and inhibits tumorgrowth in xenograft model of human prostate cancer Int J Oncol26 1087 (2005)
76 A Akinc M Goldberg J Qin J R Dorkin C Gamba-VitaloM Maier K N Jayaprakash M Jayaraman K G RajeevM Manoharan V Koteliansky I Rohl E S Leshchiner R Langerand D G Anderson Development of lipidoid-siRNA formulationsfor systemic delivery to the liver Mol Ther 17 872 (2009)
77 S Jiang A A Eltoukhy K T Love R Langer and D GAnderson Lipidoid-coated iron oxide nanoparticles for efficientDNA and siRNA delivery Nano Lett 13 1059 (2013)
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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79 J A MacDiarmid N B Amaro-Mugridge J Madrid-WeissI Sedliarou S Wetzel K Kochar V N Brahmbhatt L PhillipsS T Pattison C Petti B Stillman R M Graham andH Brahmbhatt Sequential treatment of drug-resistant tumors withtargeted minicells containing siRNA or a cytotoxic drug NatBiotechnol 27 643 (2009)
80 C G Millan C I Colino Gandarillas M L Sayalero Marineroand J M Lanao Cell-based drug-delivery platforms Ther Deliv3 25 (2012)
81 V Gujrati S Kim S H Kim J J Min H E Choy S C Kimand S Jon Bioengineered bacterial outer membrane vesicles ascell-specific drug-delivery vehicles for cancer therapy ACS Nano8 1525 (2014)
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85 K A Howard Delivery of RNA interference therapeutics usingpolycation-based nanoparticles Adv Drug Deliv Rev 61 710(2009)
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87 L Zhang Z Chen and Y Li Dual-degradable disulfide-containingPEI-PluronicDNA polyplexes Transfection efficiency and balanc-ing protection and DNA release Int J Nanomedicine 8 3689(2013)
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89 R Kircheis L Wightman and E Wagner Design and gene deliv-ery activity of modified polyethylenimines Adv Drug Deliv Rev53 341 (2001)
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Hartmann T Stoger and T H Kissel Polymer-related off-targeteffects in non-viral siRNA delivery Biomaterials 32 2388 (2011)
93 D J Gary N Puri and Y Y Won Polymer-based siRNA deliv-ery Perspectives on the fundamental and phenomenological dis-tinctions from polymer-based DNA delivery J Control Release121 64 (2007)
94 S M Moghimi P Symonds J C Murray A C HunterG Debska and A Szewczyk A two-stage poly(ethylenimine)-mediated cytotoxicity Implications for gene transfertherapy MolTher 11 990 (2005)
95 A C Hunter and S M Moghimi Cationic carriers of genetic mate-rial and cell death A mitochondrial tale Biochim Biophys Acta1797 1203 (2010)
96 K A Woodrow Y Cu C J Booth J K Saucier-Sawyer M JWood and W M Saltzman Intravaginal gene silencing usingbiodegradable polymer nanoparticles densely loaded with small-interfering RNA Nat Mater 8 526 (2009)
97 K Singha R Namgung and W J Kim Polymers in small-interfering RNA delivery Nucleic Acid Ther 21 133 (2011)
98 S Acharya and S K Sahoo PLGA nanoparticles containing var-ious anticancer agents and tumour delivery by EPR effect AdvDrug Deliv Rev 63 170 (2011)
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101 J Wu W Huang and Z He Dendrimers as carriers for siRNAdelivery and gene silencing A review Scientific World Journal2013 630654 (2013)
102 M L Patil M Zhang S Betigeri O Taratula H He andT Minko Surface-modified and internally cationic polyami-doamine dendrimers for efficient siRNA delivery Bioconjug Chem19 1396 (2008)
103 M L Patil M Zhang O Taratula O B Garbuzenko H He andT Minko Internally cationic polyamidoamine PAMAM-OH den-drimers for siRNA delivery Effect of the degree of quaternizationand cancer targeting Biomacromolecules 10 258 (2009)
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106 T Ochiya K Honma F Takeshita and S NagaharaAtelocollagen-mediated drug discovery technology Expert OpinDrug Discov 2 159 (2007)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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127 D Pantarotto R Singh D McCarthy M Erhardt J P BriandM Prato K Kostarelos and A Bianco Functionalized carbonnanotubes for plasmid DNA gene delivery Angew Chem Int EdEngl 43 5242 (2004)
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138 Y Chen W Wang G Lian C Qian L Wang L Zeng C LiaoB Liang B Huang K Huang and X Shuai Development of anMRI-visible nonviral vector for siRNA delivery targeting gastriccancer Int J Nanomedicine 7 359 (2012)
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141 M Ogris G Walker T Blessing R Kircheis M Wolschek andE Wagner Tumor-targeted gene therapy Strategies for the prepa-ration of ligand-polyethylene glycol-polyethylenimineDNA com-plexes J Control Release 91 173 (2003)
142 S Li Z Liu F Ji Z Xiao M Wang Y Peng Y Zhang L LiuZ Liang and F Li Delivery of quantum Dot-siRNA nanoplexes inSK-N-SH cells for BACE1 gene silencing and intracellular imag-ing Mol Ther Nucleic Acids 1 e20 (2012)
143 J Zhao X Qiu Z Wang J Pan J Chen and J Han Applica-tion of quantum dots as vectors in targeted survivin gene siRNAdelivery Onco Targets Ther 6 303 (2013)
144 Y Su Y He H Lu L Sai Q Li W Li L Wang P ShenQ Huang and C Fan The cytotoxicity of cadmium based aqueousphasemdashsynthesized quantum dots and its modulation by surfacecoating Biomaterials 30 19 (2009)
145 H Y Yang Y W Zhao Z Y Zhang H M Xiong and S N YuOne-pot synthesis of water-dispersible Ag2S quantum dots withbright fluorescent emission in the second near-infrared windowNanotechnology 24 055706 (2013)
146 G Hong J T Robinson Y Zhang S Diao A L AntarisQ Wang and H Dai In vivo fluorescence imaging with Ag2Squantum dots in the second near-infrared region Angew Chem IntEd Engl 51 9818 (2012)
147 Y Zhang G Hong G Chen F Li H Dai and Q Wang Ag2Squantum dot A bright and biocompatible fluorescent nanoprobe inthe second near-infrared window ACS Nano 6 3695 (2012)
148 I Hocaoglu M N Ccedilizmeciyan R Erdem C Ozen A KurtA Sennaroglu and H Y Acar Development of highly luminescentand cytocompatible near-IR-emitting aqueous Ag2S quantum dotsJ Mater Chem 22 14674 (2012)
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1780 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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169 D Lin Q Jiang Q Cheng Y Huang P Huang S Han S GuoZ Liang and A Dong Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and invivo siRNA delivery Acta Biomater 9 7746 (2013)
170 L Zou X Song T Yi S Li H Deng X Chen Z Li Y BaiQ Zhong Y Wei and X Zhao Administration of PLGA nanopar-ticles carrying shRNA against focal adhesion kinase and CD44results in enhanced antitumor effects against ovarian cancer CancerGene Ther 20 242 (2013)
171 T Yin P Wang J Li R Zheng B Zheng D Cheng R Li J Laiand X Shuai Ultrasound-sensitive siRNA-loaded nanobubblesformed by hetero-assembly of polymeric micelles and liposomesand their therapeutic effect in gliomas Biomaterials 34 4532(2013)
172 H J Cho S Chong S J Chung C K Shim and D D Kim Poly-L-arginine and dextran sulfate-based nanocomplex for epidermalgrowth factor receptor (EGFR) siRNA delivery Its application forhead and neck cancer treatment Pharm Res 29 1007 (2012)
173 F Abedini H Hosseinkhani M Ismail A J Domb A R OmarP P Chong P D Hong D S Yu and I Y Farber Cationizeddextran nanoparticle-encapsulated CXCR4-siRNA enhanced corre-lation between CXCR4 expression and serum alkaline phosphatasein a mouse model of colorectal cancer Int J Nanomedicine 7 4159(2012)
174 F Yang W Huang Y Li S Liu M Jin Y Wang L Jia andZ Gao Anti-tumor effects in mice induced by survivin-targetedsiRNA delivered through polysaccharide nanoparticles Biomateri-als 34 5689 (2013)
175 L Chen Y Ding Y Wang X Liu R Babu W Ravis and W YanCodelivery of zoledronic acid and doublestranded RNA from corendashshell nanoparticles Int J Nanomedicine 8 137 (2013)
176 H Jagani J V Rao V R Palanimuthu R C Hariharapura andS Gang A nanoformulation of siRNA and its role in cancer ther-apy In vitro and in vivo evaluation Cell Mol Biol Lett 18 120(2013)
177 L A Tobin Y Xie M Tsokos S I Chung A A Merz M AArnold G Li H L Malech and K F Kwong Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of can-cer cell internalization in vivo Biomaterials 34 2980 (2013)
178 J Shen H Sun P Xu Q Yin Z Zhang S Wang H Yu and Y LiSimultaneous inhibition of metastasis and growth of breast cancerby co-delivery of twist shRNA and paclitaxel using pluronic P85-PEITPGS complex nanoparticles Biomaterials 34 1581 (2013)
179 H Meng W X Mai H Zhang M Xue T Xia S Lin X WangY Zhao Z Ji J I Zink and A E Nel Codelivery of an optimaldrugsiRNA combination using mesoporous silica nanoparticles toovercome drug resistance in breast cancer in vitro and in vivo ACSNano 7 994 (2013)
180 C Zheng M Zheng P Gong J Deng H Yi P Zhang Y ZhangP Liu Y Ma and L Cai Polypeptide cationic micelles mediatedco-delivery of docetaxel and siRNA for synergistic tumor therapyBiomaterials 34 3431 (2013)
181 Q Hu W Li X Hu J Shen X Jin J Zhou G Tang and P KChu Synergistic treatment of ovarian cancer by co-delivery of sur-vivin shRNA and paclitaxel via supramolecular micellar assemblyBiomaterials 33 6580 (2012)
182 Y H Yu E Kim D E Park G Shim S Lee Y B KimC W Kim and Y K Oh Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA Eur J Pharm Biopharm 80 268(2012)
183 Z J Deng S W Morton E Ben-Akiva E C Dreaden K EShopsowitz and P T Hammond Layer-by-layer nanoparticles forsystemic codelivery of an anticancer drug and siRNA for potentialtriple-negative breast cancer treatment ACS Nano 7 9571 (2013)
184 X Q Liu M H Xiong X T Shu R Z Tang and J WangTherapeutic delivery of siRNA silencing HIF-1 alpha with micellarnanoparticles inhibits hypoxic tumor growth Mol Pharm 9 2863(2012)
185 J Xiao X Duan Q Yin Z Miao H Yu C Chen Z ZhangJ Wang and Y Li The inhibition of metastasis and growth ofbreast cancer by blocking the NF-kappaB signaling pathway usingbioreducible PEI-basedp65 shRNA complex nanoparticles Bioma-terials 34 5381 (2013)
186 R J Christie Y Matsumoto K Miyata T Nomoto S FukushimaK Osada J Halnaut F Pittella H J Kim N Nishiyama and
J Biomed Nanotechnol 10 1751ndash1783 2014 1781
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
187 S Ganesh A K Iyer F Gattacceca D V Morrissey and M MAmiji In vivo biodistribution of siRNA and cisplatin adminis-tered using CD44-targeted hyaluronic acid nanoparticles J ControlRelease 172 699 (2013)
188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
AIB1
Amorph
ousca
lcium
carbon
ate(ACC)pa
rticles
func
tiona
lized
with
Ca(II)-IP6co
mpo
und
(CaIP6)
T24
human
blad
der
canc
erce
llsNud
emicesc
xeno
graft
it
ND
Kno
ckdo
wnof
AIB1
onco
gene
Dec
reas
edtumor
volume
[164
]
miR-34a
E2F
3CD44
an
dSIRT1
DOTA
Pcho
lesterol
lipos
omes
T-VISA
vector
system
toen
hanc
eex
pres
sion
and
prolon
gex
pres
sion
duratio
n
MDA-M
B-231
human
brea
stca
ncer
cell
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[192
]
siRNA
Pok
emon
gene
silenc
ing
Biomim
etic
nano
vector
with
rHDLna
nopa
rticle
and
choles
terol-c
onjuga
ted
siRNA
(Cho
l-siRNA)
Con
sist
ofapo
larco
reco
ntaining
choles
teryl
estersch
oles
terolap
oA-I
andCho
l-siRNA
Hep
-G2hu
man
hepa
toce
llularca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
ARF
HDM2
Rb
E2F
pathway
Dec
reas
edtumor
volume
[220
]
siRNA
HIF-1
Cationicmixed
micellar
nano
particle
(MNP)
(poly(-cap
rolacton
e)-block-
poly(2-aminoe
thylethy
lene
phos
phate)
(PCL2
9-b-PPEEA21
)an
dpo
ly(-cap
rolacton
e)-block-
poly(ethylen
eglyco
l)(P
CL4
0-b-PEG45
))
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
HIF1-Syn
ergy
with
doxo
rubicin
Dec
reas
edtumor
volume
[184
]
shRNA
Survivin
P85
-PEIT
PGS
complex
nano
particle
Partic
leco
mbine
dwith
Pac
litax
elA54
9hu
man
lung
canc
erce
llsA54
9T
Pac
litax
elresistan
thu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[221
]
siRNA
ID4
Tumor-pen
etratin
gna
noco
mplex
(TPN)
Tand
emtumor-pen
etratin
gan
dmem
bran
e-tran
sloc
ating
peptide(R
KXXRK
C-terminal
peptide)
enab
lingde
liveryto
tumor
parenc
hyma
OVCAR-4
human
ovarianca
ncer
cells
Nud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
ID4
Dec
reas
edtumor
volume
[222
]
siRNA
CXCR4
Dex
tran
nano
particles
Spe
rmine-co
njug
ationto
obtain
catio
nicde
xtran
CT26
WTmou
seco
lorectal
canc
erce
llsSyn
geniec
sc
andiv
graft
iv
Noeffect
Kno
ckdo
wnof
CXCR4
Dec
reas
edtumor
volume
[173
]
siRNA
Luciferase
PAMAM
dend
rimer
conjug
ate
with
cyclod
extrin
Folate-PEG
appe
nded
for
targeting
Colon
-26co
lonca
ncer
cells
Syn
geniec
sc
graft
ivan
ditND
Deliverytotumor
tissu
e[163
]
1768 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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153 R Ghosh L C Singh J M Shohet and P H Gunaratne A goldnanoparticle platform for the delivery of functional microRNAs intocancer cells Biomaterials 34 807 (2013)
