Retracted: Recent Trends of Polymer Mediated Liposomal Gene … · 2020. 1. 14. · 3&53"$5&%...

RetractionRetracted Recent Trends of Polymer Mediated LiposomalGene Delivery System

BioMed Research International

Received 3 July 2019 Accepted 3 July 2019 Published 8 August 2019

Copyright copy 2019 BioMed Research International is is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

BioMed Research International has retracted the articletitled ldquoRecent Trends of Polymer Mediated Liposomal GeneDelivery Systemrdquo [1] e article was found to contain asubstantial amount of material from a number of publishedarticles including the following sources

(i) L E van Vlerken T K Vyas and M M AmijildquoPoly(ethylene glycol)-Modified Nanocarriers for Tumor-Targeted and Intracellular Deliveryrdquo Pharmaceutical Re-search vol 24 no 8 pp 1405ndash1414 2007 httpsdoiorg101007s11095-007-9284-6 [2] (cited as [98])

(ii) Daniel A Balazs and WT Godbey ldquoLiposomes forUse in Gene Deliveryrdquo Journal of Drug Delivery vol 2011Article ID 326497 12 pages 2011 httpsdoiorg1011552011326497 [3] (not cited)

(iii) Vladimir P Torchilin ldquoRecent Advances with Lipo-somes as Pharmaceutical Carriersrdquo Nature Reviews DrugDiscovery vol 4 no 2 pp 145ndash160 2005 httpsdoiorg101038nrd1632 [4] (cited as [35])

(iv) Arcadio Chonn and Pieter R Cullis ldquoRecent Ad-vances in Liposome Technologies and eir Applications forSystemic Gene Deliveryrdquo Advanced Drug Delivery Re-views 1998 httpsdoiorg101016S0169-409X(97)00108-7[5] (not cited)

(v) Marika Ruponen Seppo Yla-Herttuala and ArtoUrtti ldquoInteractions of Polymeric and Liposomal Gene Deliv-ery Systems with Extracellular Glycosaminoglycans Physic-ochemical and Transfection Studiesrdquo Biochimica et Biophys-ica Acta Biomembranes vol 1415 no 2 pp 331ndash341 1999httpsdoiorg101016S0005-2736(98)00199-0 [6] (cited as[138])

e authors do not agree to the retraction

References

[1] S K Kundu A R Sharma S S Lee et al ldquoRecent trendsof polymer mediated liposomal gene delivery systemrdquo BioMed

Research International vol 2014 Article ID 934605 15 pages2014

[2] L E van Vlerken T K Vyas and M M Amiji ldquoPoly(ethyleneglycol)-modified nanocarriers for tumor-targeted and intracel-lular deliveryrdquo Pharmaceutical Research vol 24 no 8 pp 1405ndash1414 2007

[3] D A Balazs and W T Godbey ldquoLiposomes for use in genedeliveryrdquo Journal of Drug Delivery vol 2011 Article ID 32649712 pages 2011

[4] K-L Kuo and D-C Tarng ldquoOxidative stress in chronic kidneydiseaserdquo Adaptive Medicine vol 2 no 2 pp 87ndash94 2010

[5] A Chonn and P R Cullis ldquoRecent advances in liposometechnologies and their applications for systemic gene deliveryrdquoAdvanced Drug Delivery Reviews vol 30 no 1-3 pp 73ndash831998

[6] M Ruponen S Yla-Herttuala and A Urtti ldquoInteractions ofpolymeric and liposomal gene delivery systems with extra-cellular glycosaminoglycans Physicochemical and transfectionstudiesrdquo Biochimica et Biophysica Acta (BBA) - Biomembranesvol 1415 no 2 pp 331ndash341 1999

HindawiBioMed Research InternationalVolume 2019 Article ID 8195729 1 pagehttpsdoiorg10115520198195729

RETRACTEDReview Article

Recent Trends of Polymer Mediated LiposomalGene Delivery System

Shyamal Kumar Kundu12 Ashish Ranjan Sharma3 Sang-Soo Lee3

Garima Sharma3 C George Priya Doss4 Shin Yagihara2 Do-Young Kim3

Ju-Suk Nam3 and Chiranjib Chakraborty35

1 Department of Physics School of Basic and Applied Sciences Galgotias University Greater Noida 203201 India2Department of Physics Tokai University Hiratsuka-Shi Kanagawa 259-1292 Japan3 Institute for Skeletal Aging amp Orthopedic Surgery Hallym University-Chuncheon Sacred Heart HospitalChuncheon 200704 Republic of Korea

4Medical Biotechnology Division School of Biosciences and Technology VIT University Vellore Tamil Nadu 632014 India5 Department of Bioinformatics School of Computer Sciences Galgotias University Greater Noida 203201 India

Correspondence should be addressed to Ju-Suk Nam jsnam88hallymackr and Chiranjib Chakraborty drchiranjibyahoocom

Received 9 May 2014 Revised 15 July 2014 Accepted 15 July 2014 Published 27 August 2014

Academic Editor Nagendra K Kaushik

Copyright copy 2014 Shyamal Kumar Kundu et alThis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Advancement in the gene delivery systemhave resulted in clinical successes in gene therapy for patientswith several genetic diseasessuch as immunodeficiency diseases X-linked adrenoleukodystrophy (X-ALD) blindness thalassemia and many more Amongvarious delivery systems liposomal mediated gene delivery route is offering great promises for gene therapy This review is anattempt to depict a portrait about the polymer based liposomal gene delivery systems and their future applications Herein wehave discussed in detail the characteristics of liposome importance of polymer for liposome formulation gene delivery and futuredirection of liposome based gene delivery as a whole

1 Introduction

The gene therapy has shown great promise for the potentialcure of several genetic disorders and appears to possessenormous therapeutic potential Although this news mightseem fresh and innovative the transfer of genetic materialsinto living cells has been tested around the decades In1966 Tatum [1] predicted that the transfection techniquesfor mammalian cells will be advertised as part of the futuremedicine After over 30 years of research the field of genetherapy is offering an acceptable treatment protocol for thecure for human diseases

Studying the basic structure of genes into cells of differentorigins has been a major practice in cellular biology investi-gation In addition to being a powerful research implementgene transfer is a novel idea for gene therapy and is amolecular therapeutic approach for curing inherited and

several other diseases [2 3] Diseases developed because of agenetic constituent can theoretically be corrected by geneticrefinement based on the addition of needed genes Amongthe genetic diseases muscular dystrophy cystic fibrosis andfamilial hypercholesteremia have been studied so far As forcancer most of the mutations acquired are not inherited butare a result of cumulative effect of various external factorsTherefore it is a great challenge in the area of gene therapyto correct these mutations and to repair the gene A geneitself is not able to enter into a cell as it is a large portionof DNA that is bound by several anionic charges A widerange of artificial techniques has been developed and utilizedtime to time for in vitro gene transfer Some techniques ofgene transfer are membrane perturbation by chemicals (ieorganic solvents and detergents) direct DNAmicroinjectionphysical methods (ie mechanical or osmotic method andelectric shocks) and liposomes

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 934605 15 pageshttpdxdoiorg1011552014934605

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2 BioMed Research International

Intent of gene delivery approaches is to introduce geneticmaterial into patientsrsquo cells Subsequent successful genetransfer in these cells will produce a therapeutic proteinthat will counter the cause of disease However the safetyapprehensions and the difficulties related to productionon large scale are the drawbacks that are associated withrecombinant viral vectors [4] which has prompted the searchfor efficient nonimmunogenic and easy to prepare nonviralvector systemsThe effectiveness of amounts of drugs is oftenrestricted by their potential to reach the site of therapeuticeffect In many cases the majority of drugs allocate allover the body with its physicochemical and biochemicalproperties while only a minor amount of a controlled dosereaches the targeted area Therefore emerging drug deliverysystem enhances the pharmaceutical effect of drugs whilereducing its toxicity in vivo which is a challenging taskLipid molecules of biomembranes interacting with watermolecules can control the transport phenomena and proteinfunctions with anisotropic flow ability For formulating lipid-based drug carrier systems a consistent and repeatable explo-ration of their size as well as size allocation is of paramountimportance for the nanocarrierrsquos in-vitro characteristics forexample drug loading capacity aggregation sedimentationand so forth [5 6] A considerable attention has been paidfor liposomal drug delivery systems owing to their specificattractions that is (1) fruitful encapsulation of togethertiny and large molecules (eg antigens) with a wide rangeof hydrophobic levels and pKa values (2) prolonging andtarget release of therapeutic moleculeagent by alteration ofliposome surface and (3) minimization of clinical drug doseand reducing toxicity effects [7 8]