154 A Bitar N M Ahmad H Fessi and A Elaissari Silica-basednanoparticles for biomedical applications Drug Discov Today17 1147 (2012)
1780 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
155 H Lee D Sung M Veerapandian K Yun and S W Seo PEGy-lated polyethyleneimine grafted silica nanoparticles Enhanced cel-lular uptake and efficient siRNA delivery Anal Bioanal Chem400 535 (2011)
156 X Li Y Chen M Wang Y Ma W Xia and H Gu A mesoporoussilica nanoparticlendashPEIndashfusogenic peptide system for siRNA deliv-ery in cancer therapy Biomaterials 34 1391 (2013)
157 Z Chen M F Penet S Nimmagadda C Li S R Banerjee P TWinnard Jr D Artemov K Glunde M G Pomper and Z MBhujwalla PSMA-targeted theranostic nanoplex for prostate cancertherapy ACS Nano 6 7752 (2012)
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159 W Wei P P Lv X M Chen Z G Yue Q Fu S Y Liu H Yueand G H Ma Codelivery of mTERT siRNA and paclitaxel bychitosan-based nanoparticles promoted synergistic tumor suppres-sion Biomaterials 34 3912 (2013)
160 S Ganesh A K Iyer D V Morrissey and M M AmijiHyaluronic acid based self-assembling nanosystems for CD44 tar-get mediated siRNA delivery to solid tumors Biomaterials 34 3489(2013)
161 C Dohmen D Edinger T Frohlich L Schreiner U LacheltC Troiber J Radler P Hadwiger H P Vornlocher and E WagnerNanosized multifunctional polyplexes for receptor-mediated siRNAdelivery ACS Nano 6 5198 (2012)
162 S A Jensen E S Day C H Ko L A Hurley J P LucianoF M Kouri T J Merkel A J Luthi P C Patel J I Cutler W LDaniel A W Scott M W Rotz T J Meade D A GiljohannC A Mirkin and A H Stegh Spherical nucleic acid nanoparticleconjugates as an RNAi-based therapy for glioblastoma Sci TranslMed 5 209ra152 (2013)
163 H Arima A Yoshimatsu H Ikeda A Ohyama K MotoyamaT Higashi A Tsuchiya T Niidome Y Katayama K Hattoriand T Takeuchi Folate-PEG-appended dendrimer conjugate withalpha-cyclodextrin as a novel cancer cell-selective siRNA deliverycarrier Mol Pharm 9 2591 (2012)
164 J Wei T Cheang B Tang H Xia Z Xing Z Chen Y FangW Chen A Xu S Wang and J Luo The inhibition of humanbladder cancer growth by calcium carbonateCaIP6 nanocompositeparticles delivering AIB1 siRNA Biomaterials 34 1246 (2013)
165 T Kanazawa K Sugawara K Tanaka S Horiuchi Y Takashimaand H Okada Suppression of tumor growth by systemic delivery ofanti-VEGF siRNA with cell-penetrating peptide-modified MPEG-PCL nanomicelles Eur J Pharm Biopharm 81 470 (2012)
166 M A Rahman A R Amin X Wang J E Zuckerman C HChoi B Zhou D Wang S Nannapaneni L Koenig Z ChenZ G Chen Y Yen M E Davis and D M Shin Systemic deliveryof siRNA nanoparticles targeting RRM2 suppresses head and necktumor growth J Control Release 159 384 (2012)
167 J Guo J R Ogier S Desgranges R Darcy and C OrsquoDriscollAnisamide-targeted cyclodextrin nanoparticles for siRNA deliveryto prostate tumours in mice Biomaterials 33 7775 (2012)
168 M Shen F Gong P Pang K Zhu X Meng C Wu J WangH Shan and X Shuai An MRI-visible non-viral vector for tar-geted Bcl-2 siRNA delivery to neuroblastoma Int J Nanomedicine7 3319 (2012)
169 D Lin Q Jiang Q Cheng Y Huang P Huang S Han S GuoZ Liang and A Dong Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and invivo siRNA delivery Acta Biomater 9 7746 (2013)
170 L Zou X Song T Yi S Li H Deng X Chen Z Li Y BaiQ Zhong Y Wei and X Zhao Administration of PLGA nanopar-ticles carrying shRNA against focal adhesion kinase and CD44results in enhanced antitumor effects against ovarian cancer CancerGene Ther 20 242 (2013)
171 T Yin P Wang J Li R Zheng B Zheng D Cheng R Li J Laiand X Shuai Ultrasound-sensitive siRNA-loaded nanobubblesformed by hetero-assembly of polymeric micelles and liposomesand their therapeutic effect in gliomas Biomaterials 34 4532(2013)
172 H J Cho S Chong S J Chung C K Shim and D D Kim Poly-L-arginine and dextran sulfate-based nanocomplex for epidermalgrowth factor receptor (EGFR) siRNA delivery Its application forhead and neck cancer treatment Pharm Res 29 1007 (2012)
173 F Abedini H Hosseinkhani M Ismail A J Domb A R OmarP P Chong P D Hong D S Yu and I Y Farber Cationizeddextran nanoparticle-encapsulated CXCR4-siRNA enhanced corre-lation between CXCR4 expression and serum alkaline phosphatasein a mouse model of colorectal cancer Int J Nanomedicine 7 4159(2012)
174 F Yang W Huang Y Li S Liu M Jin Y Wang L Jia andZ Gao Anti-tumor effects in mice induced by survivin-targetedsiRNA delivered through polysaccharide nanoparticles Biomateri-als 34 5689 (2013)
175 L Chen Y Ding Y Wang X Liu R Babu W Ravis and W YanCodelivery of zoledronic acid and doublestranded RNA from corendashshell nanoparticles Int J Nanomedicine 8 137 (2013)
176 H Jagani J V Rao V R Palanimuthu R C Hariharapura andS Gang A nanoformulation of siRNA and its role in cancer ther-apy In vitro and in vivo evaluation Cell Mol Biol Lett 18 120(2013)
177 L A Tobin Y Xie M Tsokos S I Chung A A Merz M AArnold G Li H L Malech and K F Kwong Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of can-cer cell internalization in vivo Biomaterials 34 2980 (2013)
178 J Shen H Sun P Xu Q Yin Z Zhang S Wang H Yu and Y LiSimultaneous inhibition of metastasis and growth of breast cancerby co-delivery of twist shRNA and paclitaxel using pluronic P85-PEITPGS complex nanoparticles Biomaterials 34 1581 (2013)
179 H Meng W X Mai H Zhang M Xue T Xia S Lin X WangY Zhao Z Ji J I Zink and A E Nel Codelivery of an optimaldrugsiRNA combination using mesoporous silica nanoparticles toovercome drug resistance in breast cancer in vitro and in vivo ACSNano 7 994 (2013)
180 C Zheng M Zheng P Gong J Deng H Yi P Zhang Y ZhangP Liu Y Ma and L Cai Polypeptide cationic micelles mediatedco-delivery of docetaxel and siRNA for synergistic tumor therapyBiomaterials 34 3431 (2013)
181 Q Hu W Li X Hu J Shen X Jin J Zhou G Tang and P KChu Synergistic treatment of ovarian cancer by co-delivery of sur-vivin shRNA and paclitaxel via supramolecular micellar assemblyBiomaterials 33 6580 (2012)
182 Y H Yu E Kim D E Park G Shim S Lee Y B KimC W Kim and Y K Oh Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA Eur J Pharm Biopharm 80 268(2012)
183 Z J Deng S W Morton E Ben-Akiva E C Dreaden K EShopsowitz and P T Hammond Layer-by-layer nanoparticles forsystemic codelivery of an anticancer drug and siRNA for potentialtriple-negative breast cancer treatment ACS Nano 7 9571 (2013)
184 X Q Liu M H Xiong X T Shu R Z Tang and J WangTherapeutic delivery of siRNA silencing HIF-1 alpha with micellarnanoparticles inhibits hypoxic tumor growth Mol Pharm 9 2863(2012)
185 J Xiao X Duan Q Yin Z Miao H Yu C Chen Z ZhangJ Wang and Y Li The inhibition of metastasis and growth ofbreast cancer by blocking the NF-kappaB signaling pathway usingbioreducible PEI-basedp65 shRNA complex nanoparticles Bioma-terials 34 5381 (2013)
186 R J Christie Y Matsumoto K Miyata T Nomoto S FukushimaK Osada J Halnaut F Pittella H J Kim N Nishiyama and
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
187 S Ganesh A K Iyer F Gattacceca D V Morrissey and M MAmiji In vivo biodistribution of siRNA and cisplatin adminis-tered using CD44-targeted hyaluronic acid nanoparticles J ControlRelease 172 699 (2013)
188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
shRNA
P21
Lipidna
nopa
rticles
(LNPs)
KU-7
cells
human
blad
derca
ncer
cell
Nud
emicesc
xeno
graft
ic
ND
Dec
reas
edtumor
volume
[223
]
siRNA
Mou
seVEGF
Cyc
lode
xtrin
PEGylated
andan
isam
ide
adde
dfortargeting
TRAMP
C1tran
sgen
icmou
sepros
tate
cell
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[167
]
siRNA
Bcl-2
Polye
thylen
eglyc
ol-grafte
dpo
lyethy
lenimine
(PEG-g-P
EI)-S
PIO
N
Neu
roblas
toma
cell-sp
ecificlig
andGD2
sing
lech
ainan
tibod
y(scA
bGD2)
fortargeting
SK-N
-SH
human
neurob
lastom
ace
llsNud
emicesc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
[168
]
siRNA
EGFR
Biode
grad
able
amph
iphilic
tri-b
lock
copo
lymer
ofof
mon
ometho
xypo
ly(ethylen
eglyc
ol)
poly(dl-la
ctide)
and
polyarginine
(mPEG(200
0)-
PLA
(300
0)-b-R
(15))
Ass
embled
toca
tionic
polymeric
nano
micelles
MCF-7
human
bres
tca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
EGFR
Dec
reas
edtumor
volume
[203
]
shRNA
Survivin
Cyc
lode
xtrin
-PEI
conjug
ates
Ada
man
tineco
njug
ated
paclita
xele
ncap
sulatio
nSKOV-3
human
ovarian
canc
erce
llsNud
emicesc
xeno
graft
it
Drugrelated
side
effects
Kno
ckdo
wnof
Survivinan
dBcl-2Dec
reas
edtumor
volume
[181
]
shRNA
MDR-1
and
Survivin
Bioredu
ciblepo
ly(-
aminoes
ters)
(PAEs)po
ly[bis(2-
hydrox
ylethy
l)-disu
lfide
-diacrylate-
-tetraethy
l-en
epen
tamine]
(PAP)
MCF-7ADR
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
P-gp
andSurvivin
Dec
reas
edtumor
volume
[224
]
siRNA
VEGF
Thiolated
glyc
olch
itosa
n(TGC)
nano
particles
SCC-7
mou
seoral
squa
mou
sca
ncer
cells
Syn
geniec
sc
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[225
]
siRNA
MDM2c-
myc
VEGF
LipidCalcium
Pho
spha
te(LCP)
nano
particles
Stabilized
with
DOPA
and
coated
with
catio
niclip
idan
dan
isam
idefor
targeting
H46
0hu
man
lung
canc
erce
llsA54
9hu
man
lung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[226
]
Anti-m
iR-155
miR-155
SHIP
PLG
Ana
nopa
rticles
Mod
ified
with
cell-pe
netratingpe
ptide
pene
tratin
Nes
Cre8
mir-15
5LSLtTA
mice
Nud
emicesc
Graft
ivan
dit
ND
Increa
sedmiR-155
leve
lDec
reas
edtumor
volume
[196
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1769
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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148 I Hocaoglu M N Ccedilizmeciyan R Erdem C Ozen A KurtA Sennaroglu and H Y Acar Development of highly luminescentand cytocompatible near-IR-emitting aqueous Ag2S quantum dotsJ Mater Chem 22 14674 (2012)
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150 P R Chandran P Appadurai K Rathinasamy and N SandhyaraniEnhanced cytotoxic effect of doxorubicin loaded multifunctionalgold nanoparticle for targeted cancer drug delivery J NanopharmDrug Delivery 1 289 (2013)
151 N L Rosi D A Giljohann C S Thaxton A K Lytton-JeanM S Han and C A Mirkin Oligonucleotide-modified goldnanoparticles for intracellular gene regulation Science 312 1027(2006)
152 W H Kong K H Bae S D Jo J S Kim and T G Park Cationiclipid-coated gold nanoparticles as efficient and non-cytotoxic intra-cellular siRNA delivery vehicles Pharm Res 29 362 (2012)
153 R Ghosh L C Singh J M Shohet and P H Gunaratne A goldnanoparticle platform for the delivery of functional microRNAs intocancer cells Biomaterials 34 807 (2013)
154 A Bitar N M Ahmad H Fessi and A Elaissari Silica-basednanoparticles for biomedical applications Drug Discov Today17 1147 (2012)
1780 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
155 H Lee D Sung M Veerapandian K Yun and S W Seo PEGy-lated polyethyleneimine grafted silica nanoparticles Enhanced cel-lular uptake and efficient siRNA delivery Anal Bioanal Chem400 535 (2011)
156 X Li Y Chen M Wang Y Ma W Xia and H Gu A mesoporoussilica nanoparticlendashPEIndashfusogenic peptide system for siRNA deliv-ery in cancer therapy Biomaterials 34 1391 (2013)
157 Z Chen M F Penet S Nimmagadda C Li S R Banerjee P TWinnard Jr D Artemov K Glunde M G Pomper and Z MBhujwalla PSMA-targeted theranostic nanoplex for prostate cancertherapy ACS Nano 6 7752 (2012)
158 F Haque D Shu Y Shu L S Shlyakhtenko P G RychahouB M Evers and P Guo Ultrastable synergistic tetravalent RNAnanoparticles for targeting to cancers Nano Today 7 245 (2012)
159 W Wei P P Lv X M Chen Z G Yue Q Fu S Y Liu H Yueand G H Ma Codelivery of mTERT siRNA and paclitaxel bychitosan-based nanoparticles promoted synergistic tumor suppres-sion Biomaterials 34 3912 (2013)
160 S Ganesh A K Iyer D V Morrissey and M M AmijiHyaluronic acid based self-assembling nanosystems for CD44 tar-get mediated siRNA delivery to solid tumors Biomaterials 34 3489(2013)
161 C Dohmen D Edinger T Frohlich L Schreiner U LacheltC Troiber J Radler P Hadwiger H P Vornlocher and E WagnerNanosized multifunctional polyplexes for receptor-mediated siRNAdelivery ACS Nano 6 5198 (2012)
162 S A Jensen E S Day C H Ko L A Hurley J P LucianoF M Kouri T J Merkel A J Luthi P C Patel J I Cutler W LDaniel A W Scott M W Rotz T J Meade D A GiljohannC A Mirkin and A H Stegh Spherical nucleic acid nanoparticleconjugates as an RNAi-based therapy for glioblastoma Sci TranslMed 5 209ra152 (2013)
163 H Arima A Yoshimatsu H Ikeda A Ohyama K MotoyamaT Higashi A Tsuchiya T Niidome Y Katayama K Hattoriand T Takeuchi Folate-PEG-appended dendrimer conjugate withalpha-cyclodextrin as a novel cancer cell-selective siRNA deliverycarrier Mol Pharm 9 2591 (2012)
164 J Wei T Cheang B Tang H Xia Z Xing Z Chen Y FangW Chen A Xu S Wang and J Luo The inhibition of humanbladder cancer growth by calcium carbonateCaIP6 nanocompositeparticles delivering AIB1 siRNA Biomaterials 34 1246 (2013)