Improvements in lipofection technique by surface mod-ifications with polyethylene glycol (PEG) have facilitatedthe safety from degradation in vivo Surface amendment ofdrug delivery systems with PEG has encountered increasinginterest to enhance biocompatibility [9] increase in systemiccirculation times [10] and change in their biodistribution[11] For example nanoparticles [12] liposomes [13] and alsoadenoviruses [14] have been ldquoPEGylatedrdquo mainly to obtainlong-circulating particulate delivery systems based on theldquostealthrdquo effect In the year 2002 Bhadra et al [15] reviewedthe PEGylation methodology PEGylation of polycations forthe purpose of gene delivery has been realized to block andgraft copolymers [16 17] PEG offers numerous attractivepotential as a liposomal covering and is obtainable in widevariety of molecular weights Due to lack of toxicity it isexcreted easily by the kidneys and also eases for applicationpurpose [18] Modifications of liposomal surfaces with PEGare achieved either by its physical adsorption onto theliposomal surface or its covalent attachment onto premadeliposomes [19]

The primary objective of this review article is to describethe polymer based liposomal gene delivery system and itspotential applications To achieve this objective we have illus-trated the topics in several headings such as characteristics ofliposome importance of polymer for liposome formulationgene delivery and future direction of liposome-based genedelivery

2 Characteristics of Liposome

Innovative studies using liposomes were first performed byBangham et al roughly 50 years ago [20ndash22] From thesestudies it was recognized that phospholipids in aqueoussystems are made up of closed bilayer structures Liposomeshave passed through several practical applications to becomepharmaceutical carrier of choice from just another exoticobject of biophysical research The real breakthroughs inthis area were established during the past 20 years whichwitnessed approval of many liposomal drugs as well asthe presence of different unique biomedical products inpharmaceutical sector Presently several types of liposomesare available for gene delivery system Therefore the devel-opment of the technologies for the liposome delivery systemsis an exciting area having both clinical and economic values

21 Liposomes Can Be Produced by the Self-Assembly In gen-eral liposomes are formed by the self-assembly of dissolvedlipid molecules Lipid molecules contain a hydrophilic headgroup and hydrophobic tails These lipid molecules form anassociation which yields entropically favorable states of lowerfree energy and in some cases appear to form bimolecularlipid leaflets Such leaflets are categorized by hydrophobichydrocarbon tails facing each other to avoid water moleculesand hydrophilic head groups pointing outward to associatewith water molecules [23] At this an argument exists thatthe bilayer formation is still energetically unfavorable as thehydrophobic portion of the molecules is still in contact withwater This difficulty has been solved by forming a vesiclewith closed edges through the curvature of developing bilayermembrane upon itself [24]Therefore the free-energy-drivenself-assembly is steady and has been exploited as powerfulmachinery for liposomes for a particular given system [25]

22 Liposomes Are Spherical Self-Assembling Vesicles withOne or Several Lipid Bilayers Liposomes are spherical self-assembling vesicles formed by one or several lipid bilayersleaving an aqueous core inside The lipid bilayers are com-posed of amphiphilic lipids derived from or based on thestructure of biological membrane lipids The hydrophobicpart of the lipid is designed of two hydrocarbon chains whichnaturally vary from 8 to 18 carbons in length and it canbe either saturated or nonsaturated A membrane with a gelphase (L120573) is made by long and saturated acyl chains resultingin increased stability and rigidity of the liposomes On theother hand the use of short andor unsaturated acyl chainsresults in more fluid liquid crystalline (L120572) bilayer structureExperimentally this gel-liquid crystal (LC) phase transitionis well observed by changing temperature [26 27] Additionof cholesterol into the lipid bilayer minimizes the effectsof membrane permeability and improves the mechanicalstrength of the liposomes Surface charge of the liposome canbe affected strongly by varying the hydrophilic head groupof the lipid which are either zwitterionic [eg phosphatidyl-choline (PC) and phosphatidylethanolamine (PE)] nega-tively charged [eg phosphatidylglycerol (PG)] or positivelycharged [eg 3-trimethylammonium-propane (TAP)] [8] In

RETRACTED

BioMed Research International 3

the water amphiphilic lipids tend to form bilayer structureas they are poorly soluble in water with a critical micelleconcentration (CMC)

23 Hydrophobic Drug Molecules Can Be Entrapped Easilythrough the Lipid Bilayer of Liposomes Hydrophobic drugmolecules can be entrapped passively in the lipid bilayerthrough the preparation of liposomes Such drug moleculesare encapsulated in the aqueous core of the liposome or theaqueous phase between bilayers (in the case of multilamellarvesicles) using passive loadingmethods such as reverse phaseevaporation [28] dehydration-rehydration method [29] oractive loading involving pH-gradient across the liposomemembrane [30 31] Remote filling of doxorubicin into pre-formed liposomes bymeans of ammonium sulfate gradient asa driving force results in the efficient and stable entrapment ofthe drug [32] Some liposomal cancer drugs that are currentlyemployed clinically utilise remote loading such as Caelyxand Myocet loaded with doxorubicin and Daunoxome withdaunorubicin

24 LiposomeDelivery SystemCanBeDeveloped into aVarietyof Sizes Liposomes may exhibit a variety of sizes and mor-phologies contrary for the assembling of lipids or lipid blendssuspended in an aqueous medium [33] The unilamellarvesicle is a common morphology which is analogous to theeukaryotic cellular membrane This vehicle is characterizedby a single bilayer membrane that encapsulates an internalaqueous solution therefore separating it from the external(bulk) solution [34] Both anionic phospholipid and cationicamine head groups are responsible for forming single-walledvesicles Vesicle sizes are covered in the range of nanometerto micrometer Spontaneously formed multilamellar vesicles(MLV) are very heterogeneous in lamellarity and size rangingfrom 500 nm to 5 120583m More sophisticated small unilamellarvesicles (SUV lt100 nm) and large unilamellar vesicles (LUV100ndash800 nm) can be prepared by sonication or extrusion[27 33 35]

Giant or gigantic vesicles also comprise additional mor-phologies such as (i) multilamellar which consists of manyconcentric bilayers (ii) oligolamellar which consists of onlytwo concentric bilayers and (iii) multivesicular which con-sists of various smaller unilamellar vesicles inside of onegiant one With the exception of multilamellar vesicles othermorphologies are very difficult to obtain without highlycontrolled processes of creation [33] Giant vesicles also havethe merit of attention owing to their large sizes ranging from1 120583m tomore than 100 120583m [33]These large vesicles have beenextensively studied andwell characterized so far partially dueto ease of observation [36]

25 Liposome Assemblies A number of assemblies havebeen recognized [37ndash42] during the compaction of polynu-cleotides into liposomal associations Each of such structuresis created in the utmost energetically favorable conformationrelying on the features of the definite lipids used in thesystem [43] Here the structure-packing parameter can beused to recommend the possible shape of the amphiphile

which in turn depends on the ratio of size variables Themain drawbacks pertaining to the use of liposomes are theswift elimination from the blood and trapping of the lipidassemblies by the cells of the reticuloendothelial systempredominantly in the liver A number of improvements arebeing tried to reduce this shortcomings of liposomes