165 T Kanazawa K Sugawara K Tanaka S Horiuchi Y Takashimaand H Okada Suppression of tumor growth by systemic delivery ofanti-VEGF siRNA with cell-penetrating peptide-modified MPEG-PCL nanomicelles Eur J Pharm Biopharm 81 470 (2012)
166 M A Rahman A R Amin X Wang J E Zuckerman C HChoi B Zhou D Wang S Nannapaneni L Koenig Z ChenZ G Chen Y Yen M E Davis and D M Shin Systemic deliveryof siRNA nanoparticles targeting RRM2 suppresses head and necktumor growth J Control Release 159 384 (2012)
167 J Guo J R Ogier S Desgranges R Darcy and C OrsquoDriscollAnisamide-targeted cyclodextrin nanoparticles for siRNA deliveryto prostate tumours in mice Biomaterials 33 7775 (2012)
168 M Shen F Gong P Pang K Zhu X Meng C Wu J WangH Shan and X Shuai An MRI-visible non-viral vector for tar-geted Bcl-2 siRNA delivery to neuroblastoma Int J Nanomedicine7 3319 (2012)
169 D Lin Q Jiang Q Cheng Y Huang P Huang S Han S GuoZ Liang and A Dong Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and invivo siRNA delivery Acta Biomater 9 7746 (2013)
170 L Zou X Song T Yi S Li H Deng X Chen Z Li Y BaiQ Zhong Y Wei and X Zhao Administration of PLGA nanopar-ticles carrying shRNA against focal adhesion kinase and CD44results in enhanced antitumor effects against ovarian cancer CancerGene Ther 20 242 (2013)
171 T Yin P Wang J Li R Zheng B Zheng D Cheng R Li J Laiand X Shuai Ultrasound-sensitive siRNA-loaded nanobubblesformed by hetero-assembly of polymeric micelles and liposomesand their therapeutic effect in gliomas Biomaterials 34 4532(2013)
172 H J Cho S Chong S J Chung C K Shim and D D Kim Poly-L-arginine and dextran sulfate-based nanocomplex for epidermalgrowth factor receptor (EGFR) siRNA delivery Its application forhead and neck cancer treatment Pharm Res 29 1007 (2012)
173 F Abedini H Hosseinkhani M Ismail A J Domb A R OmarP P Chong P D Hong D S Yu and I Y Farber Cationizeddextran nanoparticle-encapsulated CXCR4-siRNA enhanced corre-lation between CXCR4 expression and serum alkaline phosphatasein a mouse model of colorectal cancer Int J Nanomedicine 7 4159(2012)
174 F Yang W Huang Y Li S Liu M Jin Y Wang L Jia andZ Gao Anti-tumor effects in mice induced by survivin-targetedsiRNA delivered through polysaccharide nanoparticles Biomateri-als 34 5689 (2013)
175 L Chen Y Ding Y Wang X Liu R Babu W Ravis and W YanCodelivery of zoledronic acid and doublestranded RNA from corendashshell nanoparticles Int J Nanomedicine 8 137 (2013)
176 H Jagani J V Rao V R Palanimuthu R C Hariharapura andS Gang A nanoformulation of siRNA and its role in cancer ther-apy In vitro and in vivo evaluation Cell Mol Biol Lett 18 120(2013)
177 L A Tobin Y Xie M Tsokos S I Chung A A Merz M AArnold G Li H L Malech and K F Kwong Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of can-cer cell internalization in vivo Biomaterials 34 2980 (2013)
178 J Shen H Sun P Xu Q Yin Z Zhang S Wang H Yu and Y LiSimultaneous inhibition of metastasis and growth of breast cancerby co-delivery of twist shRNA and paclitaxel using pluronic P85-PEITPGS complex nanoparticles Biomaterials 34 1581 (2013)
179 H Meng W X Mai H Zhang M Xue T Xia S Lin X WangY Zhao Z Ji J I Zink and A E Nel Codelivery of an optimaldrugsiRNA combination using mesoporous silica nanoparticles toovercome drug resistance in breast cancer in vitro and in vivo ACSNano 7 994 (2013)
180 C Zheng M Zheng P Gong J Deng H Yi P Zhang Y ZhangP Liu Y Ma and L Cai Polypeptide cationic micelles mediatedco-delivery of docetaxel and siRNA for synergistic tumor therapyBiomaterials 34 3431 (2013)
181 Q Hu W Li X Hu J Shen X Jin J Zhou G Tang and P KChu Synergistic treatment of ovarian cancer by co-delivery of sur-vivin shRNA and paclitaxel via supramolecular micellar assemblyBiomaterials 33 6580 (2012)
182 Y H Yu E Kim D E Park G Shim S Lee Y B KimC W Kim and Y K Oh Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA Eur J Pharm Biopharm 80 268(2012)
183 Z J Deng S W Morton E Ben-Akiva E C Dreaden K EShopsowitz and P T Hammond Layer-by-layer nanoparticles forsystemic codelivery of an anticancer drug and siRNA for potentialtriple-negative breast cancer treatment ACS Nano 7 9571 (2013)
184 X Q Liu M H Xiong X T Shu R Z Tang and J WangTherapeutic delivery of siRNA silencing HIF-1 alpha with micellarnanoparticles inhibits hypoxic tumor growth Mol Pharm 9 2863(2012)
185 J Xiao X Duan Q Yin Z Miao H Yu C Chen Z ZhangJ Wang and Y Li The inhibition of metastasis and growth ofbreast cancer by blocking the NF-kappaB signaling pathway usingbioreducible PEI-basedp65 shRNA complex nanoparticles Bioma-terials 34 5381 (2013)
186 R J Christie Y Matsumoto K Miyata T Nomoto S FukushimaK Osada J Halnaut F Pittella H J Kim N Nishiyama and
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
187 S Ganesh A K Iyer F Gattacceca D V Morrissey and M MAmiji In vivo biodistribution of siRNA and cisplatin adminis-tered using CD44-targeted hyaluronic acid nanoparticles J ControlRelease 172 699 (2013)
188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
RFP
(Red
Fluores
cent
Protein)
Cap
sidna
noca
rrier
complex
RGD
peptides
fortargeting
v
3integrins
B16
F10
murine
melan
omace
llsNud
emicesc
Graft
iv
ND
Kno
ckdo
wnof
RFP
Dec
reas
edtumor
volume
[227
]
miR-34a
E2F
3CD44
an
dSIRT1
Porou
ssilica
nano
particles
Con
juga
tedto
adisialog
anglioside
GD2
antib
ody
NB16
91an
dSK-N
-AS
luchu
man
neurob
lastom
ace
lls
SCID
micesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[191
]
siRNA
elF5a
PEI-ba
sedSNS01
nano
particle
KAS-61
human
multip
lemye
lomace
llSCID
micesc
xeno
graft
iv
ND
Syn
ergy
with
chem
oterap
eu-
tics
Dec
reas
etumor
volume
[228
]
shRNA
IGF-1R
Com
biMAG
(com
mercial
mag
netic
)lip
ofec
tamin
mixture
Mag
netic
man
ipulation
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
Noeffect
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[229
]
siRNA
AR
PLG
A-P
EG
nano
particles
Con
juga
tionto
pros
tate-spe
cific
mem
bran
ean
tigen
aptamer
A10
for
targeting
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
Dec
reas
edtumor
volume
[230
]
anti-miR-10b
miR10
bUltras
mallm
agne
ticna
nopa
rticles
Con
juga
tionto
RGD
peptidefortargeting
MDA-M
B-231
-luc-
D3H
2LN
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Dec
reas
edmiR-10b
leve
l[194
]
siRNA
VEGF
Calcium
phos
phate
(CaP
)-ba
sed
nano
particles
BxP
C3hu
man
panc
reatic
canc
erce
lls
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[231
]
siRNA
VEGF
poly(ethylen
eglyc
ol)
andpo
ly(e-
caprolac
tone
)MPEGndash
PCL-SS-Tat
Tatpe
ptide(G
CGGGY-
GRKKRRQRRR)
coup
ledforim
prov
edde
liveryto
cells
S-180
murinesa
rcom
ace
llsSyn
geniec
sc
graft
iv
Noeffect
Dec
reas
edtumor
volume
[165
]
pre-miR-107
miR-107
Nan
ogCationiclip
idna
nopa
rticles
CAL2
7hu
man
head
andne
cksq
uamou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Increa
sedmiR-107
leve
lDec
reas
edtumor
volume
[198
]
siRNA
Neg
ative
Con
trol
mPEG-b-P
LGA-b-P
LLEnc
apsu
latedwith
adria
myc
inHuh
-7hu
man
hepa
ticca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[65]
siRNA
RRM2
CDP
AD-P
EG
AD-P
EG-Tf
Gen
erated
with
Hum
antran
sferrin
protein(Tf)
ligan
d
Tu21
2hu
man
head
and
neck
squa
mou
sce
llca
ncer
Nud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
RRMP
Dec
reas
edtumor
volume
[166
]
1770 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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cer J Clin 64 9 (2014)2 M J Espiritu A C Collier and J P Bingham A 21st-century
approach to age-old problems The ascension of biologics in clini-cal therapeutics Drug Discov Today (2014)
3 R L Schilsky Personalized medicine in oncology The future isnow Nat Rev Drug Discov 9 363 (2010)
4 M N Patel M D Halling-Brown J E Tym P Workman andB Al-Lazikani Objective assessment of cancer genes for drug dis-covery Nat Rev Drug Discov 12 35 (2013)
5 D Hanahan and R A Weinberg Hallmarks of cancer The nextgeneration Cell 144 646 (2011)
6 N F Sun Z A Liu W B Huang A L Tian and S Y Hu Theresearch of nanoparticles as gene vector for tumor gene therapyCrit Rev Oncol Hematol 89 352 (2013)
1776 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
7 M Rothe U Modlich and A Schambach Biosafety challenges foruse of lentiviral vectors in gene therapy Curr Gene Ther 13 453(2013)
8 D R Corey RNA learns from antisense Nat Chem Biol 3 8(2007)
9 V N Kim MicroRNA biogenesis Coordinated cropping and dic-ing Nat Rev Mol Cell Biol 6 376 (2005)
10 D E Golden V R Gerbasi and E J Sontheimer An inside jobfor siRNAs Mol Cell 31 309 (2008)
11 M Ghildiyal and P D Zamore Small silencing RNAs An expand-ing universe Nat Rev Genet 10 94 (2009)
12 D H Kim M A Behlke S D Rose M S Chang S Choiand J J Rossi Synthetic dsRNA Dicer substrates enhance RNAipotency and efficacy Nat Biotechnol 23 222 (2005)
13 Y Maida M Yasukawa M Furuuchi T Lassmann R PossematoN Okamoto V Kasim Y Hayashizaki W C Hahn and K Masu-tomi An RNA-dependent RNA polymerase formed by TERT andthe RMRP RNA Nature 461 230 (2009)
14 N R Smalheiser The search for endogenous siRNAs in the mam-malian brain Exp Neurol 235 455 (2012)
15 K A Tekirdag G Korkmaz D G Ozturk R Agami andD Gozuacik MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5 Autophagy 9 374(2013)
16 G Korkmaz K A Tekirdag D G Ozturk A Kosar O USezerman and D Gozuacik MIR376A Is a Regulator ofStarvation-Induced Autophagy PLoS One 8 e82556 (2013)
17 D Castanotto and J J Rossi The promises and pitfalls of RNA-interference-based therapeutics Nature 457 426 (2009)
18 E Iorns C J Lord N Turner and A Ashworth Utilizing RNAinterference to enhance cancer drug discovery Nat Rev Drug Dis-cov 6 556 (2007)
19 M A Behlke Chemical modification of siRNAs for in vivo useOligonucleotides 18 305 (2008)
20 S D Rose D H Kim M Amarzguioui J D Heidel M ACollingwood M E Davis J J Rossi and M A Behlke Func-tional polarity is introduced by Dicer processing of short substrateRNAs Nucleic Acids Res 33 4140 (2005)
21 K Nishina T Unno Y Uno T Kubodera T KanouchiH Mizusawa and T Yokota Efficient in vivo delivery of siRNAto the liver by conjugation of alpha-tocopherol Mol Ther 16 734(2008)
22 F Czauderna M Fechtner S Dames H Aygun A Klippel G JPronk K Giese and J Kaufmann Structural variations and sta-bilising modifications of synthetic siRNAs in mammalian cellsNucleic Acids Res 31 2705 (2003)
23 B A Kraynack and B F Baker Small interfering RNAs contain-ing full 2prime-O-methylribonucleotide-modified sense strands displayArgonaute2eIF2C2-dependent activity RNA 12 163 (2006)
24 F V Rivas N H Tolia J J Song J P Aragon J Liu G JHannon and L Joshua-Tor Purified Argonaute2 and an siRNAform recombinant human RISC Nat Struct Mol Biol 12 340(2005)
25 V Hornung M Guenthner-Biller C Bourquin A AblasserM Schlee S Uematsu A Noronha M Manoharan S AkiraA de Fougerolles S Endres and G Hartmann Sequence-specificpotent induction of IFN-alpha by short interfering RNA in plasma-cytoid dendritic cells through TLR7 Nat Med 11 263 (2005)
26 A D Judge G Bola A C Lee and I MacLachlan Design ofnoninflammatory synthetic siRNA mediating potent gene silencingin vivo Mol Ther 13 494 (2006)
27 A L Jackson J Burchard D Leake A Reynolds J SchelterJ Guo J M Johnson L Lim J Karpilow K NicholsW Marshall A Khvorova and P S Linsley Position-specificchemical modification of siRNAs reduces ldquooff-targetrdquo transcriptsilencing RNA 12 1197 (2006)
28 D Bumcrot M Manoharan V Koteliansky and D W Sah RNAitherapeutics A potential new class of pharmaceutical drugs NatChem Biol 2 711 (2006)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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173 F Abedini H Hosseinkhani M Ismail A J Domb A R OmarP P Chong P D Hong D S Yu and I Y Farber Cationizeddextran nanoparticle-encapsulated CXCR4-siRNA enhanced corre-lation between CXCR4 expression and serum alkaline phosphatasein a mouse model of colorectal cancer Int J Nanomedicine 7 4159(2012)
174 F Yang W Huang Y Li S Liu M Jin Y Wang L Jia andZ Gao Anti-tumor effects in mice induced by survivin-targetedsiRNA delivered through polysaccharide nanoparticles Biomateri-als 34 5689 (2013)
175 L Chen Y Ding Y Wang X Liu R Babu W Ravis and W YanCodelivery of zoledronic acid and doublestranded RNA from corendashshell nanoparticles Int J Nanomedicine 8 137 (2013)
176 H Jagani J V Rao V R Palanimuthu R C Hariharapura andS Gang A nanoformulation of siRNA and its role in cancer ther-apy In vitro and in vivo evaluation Cell Mol Biol Lett 18 120(2013)
177 L A Tobin Y Xie M Tsokos S I Chung A A Merz M AArnold G Li H L Malech and K F Kwong Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of can-cer cell internalization in vivo Biomaterials 34 2980 (2013)