26 Liposome and Surface-Attached Ligands It has beenproposed that the use of targeted liposomes with surface-attached ligands capable of recognizing and binding tocells of interest may help in increasing liposomal drugaccumulation in the desired tissues and organs For exampleimmunoglobulins (Ig) of the IgG class and their fragmentsare extensively used in targetingmoieties that can be attachedto liposomes Nothing has been found to affect the liposomalintegrity or the antibody properties that are bound covalentlyto the liposome surface or by the hydrophobic interactionwith the liposomalmembrane after alterationwith hydropho-bic residues [44] Nevertheless despite improvements in thetargeting efficacy major proportion of immune-liposomesis found accumulated in the liver as a consequence ofinadequate time for the communication between the targetand targeted liposomes Hence a better target accumulationcan only be achieved if liposomes are maintained for longcirculation time in blood stream

Differentmethods have been recommended for achievinglong circulation of liposomes in vivo including coating of theliposomal surfacewith inert biocompatible polymers such asPEG PEG forms a protective layer over the liposomal surfaceand slows down the liposome recognition by opsonins [4546] Long-circulating liposomes are being scrutinized indetail and are extensively used in biomedical in vitro andin vivo studies also leading their way into clinical practices[47 48] A significant role of protecting polymers is becauseof their flexibility which permits comparatively small numberof surface-grafted polymers to create an impermeable layerabove the liposome surface [49 50] Long-circulating lipo-somes exhibit dose-independent nonsaturable log-linearkinetics and increased bioavailability [51]

27 Liposome and Gene Delivery The challenges being facedfor the development of various techniques for liposomalgene delivery systems are not unlike compared to those thatare being faced for liposomal drug delivery systems Thetherapeutic listing of the conservative or gene-based drugs(eg plasmid DNA or RNA transcripts) are enhanced bydelivering more biologically active drug to target cells ortissues to circumvent drug-related toxicities By means ofgene-based drugs the delivery into suitable cells denotes onlya part of the problem A number of intracellular barriers arepresent inmany cell types that can inhibit the biologic activityof gene-based drugs [52 53] It is not very obvious what roleif any liposomes will play in overcoming these intracellularbarriers

28 Liposome and DNA Delivery The liposome based DNAdelivery was recognized as early as late 1970s [54] On theother hand gene-based drugs have presented interesting

RETRACTED


challenges for systemic delivery systems The gene-baseddrugs are highly susceptible to degradation by the nucleasespresent in plasma Although liposomes have the potentialto encapsulate gene-based drugs and prevent inactivation bynucleases but methods used to encapsulate plasmid DNAefficiently are not well defined small liposomes or lipidicDNA particles have only been appreciated The usefulness ofgene-based drugs is absolutely dependent on gaining entryinto the target cell cytosol in an intact formConsequently foreffectiveness of liposomes they must act as integrate agentsthat endorse intracellular delivery With a few exceptions(eg skeletal muscle [55 56] such as hepatocytes [57 58])naked plasmid DNA alone is not taken up very efficientlyby most of the cell types in vivo For certain gene therapyapproaches such as those involving the delivery of suicidegenes systemic gene delivery systemsmust have the potentialto deliver gene-based drugs selectively to specific target cells

Drug loading capacity are achieved either actively (ieafter liposome formation) or passively (ie the drug is encap-sulated during liposome formation) Hydrophobic drugs aredirectly incorporated into liposomes through vesicle forma-tion The magnitude of uptake and retention is controlledby lipid-drug interactions Trapping efficiency of 100 isfrequently attainable but totally relies on the solubility of thedrug in the liposome membrane During vesicle formationthe passive encapsulation of water-soluble drugs depends onthe capability of liposomes to hold aqueous buffer containinga drug suspension easily Trapping efficiency is restricted(usually less than 30) by the trapped volume confined inthe liposomes and drug solubility Additional method toenhance the passive encapsulation of water-soluble drugs isto give an amphipathic nature to the drugs by conjugatingor complexing the drugs to lipids [59 60] Instead water-soluble drugs that have ionizable amine functions are activelyentrapped by employing pH gradients [61] which results intrapping efficiencies approaching 100