178 J Shen H Sun P Xu Q Yin Z Zhang S Wang H Yu and Y LiSimultaneous inhibition of metastasis and growth of breast cancerby co-delivery of twist shRNA and paclitaxel using pluronic P85-PEITPGS complex nanoparticles Biomaterials 34 1581 (2013)
179 H Meng W X Mai H Zhang M Xue T Xia S Lin X WangY Zhao Z Ji J I Zink and A E Nel Codelivery of an optimaldrugsiRNA combination using mesoporous silica nanoparticles toovercome drug resistance in breast cancer in vitro and in vivo ACSNano 7 994 (2013)
180 C Zheng M Zheng P Gong J Deng H Yi P Zhang Y ZhangP Liu Y Ma and L Cai Polypeptide cationic micelles mediatedco-delivery of docetaxel and siRNA for synergistic tumor therapyBiomaterials 34 3431 (2013)
181 Q Hu W Li X Hu J Shen X Jin J Zhou G Tang and P KChu Synergistic treatment of ovarian cancer by co-delivery of sur-vivin shRNA and paclitaxel via supramolecular micellar assemblyBiomaterials 33 6580 (2012)
182 Y H Yu E Kim D E Park G Shim S Lee Y B KimC W Kim and Y K Oh Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA Eur J Pharm Biopharm 80 268(2012)
183 Z J Deng S W Morton E Ben-Akiva E C Dreaden K EShopsowitz and P T Hammond Layer-by-layer nanoparticles forsystemic codelivery of an anticancer drug and siRNA for potentialtriple-negative breast cancer treatment ACS Nano 7 9571 (2013)
184 X Q Liu M H Xiong X T Shu R Z Tang and J WangTherapeutic delivery of siRNA silencing HIF-1 alpha with micellarnanoparticles inhibits hypoxic tumor growth Mol Pharm 9 2863(2012)
185 J Xiao X Duan Q Yin Z Miao H Yu C Chen Z ZhangJ Wang and Y Li The inhibition of metastasis and growth ofbreast cancer by blocking the NF-kappaB signaling pathway usingbioreducible PEI-basedp65 shRNA complex nanoparticles Bioma-terials 34 5381 (2013)
186 R J Christie Y Matsumoto K Miyata T Nomoto S FukushimaK Osada J Halnaut F Pittella H J Kim N Nishiyama and
J Biomed Nanotechnol 10 1751ndash1783 2014 1781
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
187 S Ganesh A K Iyer F Gattacceca D V Morrissey and M MAmiji In vivo biodistribution of siRNA and cisplatin adminis-tered using CD44-targeted hyaluronic acid nanoparticles J ControlRelease 172 699 (2013)
188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Hsp
27Triethan
olam
ine
(TEA)-co
repo
ly(amidoa
mine)
(PAMAM)
dend
rimers
PC3hu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
e[232
]
siRNA
VEGF
PEG17
-PLL
-CA14
and
PEG17
-PLL
-CA32
Mod
ified
with
cholic
acid
Grafte
dwith
PEG
TRAMP
C1Murine
pros
tate
canc
erce
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[233
]
siRNA
Bcl-2VEGF
andc-Myc
Poly(disu
lfide
amine)
polymer
(ABP)
Grafte
dwith
Arginine
B16
-F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Red
uced
immun
eresp
onse
compa
reto
controls
Kno
ckdo
wnof
Bcl-2c-myc
and
VEGF
Dec
reas
edtumor
volume
[234
]
siRNA
MCL-1
Cationicso
lidlip
idna
nopa
rticles(cSLN
)Con
juga
tedwith
Pac
litax
elKB
human
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
MCL-1
Dec
reas
edtumor
volume
[182
]
siRNA
Ran
GTPas
eStablenu
cleicac
idlip
idpa
rticle
(SNALP
)HCT11
6hu
man
colon
DLD
-1hu
man
colon
Hep
G2an
dHuH
7hu
man
liver
canc
erce
lls
SCID
micesc
xeno
graft
iv
ND
Kno
ckdo
wnof
Ran
GTPas
eDec
reas
edtumor
volume
[235
]
pre-miR
miR-155
PEI-ba
sed
nano
particles
ID8murineov
ariance
llsSyn
geniec
sc
graft
iv
Noeffect
Boo
stingof
anti-tumor
immun
ity
Dec
reas
edtumor
volume
Syn
ergy
with
miR-155
[195
]
siRNA
VEGF
2-hy
drox
ypop
yl--
cyclod
extrin
(HP--C
D)
Com
bine
dwith
Folic
acid
andPEI
HeL
ahu
man
cervix
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
VEGF
Dec
reas
edtumor
volume
[236
]
siRNA
c-myc
Goldna
nopa
rticles
Con
juga
tedwith
RGD
and
PEG
LA-4
mou
selung
canc
erce
llsNud
emice
sc
xeno
graft
iv
Noeffect
Kno
ckdo
wnof
c-myc
Dec
reas
edtumor
volume
[237
]
siRNA
c-myc
LipidCalcium
Pho
spha
te(LCP)
Enc
apsu
latedwith
gemcitabine
mon
opho
spha
te(G
MP)
H46
0largece
lllung
canc
erce
llsNud
emicesc
xeno
graft
iv
Red
uced
side
effects
compa
reto
control
Kno
ckdo
wnof
c-myc
Syn
ergy
with
chem
othe
r-au
petic
sDec
reae
sed
tumor
volume
[238
]
J Biomed Nanotechnol 10 1751ndash1783 2014 1771
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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1776 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
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1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Table
IContinued
Nuc
leic
acid
Target
Nan
opartic
leMod
ifica
tion
Cellline
Tumor
mod
elDelivery
Sideeffect
Outco
me
Ref
siRNA
Kras
Poly(ethy
lene
glyc
ol)-
bloc
k-po
ly(l-ly
sine
)an
dpo
ly(ethylen
eglyc
ol)-bloc
k-po
ly(dl-
lactide)
Com
bine
dwith
arse
nic
PANC-1
human
panc
reatic
canc
erce
lls
Nud
emice
sc
xeno
graft
iv
ND
Dec
reas
edtumor
volume
Syn
ergy
with
chem
othe
r-au
peutics
[239
]
siRNA
RFP
Gelatin
(tGel)
Mod
ified
with
sulfh
ydryl
grou
psThiolation
RFPB16
F10
murine
melan
omace
llsSyn
geniec
sc
graft
iv
Noeffect
Kno
ckdo
wnof
RFP
[240
]
siRNA
Survivin
Hya
luronicac
id(H
A)
nano
particles
Com
bina
tionwith
PEIan
dPEG
A54
9no
n-sm
alllun
gca
ncer
cells
H69
smallc
elllun
gca
ncer
cells
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
grow
th
[187
]
siRNA
PLK
1Chitosa
npo
lyethy
lene
glyc
olCom
bine
dwith
peptide
CP15
SW48
0hu
man
colon
canc
erce
llsNud
emicesc
xeno
graft
ip
Noeffect
Deliveryto
tumor
tissu
eKno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[201
]
siRNA
XIAP
Triple-she
llca
lcium
phos
phate
Com
bine
dwith
doxo
rubicinan
dun
boun
dca
veolin-1
H29
2hu
man
lung
carcinom
ace
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
XIAP
Dec
reas
edtumor
volume
[177
]
siRNA
PLK
1mPEG45
-b-PAEP75
-Cya
Coa
tedwith
PEGylated
anionicpo
lymer
PPC-D
A
MDA-M
B-231
human
brea
stca
ncer
cells
Nud
emicesc
xeno
graft
iv
ND
Deliveryto
tumor
tissu
eDec
reas
edtumor
volume
[241
]
siRNA
AR
Cationiclip
idna
nopa
rticles
LNca
Phu
man
pros
tate
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
AR
[242
]
siRNA
PLK
1Poly(lactic-co-glyc
olic
acid)an
dpo
ly(-
carbob
enzo
xyl-l-
lysine
)
Con
juga
tedwith
avidin
palm
iticac
idan
dPEG
A54
9hu
man
lung
canc
erce
llsNud
emicesc
xeno
graft
iv
ND
Kno
ckdo
wnof
PLK
1Dec
reas
edtumor
volume
[243
]
shRNA
Survivin
D--toc
ophe
ryl
polyethy
lene
glyc
ol10
00su
ccinate
(TPGS)
Con
juga
tedwith
RGD
peptidean
den
caps
ulated
with
paclita
xel
A54
9Thu
man
Pac
litax
elresistan
tlung
canc
erce
lls
Nud
emicesc
xeno
graft
iv
Noeffect
Dec
reas
edtumor
volume
[202
]
microRNA
miR-29b
Lipo
somal
nano
particle
Con
juga
tedwith
Tran
sferrin
MV4-11
Bleuk
emia
cells
NOSCID
-ga
mma
iv
Noeffect
Deliveryto
tumor
tissu
e[244
]
Notes
NDNot
Determined
ivintrav
enou
sip
intrap
erito
nealitintratum
oralicintrac
avita
rypt
peritum
oral
1772 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
J Biomed Nanotechnol 10 1751ndash1783 2014 1773
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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cer J Clin 64 9 (2014)2 M J Espiritu A C Collier and J P Bingham A 21st-century
approach to age-old problems The ascension of biologics in clini-cal therapeutics Drug Discov Today (2014)
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4 M N Patel M D Halling-Brown J E Tym P Workman andB Al-Lazikani Objective assessment of cancer genes for drug dis-covery Nat Rev Drug Discov 12 35 (2013)
5 D Hanahan and R A Weinberg Hallmarks of cancer The nextgeneration Cell 144 646 (2011)
6 N F Sun Z A Liu W B Huang A L Tian and S Y Hu Theresearch of nanoparticles as gene vector for tumor gene therapyCrit Rev Oncol Hematol 89 352 (2013)
1776 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
7 M Rothe U Modlich and A Schambach Biosafety challenges foruse of lentiviral vectors in gene therapy Curr Gene Ther 13 453(2013)
8 D R Corey RNA learns from antisense Nat Chem Biol 3 8(2007)
9 V N Kim MicroRNA biogenesis Coordinated cropping and dic-ing Nat Rev Mol Cell Biol 6 376 (2005)
10 D E Golden V R Gerbasi and E J Sontheimer An inside jobfor siRNAs Mol Cell 31 309 (2008)
11 M Ghildiyal and P D Zamore Small silencing RNAs An expand-ing universe Nat Rev Genet 10 94 (2009)
12 D H Kim M A Behlke S D Rose M S Chang S Choiand J J Rossi Synthetic dsRNA Dicer substrates enhance RNAipotency and efficacy Nat Biotechnol 23 222 (2005)
13 Y Maida M Yasukawa M Furuuchi T Lassmann R PossematoN Okamoto V Kasim Y Hayashizaki W C Hahn and K Masu-tomi An RNA-dependent RNA polymerase formed by TERT andthe RMRP RNA Nature 461 230 (2009)
14 N R Smalheiser The search for endogenous siRNAs in the mam-malian brain Exp Neurol 235 455 (2012)
15 K A Tekirdag G Korkmaz D G Ozturk R Agami andD Gozuacik MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5 Autophagy 9 374(2013)
16 G Korkmaz K A Tekirdag D G Ozturk A Kosar O USezerman and D Gozuacik MIR376A Is a Regulator ofStarvation-Induced Autophagy PLoS One 8 e82556 (2013)
17 D Castanotto and J J Rossi The promises and pitfalls of RNA-interference-based therapeutics Nature 457 426 (2009)
18 E Iorns C J Lord N Turner and A Ashworth Utilizing RNAinterference to enhance cancer drug discovery Nat Rev Drug Dis-cov 6 556 (2007)
19 M A Behlke Chemical modification of siRNAs for in vivo useOligonucleotides 18 305 (2008)
20 S D Rose D H Kim M Amarzguioui J D Heidel M ACollingwood M E Davis J J Rossi and M A Behlke Func-tional polarity is introduced by Dicer processing of short substrateRNAs Nucleic Acids Res 33 4140 (2005)
21 K Nishina T Unno Y Uno T Kubodera T KanouchiH Mizusawa and T Yokota Efficient in vivo delivery of siRNAto the liver by conjugation of alpha-tocopherol Mol Ther 16 734(2008)
22 F Czauderna M Fechtner S Dames H Aygun A Klippel G JPronk K Giese and J Kaufmann Structural variations and sta-bilising modifications of synthetic siRNAs in mammalian cellsNucleic Acids Res 31 2705 (2003)
23 B A Kraynack and B F Baker Small interfering RNAs contain-ing full 2prime-O-methylribonucleotide-modified sense strands displayArgonaute2eIF2C2-dependent activity RNA 12 163 (2006)
24 F V Rivas N H Tolia J J Song J P Aragon J Liu G JHannon and L Joshua-Tor Purified Argonaute2 and an siRNAform recombinant human RISC Nat Struct Mol Biol 12 340(2005)
25 V Hornung M Guenthner-Biller C Bourquin A AblasserM Schlee S Uematsu A Noronha M Manoharan S AkiraA de Fougerolles S Endres and G Hartmann Sequence-specificpotent induction of IFN-alpha by short interfering RNA in plasma-cytoid dendritic cells through TLR7 Nat Med 11 263 (2005)
26 A D Judge G Bola A C Lee and I MacLachlan Design ofnoninflammatory synthetic siRNA mediating potent gene silencingin vivo Mol Ther 13 494 (2006)
27 A L Jackson J Burchard D Leake A Reynolds J SchelterJ Guo J M Johnson L Lim J Karpilow K NicholsW Marshall A Khvorova and P S Linsley Position-specificchemical modification of siRNAs reduces ldquooff-targetrdquo transcriptsilencing RNA 12 1197 (2006)
28 D Bumcrot M Manoharan V Koteliansky and D W Sah RNAitherapeutics A potential new class of pharmaceutical drugs NatChem Biol 2 711 (2006)
29 A S Peek and M A Behlke Design of active small interferingRNAs Curr Opin Mol Ther 9 110 (2007)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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176 H Jagani J V Rao V R Palanimuthu R C Hariharapura andS Gang A nanoformulation of siRNA and its role in cancer ther-apy In vitro and in vivo evaluation Cell Mol Biol Lett 18 120(2013)
177 L A Tobin Y Xie M Tsokos S I Chung A A Merz M AArnold G Li H L Malech and K F Kwong Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of can-cer cell internalization in vivo Biomaterials 34 2980 (2013)
178 J Shen H Sun P Xu Q Yin Z Zhang S Wang H Yu and Y LiSimultaneous inhibition of metastasis and growth of breast cancerby co-delivery of twist shRNA and paclitaxel using pluronic P85-PEITPGS complex nanoparticles Biomaterials 34 1581 (2013)
179 H Meng W X Mai H Zhang M Xue T Xia S Lin X WangY Zhao Z Ji J I Zink and A E Nel Codelivery of an optimaldrugsiRNA combination using mesoporous silica nanoparticles toovercome drug resistance in breast cancer in vitro and in vivo ACSNano 7 994 (2013)
180 C Zheng M Zheng P Gong J Deng H Yi P Zhang Y ZhangP Liu Y Ma and L Cai Polypeptide cationic micelles mediatedco-delivery of docetaxel and siRNA for synergistic tumor therapyBiomaterials 34 3431 (2013)
181 Q Hu W Li X Hu J Shen X Jin J Zhou G Tang and P KChu Synergistic treatment of ovarian cancer by co-delivery of sur-vivin shRNA and paclitaxel via supramolecular micellar assemblyBiomaterials 33 6580 (2012)
182 Y H Yu E Kim D E Park G Shim S Lee Y B KimC W Kim and Y K Oh Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA Eur J Pharm Biopharm 80 268(2012)
183 Z J Deng S W Morton E Ben-Akiva E C Dreaden K EShopsowitz and P T Hammond Layer-by-layer nanoparticles forsystemic codelivery of an anticancer drug and siRNA for potentialtriple-negative breast cancer treatment ACS Nano 7 9571 (2013)
184 X Q Liu M H Xiong X T Shu R Z Tang and J WangTherapeutic delivery of siRNA silencing HIF-1 alpha with micellarnanoparticles inhibits hypoxic tumor growth Mol Pharm 9 2863(2012)
185 J Xiao X Duan Q Yin Z Miao H Yu C Chen Z ZhangJ Wang and Y Li The inhibition of metastasis and growth ofbreast cancer by blocking the NF-kappaB signaling pathway usingbioreducible PEI-basedp65 shRNA complex nanoparticles Bioma-terials 34 5381 (2013)
186 R J Christie Y Matsumoto K Miyata T Nomoto S FukushimaK Osada J Halnaut F Pittella H J Kim N Nishiyama and
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
187 S Ganesh A K Iyer F Gattacceca D V Morrissey and M MAmiji In vivo biodistribution of siRNA and cisplatin adminis-tered using CD44-targeted hyaluronic acid nanoparticles J ControlRelease 172 699 (2013)
188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Scheme 4 A typical study testing the antitumor potential of nanocarriers and RNA interference
Combination TreatmentsCombination therapies of small RNA molecules andchemotherapy agents such as paclitaxel doxorubicin orgemcitabine were tested to obtain synergistic antitumoreffects139159176ndash180 Several studies chose to load thechemotherapy agent to RNA carrier nanoparticles ratherthan systemic chemotherapy administrationIn fact in the literature small molecule drug deliv-
ery using nanoparticles was studied extensively with thegoal of achieving higher local doses in tumors followinglow dose systemic drug administrations Very promisingexperimental results were obtained and nanocarrier loadeddrugs even entered clinical use31 Nanoparticles loadedwith chemotherapy agents including liposomal formula-tions of doxorubicin daunorubicin irinotecan vincristinepaclitaxeldocetaxel lurtotecan and oxaliplatin and poly-mers carrying camptothecin and docetaxel reached clinicaltrials and even some of them are already in the market31
Combinations of small RNAs and chemotherapy agentsobtained by loading both components intoonto samenanocarriers may offer several advantages Experimentalresults obtained with these combinations were encour-aging For example combination of paclitaxel withmTERT siRNA or survivin shRNA in experimental lungcancers159178 with survivin and Bcl-2 shRNA in ovarian
cancer181 and Mcl-1 siRNA in cervix ca models182 resultedin synergistic antitumor effects Similar results wereobtained with survivin shRNA combined with doxorubicinin breast cancer171 Small RNA combinations were usedto counteract multiple drug resistance during chemother-apy siRNA targeting major multiple drug resistanceproteins P-glycoprotein drug exporterMDR1ABCB1 orMRP1ABCC1 in nano combinations with doxorubicinenhanced antitumor effects of the chemotherapy in exper-imental breast cancer models179183 HIF-1 knockdownusing siRNAs sensitized prostate cancer tumors to dox-orubicin and MDR1 downregulation was also observed inthis model184 In an alternative strategy a drug-activatingenzyme (bacterial cytosine deaminase bCD) was deliv-ered together with the siRNA against choline kinase(Chk)157 In this context while bCD activated local conver-sion of nontoxic prodrug 5-fluorocytosine (5-FC) to cyto-toxic 5-fluorouracil (5-FU) inside prostate tumors siRNAChk targeted choline metabolism offering the possibilityof combined treatment157 Therefore packaging of smallRNAs together with chemotherapy agents in multifunc-tional targeted nanoparticles might further sensitize can-cer cells to the toxic effects of chemotherapy agents fightmulti drug resistance and allow the use of local activationstrategies
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Copyright American Scientific Publishers
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
155 H Lee D Sung M Veerapandian K Yun and S W Seo PEGy-lated polyethyleneimine grafted silica nanoparticles Enhanced cel-lular uptake and efficient siRNA delivery Anal Bioanal Chem400 535 (2011)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
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196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
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200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
Scheme 5 Schematic representation of proteins targeted by RNA interference in recent cancer studies Targeted proteins fallinto 6 major groups based on their cellular functions 1-Cell cycle 2-Apoptosis 3-Proliferation and transcription 4-Angiogenesis5-Translation 6-Drug resistance
RNAi-Targeted GenesGenes that were frequently targeted by siRNAshRNAsor miRNAs in recent studies fall into a few categories(Scheme 5) In recent studies cell cycle regulators suchas Polo-like kinase 1 (PLK1) kinesin spindle protein(KSPEG5) p21 antiapoptotic proteins Bcl-2 BCL2L12MCL-1 survivin XIAP or p65RELA and proteins-related to tumor angiogenesis namely VEGF and VEGFreceptors were targeted by several groups to block growthof tumors of different origins162165176177182185ndash187 Addi-tionally growth factor receptors such as epidermal growthfactor receptor (EGFR) were targeted in head and neckand breast cancers while epithelial cell receptor protein-tyrosine kinase (EphA2) downregulation showed antitumoreffects in ovarian tumors172188
EWSFli-1 is an abnormal protein produced by the 1122 chromosomal translocation and the fusion of the N -terminal of part of the EWS protein to the DNA-bindingdomain of the Fli-1 protein Resulting EWSFli-1 chimerictranscription factor was shown to drive the developmentof the pediatric bone cancer called Ewing sarcoma189 Thework of Ramon et al showed that siRNA-mediated knock-down of the EWSFli-1 chimeric oncogene using targetednanoparticles led to tumor regression in vivo confirm-ing the use of this strategy for cancer-specific proteinsproduced by chromosomal abnormalities190 Moreover
oncogenes such as MYC STAT-3 hTERT were targetedby nanoparticle-coupled small RNAs leading to tumortreatment
miRNAs and AntagomirsA number of microRNAs or antagomirs (anti-miRNAoligonucleotides) were used as anticancer molecules aswell The list includes miR-34a miR-10b miR-107 andmiR-155191ndash196 miR-34 expression is lost in a very broadrange of cancer types pointing out to its key role inthe regulation of tumor suppression191ndash193 This miRNAwas shown to have various anticancer effects includingblockage of cell proliferation and metastasis and induc-tion of apoptosis197 Recent works showed that miR-34coupled to nanoparticles could block the growth of pan-creas breast and neuroblastoma experimental tumors191ndash193
Nano-targeted delivery of the tumor suppressor miR-107into head and neck cancers also led to the treatment ofexperimental tumors198 On the other hand overexpres-sion of miR-155 in mice led to lymphoma developmentand transplanted tumors of miR-155 overexpressing lym-phomas responded miR-155 antagomirs (anti-miR-155)delivered on nanocarriers196 Similarily antagomirs againstmiR-10a (anti-miR-10a) delivered in nanoparticles couldprevent lymph node metastasis of xenografted breasttumors and decreased primary tumor volume194
1774 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
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193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
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196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
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198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
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201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
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209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
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215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
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219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
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226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
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238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
Targeted Delivery StrategiesA number of targeting strategies were used to concen-trate nanoparticles in and around the tumor mass A num-ber of studies relied on the enhanced permeability andretention (EPR) effect andor cleavage-mediated releaseof PEG components in the tumor area as a result oflow pH environment and metalloproteases180184 Othersused ultrasonic cavitation or magnetic manipulation asmeans of tumoral delivery171 Different targeting strategiesincluding attachment of antibodies (eg anti-GD2 anti-bodies for targeting neuroblastomas anti-CD99 antibodyfor Ewingrsquos sarcomas anti-Human epidermal growth fac-tor receptor 2 (HER2) antibodies for breast cancers andanti-CD44 antibodies for gastric cancers and melanomas)aptamers (prostate-specific membrane antigen (PSMA)aptamers for prostate cancers) peptides (eg RGD orNGR peptides targeting tumor vasculature) proteins (egHyaluronan to target CD44 receptors on breast tumors) ormolecules such as anisamide (targeting sigma-1 receptors)or urea-based PSMA-targeting moiety were exploited toselectively deliver nanoparticles and RNA drugs to tumortissues and cells81157183186190
Another problem encountered during nanoparticle-basedtherapies is the efficacy with which the particles entercells Here in addition to relying on single or multilayeredlipids for cell membrane fusion the delivery of many par-ticles into cells was achieved by the addition of peptidesor proteins onto the particles including TAT CC9 KALApeptides or hyaluronan that facilitate endosomal uptakeby target cells156174183193
A bottleneck in the effectiveness of RNA-based ther-apeutics is encountered following endocytosis In factendosomes mature into lysosomes through acidification oftheir interior and acquirement of lytic enzymes includingproteases nucleases and lipases Delivery to the tumor tis-sue and endocytosis per se do not guarantee anticancereffects and small RNAs carrier particles might well endup in lysosomes and degraded before having the chanceto show any therapeutic effect To circumvent lysis inlysosomes several strategies were applied in the reviewedworks As mentioned in previous sections an essentialdilemma stems from the use of PEG While PEGyla-tion changes surface charges allow addition of functionalmolecules and prolong half-life in blood circulation PEGprevents endosomal escape In order to benefit from thepositive effects but still allow the release of the particleto the cytosol where small RNA action occurs severalstrategies were followed The strategies included additionof pH-sensitive andor cleavable linkers to PEG itself orto the linkers of the RNA molecules51199200 Inclusionof PEI to the particles was another strategy to destabi-lize endosomes and release the contents to the cytosolthrough its proton sponge effects157178179201202 Finallyin some studies authors preferred to add peptides such asInfluenza Inf7 peptide or Arginine-rich polypeptides thatfacilitated endosomal escape of the particles161172203204
Indeed in almost all cases manipulations favoring therelease of RNA andor particles from endosomes increasedtransfection efficacies and antitumor effects of RNA car-rier nanoparticles (For example Ref [161])
Delivery MethodsMost commonly studied nanoparticle delivery modein experimental cancers appears to be intravenous orintratumoral injections of RNA-nanocarrier complexesAs expected intravenous systemic injections were moreeffective if targeting of the nano drugs to tumorous tis-sues using antibodies pepetides etc were achieved (Forexample Ref [81]) Strikingly in a few studies oraladministration and enema were tested159205 Ideally oraladministration would be the most practical administra-tion method for any drug be it a small molecule or anRNA-based drug Although intravenous or intratumoraladministrations better meet consistency and reproducibil-ity concerns during animal studies and they are viablealternatives for cancer treatment drug development effortsneed to include per os (oral) and other alternative deliverymethods as well and deal with problems related to gas-trointestinal environments and absorption