Cationic liposomes (lipoplexes) are the most frequentlyused in nonviral gene transfer systems Nevertheless incontact with negatively charged DNA lipid molecules formelectrostatic complexes with DNA In the meantime the pio-neeringwork of Felgner andRingold [62] introduced cationicDOTMADOPE liposomes and numerous other cationiclipids that have been designated Selected lipids have mono-valent head groups for example DOTMA [62] and DOTAP[63] and some others like DOGS and DPPES [64] includemultivalent head groups Cationic lipids may also includea neutral fusogenic lipid dioleoylphosphatidylethanolamine(DOPE) Complexes of cationic lipids with genes are het-erogeneous [65 66] and susceptible to changes in the sur-rounding solution [67] Cationic liposomes have been studiedin vitro in vivo and even in clinical trials [68] but themain difficulty that remains to be resolved is low transfectionefficiency for in vivo applications Although the endosomalbuffering capacity has not been proven directly but due tothe pKa values of their secondary and tertiary amines itis widely believed [64 69ndash72] that polyethyleneimines anddendrimers as well as DOGS lipid may buffer endosomes

3 Importance of Polymer forLiposome Formulation

31 PEG-Liposomes andTheir Uses in Different Diseases Kimand his coworkers revealed that PEGylated lipoplexes yieldamplified transfection efficiencies in the occurrence of serumas compared to liposomal transfection methods The PEGy-lated lipoplexes presented enhanced stabilities and longerpassage times in the blood It is supposed that the PEG formsa steric barrier surrounding lipoplexes which stifles clearancedue to compact macrophagocytes uptake [19] and maypermit the liposome to overcome accumulation problemsover mutually repulsive interactions between PEGmolecules[73] These characteristics facilitate higher transfection effi-ciencies increased bioavailability due to larger availableconcentrations and improved tissue distribution [74] Theseparticles are sometimes denoted as ldquostealth liposomesrdquo sincethey can decrease immune responses and improve circulationtime associated with PEG-modified liposomes By meansof cellular targeting such liposomes lack specificity Shiet al [75] developed the technique to inhibit the endocytosisthrough PEGylation of the lipoplexes that was dependentupon themole fraction of PEG on the liposome It has uniquefunctional groups that are combined with the lipoplexesPEG on the liposome is a proper complex which separatesDNA packing upon incorporation into the cell Based onthese findings a need has arisen for the formation ofPEG-containing liposomes whereby the attached PEG isdetached following endocytosis via a hydrolysable connect-ing molecule Thus current researches on PEG-liposomesare focused on joining the PEG in a removable fashion tofacilitate liposome capture by the cells The PEG coatingis separated during the performance of some pathologicalconditions (decreased pH in tumours) It has been foundthat the enhanced permeability and retention (EPR) causePEG-liposomes accumulation at the target site [76] A newdetachable PEG conjugates have been described by Zalipskyet al [77] wherein the detachment process mainly dependson the mild thiolysis of the dithiobenzylurethane linkedbetween PEG and amino-containing substrates

The delivery of the anticancer agent doxorubicin in PEGliposomes has been found for treatment of solid tumourswith breast-carcinomametastases patients and it resulted in asubsequent improvement in survival [78ndash80] The similar setof indications was targeted by a combination therapy com-prising liposomal doxorubicin and paclitaxel [81] as well asCaelyx (Schering-Plough) (doxorubicin in PEG liposomes)and carboplatin [82] For patients the Caelyx is in Phase IIclinical trials with squamous cell cancer of the head and neck[83] and ovarian cancer [84] Clinical research revealed thatthe effect of doxorubicin in PEG liposomes is very impressiveagainst unresectable hepatocellular carcinoma [85] cuta-neous T-cell lymphoma [86] and sarcoma [87] Liposomallurtotecan was presented to be effective in patients withtopotecan-resistant ovarian cancer [88] Additional signstargeted by liposomal formulations include amphotericin Bfor the treatment of visceral leishmaniasis [89] and liposomalbupivacaine long-acting analgesia [90]