CONCLUSIONSStudies cited above and others are the proof that thereis an increasing interest in nanoparticle-based drugs forcancer treatment The ideal cancer drug should have sev-eral properties including high efficiency high selectiv-ity for cancer cells and minimal side effects in normalorgans and tissues In addition drugs should have limitedeffects on the life standard of patients during the treat-ment period and after Lower metastasis rates and higherrates of complete remission and cure are expected in theideal treatment of cancer Moreover some nanoparticlessuch as quantum dots and SPIONs might offer advan-tages for more accurate and sensitive diagnosis and in thefollow-up of relapses and metastasis Nanoparticles mightfit the description of such ldquomagic bullet drugsrdquo makingclose to ideal medical approaches possible Progress in thefields of nanotechnology and biomedicine and experiencesobtained during both preclinical and clinical studies aboutthe use of nanoparticles as anticancer molecule carrierswill surely pay off in the coming yearsNanoparticle carried and targeted drugs are studied
extensively In addition to nanocarrier-delivered conven-tional chemotherapeutics that are currently in advancedclinical phases or already in the market several RNAi-based drugs entered or are entering clinical trials31206207
Today nanoparticles that reached clinical phases areliposomal or lipid-based RNAi formulations and theyare mainly tested in patients with solid tumors (Ref-erences herein [31] and for example clinical trial codeNCT01505153) Yet clinical studies for the treatment ofnon-solid cancers including non-Hodgkinrsquos lymphomas
J Biomed Nanotechnol 10 1751ndash1783 2014 1775
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
and multiple myelomas are ongoing (eg clinical trialcodes NCT01733238 and NCT01435720) Publicationsof the results of a clinical study using lipid nanoparti-cles carrying siRNAs against VEGF and kinesin spindleshowed that trials using the right strategies and combi-nations may be well tolerated less toxic and effectiveagainst advanced stage cancers (here liver metastases inendometrial cancer)208 Additionally studies with some ofthe siRNA carrier non-liposomal particles were reported tobe relatively safe and feasible both in non-human primatesand human120209
Overall data provided here point out to the fact thatnucleic acid nanocarriers have a great potential as optimalcancer drugs Effective carriers that may be synthesizedusing feasible chemistry allowing large scale productionand having reasonably long shelf-lives will surely be avail-able for routine use in clinics in the near future As aconsequence global market size of nano-based pharma-ceuticals is expected to increase exponentially in the com-ing years210
ABBREVIATIONSsiRNA Small interfering RNAshRNA Small hairpin RNAmiRNA Micro RNA
GI GastrointestinalcDNA Complementary DNARNAi RNA interferenceAGO argonauteRISC RNA-Induced Silencing ComplexRdRP RNA-dependent RNA polymerases
hTERT Human telomerase catalytic subunitRMRP RNA processing endoribonucleaseLNA Locked nucleic acids
FANA 2prime-deoxy-2prime-Fluoro--d-arabinonucleicacid
RES Reticuloendothelial systemNPs NanoparticlesEPR Enhanced permeability and retention
PAMAM Poly(amido amine)PEI Polyethyleneimine
PDMAEMA Poly(dimethylaminoethyl methacrylate)RGD Arginylglycylaspartic acidPEG Polyethylene glycolPC PhosphatidylcholinePE Phosphatidylserine
DOPC 12-Oleoyl-sn-Glycero-3-phosphatidyl-choline
DOPE 12-Dioleoyl-sn-Glycero-3-phosphatidyl-ethanolamine
SNALPs Solid nucleic acid lipid particlesLPS Lipopolysaccharides
PLGA Poly-dl-lactide-co-glycolidePLL Poly-L-lysine
DOTAP N -[1-(23-Dioleoyloxy)propyl]-N N N -trimethylammonium methyl-sulfate
PPI Poly-propyleneimineCNTs Carbon nanotubes
SPIONs Superparamagnetic iron oxidenanoparticles
APTES Aminopropyltriethoxy silaneQDs Quantum DotsSCID Severe-combined immuno deficient
mTERT Mouse telomerase catalytic subunitMDR1 Multidrug resistance protein 1
Chk Choline kinasebCD Bacterial cytosine deaminase5-FC 5-fluorocytosine5-FU 5-fluorouracilPLK1 Polo like kinase 1KSP Kinesin spindle proteinXIAP X-linked inhibitor of apoptosis proteinVEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factorreceptor
EGFR Epithelial growth factor receptorEphA2 Tyrosine kinase stimulatesHER2 Human epidermal growth factor receptor 2PSMA Prostate-specific membrane antigenNGR Asn-Gly-Arg peptide
Acknowledgments This work was supported byScientific and Technological Research Council ofTurkey-1001 (TUBITAK-1001 Grant number 112T272)European Molecular Biology Organization (EMBO)Sabanci and Koc Universities D Gozuacik is a recipi-ent of EMBO-SDIG Award A Kosar received TUBITAKIncentive Award D Gozuacik and A Kosar are recipientsof Turkish Academy of Sciences (TUBA) GEBIP AwardH F Yagci-Acar is a recipient of LrsquoOREAL TurkeyNational Fellowship for Women in Science Y Akkocis supported by TUBITAK-BIDEB Scholarship for PhDstudies
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
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1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
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230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
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234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
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242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
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J Biomed Nanotechnol 10 1751ndash1783 2014 1783
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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29 A S Peek and M A Behlke Design of active small interferingRNAs Curr Opin Mol Ther 9 110 (2007)
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33 D V Morrissey J A Lockridge L Shaw K Blanchard K JensenW Breen K Hartsough L Machemer S Radka V JadhavN Vaish S Zinnen C Vargeese K Bowman C S Shaffer L BJeffs A Judge I MacLachlan and B Polisky Potent and persis-tent in vivo anti-HBV activity of chemically modified siRNAs NatBiotechnol 23 1002 (2005)
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35 A Akinc A Zumbuehl M Goldberg E S Leshchiner V BusiniN Hossain S A Bacallado D N Nguyen J Fuller R AlvarezA Borodovsky T Borland R Constien A de Fougerolles J RDorkin K Narayanannair Jayaprakash M Jayaraman M JohnV Koteliansky M Manoharan L Nechev J Qin T RacieD Raitcheva K G Rajeev D W Sah J Soutschek I ToudjarskaH P Vornlocher T S Zimmermann R Langer and D G Ander-son A combinatorial library of lipid-like materials for delivery ofRNAi therapeutics Nat Biotechnol 26 561 (2008)
36 S C Semple A Akinc J Chen A P Sandhu B L Mui C KCho D W Sah D Stebbing E J Crosley E Yaworski I MHafez J R Dorkin J Qin K Lam K G Rajeev K F WongL B Jeffs L Nechev M L Eisenhardt M Jayaraman M KazemM A Maier M Srinivasulu M J Weinstein Q Chen R AlvarezS A Barros S De S K Klimuk T Borland V Kosovrasti W LCantley Y K Tam M Manoharan M A Ciufolini M A TracyA de Fougerolles I MacLachlan P R Cullis T D Madden andM J Hope Rational design of cationic lipids for siRNA deliveryNat Biotechnol 28 172 (2010)
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40 Y Matsumura and H Maeda A new concept for macromoleculartherapeutics in cancer chemotherapy Mechanism of tumoritropicaccumulation of proteins and the antitumor agent smancs CancerRes 46 6387 (1986)
41 T Ishimoto Y Takei Y Yuzawa K Hanai S Nagahara Y TarumiS Matsuo and K Kadomatsu Downregulation of monocytechemoattractant protein-1 involving short interfering RNA atten-uates hapten-induced contact hypersensitivity Mol Ther 16 387(2008)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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43 E Kawata E Ashihara S Kimura K Takenaka K SatoR Tanaka A Yokota Y Kamitsuji M Takeuchi J KurodaF Tanaka T Yoshikawa and T Maekawa Administration of PLK-1 small interfering RNA with atelocollagen prevents the growth ofliver metastases of lung cancer Mol Cancer Ther 7 2904 (2008)
44 H Maeda J Wu T Sawa Y Matsumura and K Hori Tumorvascular permeability and the EPR effect in macromolecular thera-peutics A review J Control Release 65 271 (2000)
45 H Hatakeyama H Akita and H Harashima The polyethyleneg-lycol dilemma Advantage and disadvantage of PEGylation of lipo-somes for systemic genes and nucleic acids delivery to tumorsBiol Pharm Bull 36 892 (2013)
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48 S D Li S Chono and L Huang Efficient gene silencingin metastatic tumor by siRNA formulated in surface-modifiednanoparticles J Control Release 126 77 (2008)
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56 H Tian S Liu J Zhang S Zhang L Cheng C Li X ZhangL Dai P Fan L Dai N Yan R Wang Y Wei and H DengEnhancement of Cisplatin sensitivity in lung cancer xenografts byliposome-mediated delivery of the plasmid expressing small hairpinRNA targeting survivin J Biomed Nanotechnol 8 633 (2012)
57 I R Gilmore S P Fox A J Hollins M Sohail andS Akhtar The design and exogenous delivery of siRNA for post-transcriptional gene silencing J Drug Target 12 315 (2004)
58 I R Gilmore S P Fox A J Hollins and S Akhtar Deliverystrategies for siRNA-mediated gene silencing Curr Drug Deliv3 147 (2006)
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60 B Ozpolat A K Sood and G Lopez-Berestein Nanomedicinebased approaches for the delivery of siRNA in cancer J InternMed 267 44 (2010)
61 S Dokka D Toledo X Shi V Castranova and Y RojanasakulOxygen radical-mediated pulmonary toxicity induced by somecationic liposomes Pharm Res 17 521 (2000)
62 S Spagnou A D Miller and M Keller Lipidic carriers of siRNADifferences in the formulation cellular uptake and delivery withplasmid DNA Biochemistry (Mosc) 43 13348 (2004)
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65 P Liu H Yu Y Sun M Zhu and Y Duan A mPEG-PLGA-b-PLLcopolymer carrier for adriamycin and siRNA delivery Biomaterials33 4403 (2012)
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69 O Meyer D Kirpotin K Hong B Sternberg J W Park M CWoodle and D Papahadjopoulos Cationic liposomes coated withpolyethylene glycol as carriers for oligonucleotides J Biol Chem273 15621 (1998)
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71 C N Landen Jr A Chavez-Reyes C Bucana R Schmandt M TDeavers G Lopez-Berestein and A K Sood Therapeutic EphA2gene targeting in vivo using neutral liposomal small interferingRNA delivery Cancer Res 65 6910 (2005)
72 Z Ma J Li F He A Wilson B Pitt and S Li Cationic lipidsenhance siRNA-mediated interferon response in mice BiochemBiophys Res Commun 330 755 (2005)
73 J Jin K H Bae H Yang S J Lee H Kim Y Kim K M JooS W Seo T G Park and D H Nam In vivo specific delivery of c-Met siRNA to glioblastoma using cationic solid lipid nanoparticlesBioconjug Chem 22 2568 (2011)
74 P Y Chien J Wang D Carbonaro S Lei B Miller S SheikhS M Ali M U Ahmad and I Ahmad Novel cationic cardiolipinanalogue-based liposome for efficient DNA and small interferingRNA delivery in vitro and in vivo Cancer Gene Ther 12 321(2005)
75 A Pal A Ahmad S Khan I Sakabe C Zhang U N Kasidand I Ahmad Systemic delivery of RafsiRNA using cationic car-diolipin liposomes silences Raf-1 expression and inhibits tumorgrowth in xenograft model of human prostate cancer Int J Oncol26 1087 (2005)
76 A Akinc M Goldberg J Qin J R Dorkin C Gamba-VitaloM Maier K N Jayaprakash M Jayaraman K G RajeevM Manoharan V Koteliansky I Rohl E S Leshchiner R Langerand D G Anderson Development of lipidoid-siRNA formulationsfor systemic delivery to the liver Mol Ther 17 872 (2009)
77 S Jiang A A Eltoukhy K T Love R Langer and D GAnderson Lipidoid-coated iron oxide nanoparticles for efficientDNA and siRNA delivery Nano Lett 13 1059 (2013)
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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79 J A MacDiarmid N B Amaro-Mugridge J Madrid-WeissI Sedliarou S Wetzel K Kochar V N Brahmbhatt L PhillipsS T Pattison C Petti B Stillman R M Graham andH Brahmbhatt Sequential treatment of drug-resistant tumors withtargeted minicells containing siRNA or a cytotoxic drug NatBiotechnol 27 643 (2009)
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81 V Gujrati S Kim S H Kim J J Min H E Choy S C Kimand S Jon Bioengineered bacterial outer membrane vesicles ascell-specific drug-delivery vehicles for cancer therapy ACS Nano8 1525 (2014)
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85 K A Howard Delivery of RNA interference therapeutics usingpolycation-based nanoparticles Adv Drug Deliv Rev 61 710(2009)
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Hartmann T Stoger and T H Kissel Polymer-related off-targeteffects in non-viral siRNA delivery Biomaterials 32 2388 (2011)
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95 A C Hunter and S M Moghimi Cationic carriers of genetic mate-rial and cell death A mitochondrial tale Biochim Biophys Acta1797 1203 (2010)
96 K A Woodrow Y Cu C J Booth J K Saucier-Sawyer M JWood and W M Saltzman Intravaginal gene silencing usingbiodegradable polymer nanoparticles densely loaded with small-interfering RNA Nat Mater 8 526 (2009)
97 K Singha R Namgung and W J Kim Polymers in small-interfering RNA delivery Nucleic Acid Ther 21 133 (2011)
98 S Acharya and S K Sahoo PLGA nanoparticles containing var-ious anticancer agents and tumour delivery by EPR effect AdvDrug Deliv Rev 63 170 (2011)
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101 J Wu W Huang and Z He Dendrimers as carriers for siRNAdelivery and gene silencing A review Scientific World Journal2013 630654 (2013)
102 M L Patil M Zhang S Betigeri O Taratula H He andT Minko Surface-modified and internally cationic polyami-doamine dendrimers for efficient siRNA delivery Bioconjug Chem19 1396 (2008)
103 M L Patil M Zhang O Taratula O B Garbuzenko H He andT Minko Internally cationic polyamidoamine PAMAM-OH den-drimers for siRNA delivery Effect of the degree of quaternizationand cancer targeting Biomacromolecules 10 258 (2009)
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106 T Ochiya K Honma F Takeshita and S NagaharaAtelocollagen-mediated drug discovery technology Expert OpinDrug Discov 2 159 (2007)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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127 D Pantarotto R Singh D McCarthy M Erhardt J P BriandM Prato K Kostarelos and A Bianco Functionalized carbonnanotubes for plasmid DNA gene delivery Angew Chem Int EdEngl 43 5242 (2004)
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138 Y Chen W Wang G Lian C Qian L Wang L Zeng C LiaoB Liang B Huang K Huang and X Shuai Development of anMRI-visible nonviral vector for siRNA delivery targeting gastriccancer Int J Nanomedicine 7 359 (2012)
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142 S Li Z Liu F Ji Z Xiao M Wang Y Peng Y Zhang L LiuZ Liang and F Li Delivery of quantum Dot-siRNA nanoplexes inSK-N-SH cells for BACE1 gene silencing and intracellular imag-ing Mol Ther Nucleic Acids 1 e20 (2012)
143 J Zhao X Qiu Z Wang J Pan J Chen and J Han Applica-tion of quantum dots as vectors in targeted survivin gene siRNAdelivery Onco Targets Ther 6 303 (2013)
144 Y Su Y He H Lu L Sai Q Li W Li L Wang P ShenQ Huang and C Fan The cytotoxicity of cadmium based aqueousphasemdashsynthesized quantum dots and its modulation by surfacecoating Biomaterials 30 19 (2009)
145 H Y Yang Y W Zhao Z Y Zhang H M Xiong and S N YuOne-pot synthesis of water-dispersible Ag2S quantum dots withbright fluorescent emission in the second near-infrared windowNanotechnology 24 055706 (2013)
146 G Hong J T Robinson Y Zhang S Diao A L AntarisQ Wang and H Dai In vivo fluorescence imaging with Ag2Squantum dots in the second near-infrared region Angew Chem IntEd Engl 51 9818 (2012)
147 Y Zhang G Hong G Chen F Li H Dai and Q Wang Ag2Squantum dot A bright and biocompatible fluorescent nanoprobe inthe second near-infrared window ACS Nano 6 3695 (2012)
148 I Hocaoglu M N Ccedilizmeciyan R Erdem C Ozen A KurtA Sennaroglu and H Y Acar Development of highly luminescentand cytocompatible near-IR-emitting aqueous Ag2S quantum dotsJ Mater Chem 22 14674 (2012)
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152 W H Kong K H Bae S D Jo J S Kim and T G Park Cationiclipid-coated gold nanoparticles as efficient and non-cytotoxic intra-cellular siRNA delivery vehicles Pharm Res 29 362 (2012)
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1780 J Biomed Nanotechnol 10 1751ndash1783 2014
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
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1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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1782 J Biomed Nanotechnol 10 1751ndash1783 2014
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
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Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
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206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
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Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
155 H Lee D Sung M Veerapandian K Yun and S W Seo PEGy-lated polyethyleneimine grafted silica nanoparticles Enhanced cel-lular uptake and efficient siRNA delivery Anal Bioanal Chem400 535 (2011)
156 X Li Y Chen M Wang Y Ma W Xia and H Gu A mesoporoussilica nanoparticlendashPEIndashfusogenic peptide system for siRNA deliv-ery in cancer therapy Biomaterials 34 1391 (2013)
157 Z Chen M F Penet S Nimmagadda C Li S R Banerjee P TWinnard Jr D Artemov K Glunde M G Pomper and Z MBhujwalla PSMA-targeted theranostic nanoplex for prostate cancertherapy ACS Nano 6 7752 (2012)
158 F Haque D Shu Y Shu L S Shlyakhtenko P G RychahouB M Evers and P Guo Ultrastable synergistic tetravalent RNAnanoparticles for targeting to cancers Nano Today 7 245 (2012)
159 W Wei P P Lv X M Chen Z G Yue Q Fu S Y Liu H Yueand G H Ma Codelivery of mTERT siRNA and paclitaxel bychitosan-based nanoparticles promoted synergistic tumor suppres-sion Biomaterials 34 3912 (2013)
160 S Ganesh A K Iyer D V Morrissey and M M AmijiHyaluronic acid based self-assembling nanosystems for CD44 tar-get mediated siRNA delivery to solid tumors Biomaterials 34 3489(2013)
161 C Dohmen D Edinger T Frohlich L Schreiner U LacheltC Troiber J Radler P Hadwiger H P Vornlocher and E WagnerNanosized multifunctional polyplexes for receptor-mediated siRNAdelivery ACS Nano 6 5198 (2012)
162 S A Jensen E S Day C H Ko L A Hurley J P LucianoF M Kouri T J Merkel A J Luthi P C Patel J I Cutler W LDaniel A W Scott M W Rotz T J Meade D A GiljohannC A Mirkin and A H Stegh Spherical nucleic acid nanoparticleconjugates as an RNAi-based therapy for glioblastoma Sci TranslMed 5 209ra152 (2013)
163 H Arima A Yoshimatsu H Ikeda A Ohyama K MotoyamaT Higashi A Tsuchiya T Niidome Y Katayama K Hattoriand T Takeuchi Folate-PEG-appended dendrimer conjugate withalpha-cyclodextrin as a novel cancer cell-selective siRNA deliverycarrier Mol Pharm 9 2591 (2012)
164 J Wei T Cheang B Tang H Xia Z Xing Z Chen Y FangW Chen A Xu S Wang and J Luo The inhibition of humanbladder cancer growth by calcium carbonateCaIP6 nanocompositeparticles delivering AIB1 siRNA Biomaterials 34 1246 (2013)
165 T Kanazawa K Sugawara K Tanaka S Horiuchi Y Takashimaand H Okada Suppression of tumor growth by systemic delivery ofanti-VEGF siRNA with cell-penetrating peptide-modified MPEG-PCL nanomicelles Eur J Pharm Biopharm 81 470 (2012)
166 M A Rahman A R Amin X Wang J E Zuckerman C HChoi B Zhou D Wang S Nannapaneni L Koenig Z ChenZ G Chen Y Yen M E Davis and D M Shin Systemic deliveryof siRNA nanoparticles targeting RRM2 suppresses head and necktumor growth J Control Release 159 384 (2012)
167 J Guo J R Ogier S Desgranges R Darcy and C OrsquoDriscollAnisamide-targeted cyclodextrin nanoparticles for siRNA deliveryto prostate tumours in mice Biomaterials 33 7775 (2012)
168 M Shen F Gong P Pang K Zhu X Meng C Wu J WangH Shan and X Shuai An MRI-visible non-viral vector for tar-geted Bcl-2 siRNA delivery to neuroblastoma Int J Nanomedicine7 3319 (2012)
169 D Lin Q Jiang Q Cheng Y Huang P Huang S Han S GuoZ Liang and A Dong Polycation-detachable nanoparticles self-assembled from mPEG-PCL-g-SS-PDMAEMA for in vitro and invivo siRNA delivery Acta Biomater 9 7746 (2013)
170 L Zou X Song T Yi S Li H Deng X Chen Z Li Y BaiQ Zhong Y Wei and X Zhao Administration of PLGA nanopar-ticles carrying shRNA against focal adhesion kinase and CD44results in enhanced antitumor effects against ovarian cancer CancerGene Ther 20 242 (2013)
171 T Yin P Wang J Li R Zheng B Zheng D Cheng R Li J Laiand X Shuai Ultrasound-sensitive siRNA-loaded nanobubblesformed by hetero-assembly of polymeric micelles and liposomesand their therapeutic effect in gliomas Biomaterials 34 4532(2013)
172 H J Cho S Chong S J Chung C K Shim and D D Kim Poly-L-arginine and dextran sulfate-based nanocomplex for epidermalgrowth factor receptor (EGFR) siRNA delivery Its application forhead and neck cancer treatment Pharm Res 29 1007 (2012)
173 F Abedini H Hosseinkhani M Ismail A J Domb A R OmarP P Chong P D Hong D S Yu and I Y Farber Cationizeddextran nanoparticle-encapsulated CXCR4-siRNA enhanced corre-lation between CXCR4 expression and serum alkaline phosphatasein a mouse model of colorectal cancer Int J Nanomedicine 7 4159(2012)
174 F Yang W Huang Y Li S Liu M Jin Y Wang L Jia andZ Gao Anti-tumor effects in mice induced by survivin-targetedsiRNA delivered through polysaccharide nanoparticles Biomateri-als 34 5689 (2013)
175 L Chen Y Ding Y Wang X Liu R Babu W Ravis and W YanCodelivery of zoledronic acid and doublestranded RNA from corendashshell nanoparticles Int J Nanomedicine 8 137 (2013)
176 H Jagani J V Rao V R Palanimuthu R C Hariharapura andS Gang A nanoformulation of siRNA and its role in cancer ther-apy In vitro and in vivo evaluation Cell Mol Biol Lett 18 120(2013)
177 L A Tobin Y Xie M Tsokos S I Chung A A Merz M AArnold G Li H L Malech and K F Kwong Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of can-cer cell internalization in vivo Biomaterials 34 2980 (2013)
178 J Shen H Sun P Xu Q Yin Z Zhang S Wang H Yu and Y LiSimultaneous inhibition of metastasis and growth of breast cancerby co-delivery of twist shRNA and paclitaxel using pluronic P85-PEITPGS complex nanoparticles Biomaterials 34 1581 (2013)
179 H Meng W X Mai H Zhang M Xue T Xia S Lin X WangY Zhao Z Ji J I Zink and A E Nel Codelivery of an optimaldrugsiRNA combination using mesoporous silica nanoparticles toovercome drug resistance in breast cancer in vitro and in vivo ACSNano 7 994 (2013)
180 C Zheng M Zheng P Gong J Deng H Yi P Zhang Y ZhangP Liu Y Ma and L Cai Polypeptide cationic micelles mediatedco-delivery of docetaxel and siRNA for synergistic tumor therapyBiomaterials 34 3431 (2013)
181 Q Hu W Li X Hu J Shen X Jin J Zhou G Tang and P KChu Synergistic treatment of ovarian cancer by co-delivery of sur-vivin shRNA and paclitaxel via supramolecular micellar assemblyBiomaterials 33 6580 (2012)
182 Y H Yu E Kim D E Park G Shim S Lee Y B KimC W Kim and Y K Oh Cationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA Eur J Pharm Biopharm 80 268(2012)
183 Z J Deng S W Morton E Ben-Akiva E C Dreaden K EShopsowitz and P T Hammond Layer-by-layer nanoparticles forsystemic codelivery of an anticancer drug and siRNA for potentialtriple-negative breast cancer treatment ACS Nano 7 9571 (2013)
184 X Q Liu M H Xiong X T Shu R Z Tang and J WangTherapeutic delivery of siRNA silencing HIF-1 alpha with micellarnanoparticles inhibits hypoxic tumor growth Mol Pharm 9 2863(2012)
185 J Xiao X Duan Q Yin Z Miao H Yu C Chen Z ZhangJ Wang and Y Li The inhibition of metastasis and growth ofbreast cancer by blocking the NF-kappaB signaling pathway usingbioreducible PEI-basedp65 shRNA complex nanoparticles Bioma-terials 34 5381 (2013)
186 R J Christie Y Matsumoto K Miyata T Nomoto S FukushimaK Osada J Halnaut F Pittella H J Kim N Nishiyama and
J Biomed Nanotechnol 10 1751ndash1783 2014 1781
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
187 S Ganesh A K Iyer F Gattacceca D V Morrissey and M MAmiji In vivo biodistribution of siRNA and cisplatin adminis-tered using CD44-targeted hyaluronic acid nanoparticles J ControlRelease 172 699 (2013)
188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
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Copyright American Scientific Publishers
Anticancer Use of Nanoparticles as Nucleic Acid Carriers Gozuacik et al
K Kataoka Targeted polymeric micelles for siRNA treatment ofexperimental cancer by intravenous injection ACS Nano 6 5174(2012)
187 S Ganesh A K Iyer F Gattacceca D V Morrissey and M MAmiji In vivo biodistribution of siRNA and cisplatin adminis-tered using CD44-targeted hyaluronic acid nanoparticles J ControlRelease 172 699 (2013)
188 H Shen C Rodriguez-Aguayo R Xu V Gonzalez-VillasanaJ Mai Y Huang G Zhang X Guo L Bai G Qin X DengQ Li D R Erm B Aslan X Liu J Sakamoto A Chavez-Reyes H D Han A K Sood M Ferrari and G Lopez-BeresteinEnhancing chemotherapy response with sustained EphA2 silenc-ing using multistage vector delivery Clin Cancer Res 19 1806(2013)
189 W A May S L Lessnick B S Braun M Klemsz B C LewisL B Lunsford R Hromas and C T Denny The Ewingrsquos sarcomaEWSFLI-1 fusion gene encodes a more potent transcriptional acti-vator and is a more powerful transforming gene than FLI-1 MolCell Biol 13 7393 (1993)
190 A L Ramon J R Bertrand H de Martimprey G BernardG Ponchel C Malvy and C Vauthier siRNA associated withimmunonanoparticles directed against cd99 antigen improves geneexpression inhibition in vivo in Ewingrsquos sarcoma J Mol Recognit26 318 (2013)
191 A Tivnan W S Orr V Gubala R Nooney D E WilliamsC McDonagh S Prenter H Harvey R Domingo-Fernandez I MBray O Piskareva C Y Ng H N Lode A M Davidoff andR L Stallings Inhibition of neuroblastoma tumor growth by tar-geted delivery of microRNA-34a using anti-disialoganglioside GD2coated nanoparticles PLoS One 7 e38129 (2012)
192 L Li X Xie J Luo M Liu S Xi J Guo Y Kong M WuJ Gao Z Xie J Tang X Wang W Wei M Yang and M CHung Targeted expression of miR-34a using the T-VISA sys-tem suppresses breast cancer cell growth and invasion Mol Ther20 2326 (2012)
193 Q L Hu Q Y Jiang X Jin J Shen K Wang Y B Li F J XuG P Tang and Z H Li Cationic microRNA-delivering nanovec-tors with bifunctional peptides for efficient treatment of PANC-1xenograft model Biomaterials 34 2265 (2013)
194 M V Yigit S K Ghosh M Kumar V Petkova A KavishwarA Moore and Z Medarova Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrestof lymph node metastasis Oncogene 32 1530 (2013)
195 J R Cubillos-Ruiz J R Baird A J Tesone M R RutkowskiU K Scarlett A L Camposeco-Jacobs J Anadon-Arnillas N MHarwood M Korc S N Fiering L F Sempere and J R Conejo-Garcia Reprogramming tumor-associated dendritic cells in vivousing miRNA mimetics triggers protective immunity against ovar-ian cancer Cancer Res 72 1683 (2012)
196 I A Babar C J Cheng C J Booth X Liang J B WeidhaasW M Saltzman and F J Slack Nanoparticle-based therapy inan in vivo microRNA-155 (miR-155)-dependent mouse model oflymphoma Proc Natl Acad Sci USA 109 E1695 (2012)
197 A G Bader miR-34mdasha microRNA replacement therapy is headedto the clinic Front Genet 3 120 (2012)
198 L Piao M Zhang J Datta X Xie T Su H Li T N Teknos andQ Pan Lipid-based nanoparticle delivery of Pre-miR-107 inhibitsthe tumorigenicity of head and neck squamous cell carcinoma MolTher 20 1261 (2012)
199 Y Wang L Zhang S Guo A Hatefi and L Huang Incorporationof histone derived recombinant protein for enhanced disassemblyof core-membrane structured liposomal nanoparticles for efficientsiRNA delivery J Control Release 172 179 (2013)
200 H Yu Y Zou L Jiang Q Yin X He L Chen Z ZhangW Gu and Y Li Induction of apoptosis in non-small cell lung
cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPAsiRNA complex nanoparticles Biomaterials 34 2738(2013)
201 M Malhotra C Tomaro-Duchesneau S Saha and S Prakash Sys-temic siRNA delivery via peptide-tagged polymeric nanoparticlestargeting PLK1 gene in a mouse xenograft model of colorectal can-cer Int J Biomater 2013 252531 (2013)
202 J Shen Q Meng H Sui Q Yin Z Zhang H Yu and Y Li iRGDConjugated TPGS mediates codelivery of paclitaxel and survivinshRNA for the reversal of lung cancer resistance Mol Pharm(2013) Epub a head of print doi dxdoiorg101021mp400576f
203 Z X Zhao S Y Gao J C Wang C J Chen E Y ZhaoW J Hou Q Feng L Y Gao X Y Liu L R Zhang andQ Zhang Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA deliveryBiomaterials 33 6793 (2012)
204 J Shen R Xu J Mai H C Kim X Guo G Qin Y YangJ Wolfram C Mu X Xia J Gu X Liu Z W Mao M Ferrariand H Shen High capacity nanoporous silicon carrier for systemicdelivery of gene silencing therapeutics ACS Nano 7 9867 (2013)
205 W Ding F Wang J Zhang Y Guo S Ju and H Wang A novellocal anti-colorectal cancer drug delivery system Negative lipidoidnanoparticles with a passive target via a size-dependent patternNanotechnology 24 375101 (2013)
206 B L Davidson and P B McCray Jr Current prospects for RNAinterference-based therapies Nat Rev Genet 12 329 (2011)
207 A C Eifler and C S Thaxton Nanoparticle therapeutics FDAapproval clinical trials regulatory pathways and case study Meth-ods Mol Biol 726 325 (2011)
208 J Tabernero G I Shapiro P M LoRusso A Cervantes G KSchwartz G J Weiss L Paz-Ares D C Cho J R InfanteM Alsina M M Gounder R Falzone J Harrop A C WhiteI Toudjarska D Bumcrot R E Meyers G Hinkle N SvrzikapaR M Hutabarat V A Clausen J Cehelsky S V NochurC Gamba-Vitalo A K Vaishnaw D W Sah J A Gollob andH A Burris 3rd First-in-humans trial of an RNA interferencetherapeutic targeting VEGF and KSP in cancer patients with liverinvolvement Cancer Discov 3 406 (2013)
209 M E Davis J E Zuckerman C H Choi D Seligson A TolcherC A Alabi Y Yen J D Heidel and A Ribas Evidence ofRNAi in humans from systemically administered siRNA via tar-geted nanoparticles Nature 464 1067 (2010)
210 A Daka and D Peer RNAi-based nanomedicines for targeted per-sonalized therapy Adv Drug Deliv Rev 64 1508 (2012)
211 J Li Y Yang and L Huang Calcium phosphate nanoparticleswith an asymmetric lipid bilayer coating for siRNA delivery to thetumor J Control Release 158 108 (2012)
212 T Suma K Miyata Y Anraku S Watanabe R J ChristieH Takemoto M Shioyama N Gouda T Ishii N Nishiyama andK Kataoka Smart multilayered assembly for biocompatible siRNAdelivery featuring dissolvable silica endosome-disrupting polyca-tion and detachable PEG ACS Nano 6 6693 (2012)
213 X Z Yang S Dou Y C Wang H Y Long M H Xiong C QMao Y D Yao and J Wang Single-step assembly of cationiclipid-polymer hybrid nanoparticles for systemic delivery of siRNAACS Nano 6 4955 (2012)
214 Q Yin J Shen Z Zhang H Yu L Chen W Gu and Y Li Multi-functional nanoparticles improve therapeutic effect for breast cancerby simultaneously antagonizing multiple mechanisms of multidrugresistance Biomacromolecules 14 2242 (2013)
215 C Boyer J Teo P Phillips R B Erlich S Sagnella G SharbeenT Dwarte H T Duong D Goldstein T P Davis M Kavallarisand J McCarroll Effective delivery of siRNA into cancer cells andtumors using well-defined biodegradable cationic star polymersMol Pharm 10 2435 (2013)
1782 J Biomed Nanotechnol 10 1751ndash1783 2014
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783
Delivered by Ingenta to SUNY Upstate Medical UniversityIP 5189201181 On Wed 11 May 2016 102245
Copyright American Scientific Publishers
Gozuacik et al Anticancer Use of Nanoparticles as Nucleic Acid Carriers
216 D Lin Q Cheng Q Jiang Y Huang Z Yang S Han Y ZhaoS Guo Z Liang and A Dong Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous sil-ica nanoparticles for efficient siRNA delivery in vitro and in vivoNanoscale 5 4291 (2013)
217 R F Place J Wang E J Noonan R Meyers M ManoharanK Charisse R Duncan V Huang X Wang and L C Li Formu-lation of small activating RNA into lipidoid nanoparticles inhibitsxenograft prostate tumor growth by inducing p21 expression MolTher Nucleic Acids 1 e15 (2012)
218 J S Kim M H Oh J Y Park T G Park and Y S Nam Protein-resistant reductively dissociable polyplexes for in vivo systemicdelivery and tumor-targeting of siRNA Biomaterials 34 2370(2013)
219 E A Ho M Osooly D Strutt D Masin Y Yang H Yan andM Bally Characterization of long-circulating cationic nanoparti-cle formulations consisting of a two-stage PEGylation step for thedelivery of siRNA in a breast cancer tumor model J Pharm Sci102 227 (2013)
220 Y Ding W Wang M Feng Y Wang J Zhou X Ding X ZhouC Liu R Wang and Q Zhang A biomimetic nanovector-mediatedtargeted cholesterol-conjugated siRNA delivery for tumor genetherapy Biomaterials 33 8893 (2012)
221 J Shen Q Yin L Chen Z Zhang and Y Li Co-delivery ofpaclitaxel and survivin shRNA by pluronic P85-PEITPGS complexnanoparticles to overcome drug resistance in lung cancer Biomate-rials 33 8613 (2012)
222 Y Ren H W Cheung G von Maltzhan A Agrawal G SCowley B A Weir J S Boehm P Tamayo A M Karst J F LiuM S Hirsch J P Mesirov R Drapkin D E Root J Lo V FogalE Ruoslahti W C Hahn and S N Bhatia Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovariancancer oncogene ID4 Sci Transl Med 4 147ra12 (2012)
223 M R Kang G Yang R F Place K Charisse H Epstein-BarashM Manoharan and L C Li Intravesical delivery of small acti-vating RNA formulated into lipid nanoparticles inhibits orthotopicbladder tumor growth Cancer Res 72 5069 (2012)
224 Q Yin J Shen L Chen Z Zhang W Gu and Y Li Overcomingmultidrug resistance by co-delivery of Mdr-1 and survivin-targetingRNA with reduction-responsible cationic poly(beta-amino esters)Biomaterials 33 6495 (2012)
225 S J Lee M S Huh S Y Lee S Min S Lee H Koo J U ChuK E Lee H Jeon Y Choi K Choi Y Byun S Y Jeong K ParkK Kim and I C Kwon Tumor-homing poly-siRNAglycol chi-tosan self-cross-linked nanoparticles for systemic siRNA deliveryin cancer treatment Angew Chem Int Ed Engl 51 7203 (2012)
226 Y Yang Y Hu Y Wang J Li F Liu and L Huang Nanoparticledelivery of pooled siRNA for effective treatment of non-small celllung caner Mol Pharm 9 2280 (2012)
227 K M Choi K Kim I C Kwon I S Kim and H J Ahn Systemicdelivery of siRNA by chimeric capsid protein Tumor targeting andRNAi activity in vivo Mol Pharm 10 18 (2013)
228 C A Taylor Z Liu T C Tang Q Zheng S Francis T W WangB Ye J A Lust R Dondero and J E Thompson Modulation ofeIF5A expression using SNS01 nanoparticles inhibits NF-kappaBactivity and tumor growth in murine models of multiple myelomaMol Ther 20 1305 (2012)
229 M Kong X Li C Wang C Ding A Dong Q Duan andZ Shen Tissue distribution and cancer growth inhibition of mag-netic lipoplex-delivered type 1 insulin-like growth factor recep-tor shRNA in nude mice Acta Biochim Biophys Sin (Shanghai)44 591 (2012)
230 J Yang S X Xie Y Huang M Ling J Liu Y Ran Y WangJ B Thrasher C Berkland and B Li Prostate-targeted biodegrad-able nanoparticles loaded with androgen receptor silencing con-structs eradicate xenograft tumors in mice Nanomedicine (Lond)7 1297 (2012)
231 F Pittella K Miyata Y Maeda T Suma S Watanabe Q ChenR J Christie K Osada N Nishiyama and K Kataoka Pancreaticcancer therapy by systemic administration of VEGF siRNA con-tained in calcium phosphatecharge-conversional polymer hybridnanoparticles J Control Release 161 868 (2012)
232 X Liu C Liu E Laurini P Posocco S Pricl F Qu P Rocchiand L Peng Efficient delivery of sticky siRNA and potentgene silencing in a prostate cancer model using a generation5 triethanolamine-core PAMAM dendrimer Mol Pharm 9 470(2012)
233 J Guo W P Cheng J Gu C Ding X Qu Z Yang andC OrsquoDriscoll Systemic delivery of therapeutic small interferingRNA using a pH-triggered amphiphilic poly-L-lysine nanocarrierto suppress prostate cancer growth in mice Eur J Pharm Sci45 521 (2012)
234 J Beloor C S Choi H Y Nam M Park S H Kim A JacksonK Y Lee S W Kim P Kumar and S K Lee Arginine-engraftedbiodegradable polymer for the systemic delivery of therapeuticsiRNA Biomaterials 33 1640 (2012)
235 L Li R Wang D Wilcox X Zhao J Song X Lin W MKohlbrenner S W Fesik and Y Shen Tumor vasculature is akey determinant for the efficiency of nanoparticle-mediated siRNAdelivery Gene Ther 19 775 (2012)
236 J M Li Y Y Wang W Zhang H Su L N Ji and Z WMao Low-weight polyethylenimine cross-linked 2-hydroxypopyl-beta-cyclodextrin and folic acid as an efficient and nontoxic siRNAcarrier for gene silencing and tumor inhibition by VEGF siRNAInt J Nanomedicine 8 2101 (2013)
237 J Conde F Tian Y Hernandez C Bao D Cui K P JanssenM R Ibarra P V Baptista T Stoeger and J M de la FuenteIn vivo tumor targeting via nanoparticle-mediated therapeuticsiRNA coupled to inflammatory response in lung cancer mousemodels Biomaterials 34 7744 (2013)
238 Y Zhang L Peng R J Mumper and L Huang Combina-tional delivery of c-myc siRNA and nucleoside analogs in a sin-gle synthetic nanocarrier for targeted cancer therapy Biomaterials34 8459 (2013)
239 L Zeng J Li Y Wang C Qian Y Chen Q Zhang W WuZ Lin J Liang X Shuai and K Huang Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosisusing a nanomedicine strategy for the effective treatment of pan-creatic cancer Nanomedicine 10 463 (2013)
240 S J Lee J Y Yhee S H Kim I C Kwon and K Kim Biocom-patible gelatin nanoparticles for tumor-targeted delivery of poly-merized siRNA in tumor-bearing mice J Control Release 172 358(2013)
241 X Z Yang J Z Du S Dou C Q Mao H Y Long and J WangSheddable ternary nanoparticles for tumor acidity-targeted siRNAdelivery ACS Nano 6 771 (2012)
242 J B Lee K Zhang Y Y Tam Y K Tam N M Belliveau V YSung P J Lin E LeBlanc M A Ciufolini P S Rennie andP R Cullis Lipid nanoparticle siRNA systems for silencing theandrogen receptor in human prostate cancer in vivo Int J Cancer131 E781 (2012)
243 J Zhou T R Patel M Fu J P Bertram and W M SaltzmanOcta-functional PLGA nanoparticles for targeted and efficientsiRNA delivery to tumors Biomaterials 33 583 (2012)
244 X Huang S Schwind B Yu R Santhanam H WangP Hoellerbauer A Mims R Klisovic A R Walker K KChan W Blum D Perrotti J C Byrd C D Bloomfield M ACaligiuri R J Lee R Garzon N Muthusamy L J Lee andG Marcucci Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles A novel therapeuticstrategy in acute myeloid leukemia Clin Cancer Res 19 2355(2013)
J Biomed Nanotechnol 10 1751ndash1783 2014 1783