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32 PEG Co-Polymers and Its Assembly Among variousstrategies to provide elements with stealth-shielding incor-porate surface modification with poly(acrylamide) poly(vinyl alcohol) and polysaccharides as well as surface mod-ification with PEG and PEG copolymers was found tobe the most effective methods Wide-spread use of thoseelements was noted in these references [91ndash93] PEG hasa universal assembly of HOndash(CH2CH2O)nndashCH2CH2ndashOHsurrounding a polyether backbone that is chemically inactivewith terminal hydroxyl groups that can be triggered forconjugation to diverse types of polymers and drugs Amphi-philic block copolymers like poloxamers and poloxaminescomprising hydrophilic PEG (or PEO) and hydrophobicPPO [poly(propylene oxide)] are additional forms of PEGproducts These molecules are frequently employed formodification by surface adsorption or entrapment [91 93]The hydrophobic block of PPO anchors onto or entangleswithin the surface of hydrophobic nanoparticles matricesThe poloxamers are commercially available such as Pluronicsfrom BASF Corporation that are a-b-a type triblock copoly-mers (PEOndashPPOndashPEO) poloxamines (or Tetronics) aretetrablock copolymers of PEOndashPPO joined by an ethylenedi-amine bridge ((PEOndashPPO)2ndashxndash(PPOndashPEO)2) [94ndash96] Theequilibrium among hydrophilic and lipophilic segment ofthese copolymers can be adjusted through variations of themolecular weight of ldquoardquo and ldquobrdquo blocks As an examplePluronic F-108 NF a poloxamer 338 molecule has a bulkiermiddle block It has longer side arms containing a = 122and b = 56 These side arms can be compared to PluronicF-68 NF containing poloxamer 188 possessing longer sidearms with a = 76 and b = 30 This dissimilarity can imparta significant modification property such as in the physico-chemical properties of the triblock copolymer that control itsapplicability An instance of surface modification helps in thevariation of poloxamers In this case variation of a b ratiosis important and can be prejudiced for biodistribution ofPCL nanoparticles For example it was observed that 74 ofPluronic F-68 NF and modified nanoparticles gather withinthe liver after 1 hour of administration Whereas only 67 ofPluronic F-108 NF altered nanoparticles accumulated in theliver Moreover modified nanoparticles are less toxic com-pared to unmodified (83) nanoparticles as PEG surface-shielding helps to avoid recognition by the RES system [97]

33 Polymeric Nanoparticles and PEG Chains Surface mod-ification of the polymeric nanoparticles can also be achievedthrough covalent bonding by grafting of PEG chains againstthe nanoparticle surface and likewise through the use ofcopolymers according to which PEG is covalently linked toanother polymer type However PEG modification can alsobe achieved by noncovalent bonding of surface adsorptionor entrapment into the nanoparticle matrix [91] Some ofexamples regarding PEG modification by covalent and non-covalent bonding are presented elsewhere [98] PEG offers animportant advantage for the nontoxic and nonimmunogenicgene transfer which is internally used in humans It proves theevidence for inactive ingredients for oral as well as parenteral

applications which is approved by the USFDA [99] Anextensive range of molecular weights of PEG is available upto several million daltons (Da) It is not biodegradable andinfluences its elimination from the body Yamaoka et al [100]discovered that molecular weight of PEG up to 20 kDa isinitially excreted through the renal system Finally the PEGchains show higher molecular weight transition from urinaryto fecal excretion

34 Molecular Weight Size Shape and Other Parameters ofPEG Chains and Application as Delivery System Dependingon the increase in variations of molecular weight defined bythe number of repeating units PEG chains can be producedin two conformations as either linear or branched chains[101] The defensive performance of PEG is usually due tothe development of thick hydrophilic cloud of long flexiblechains on the colloidal surface that reduces the hydrophobicinteractions with the RES The tethered and chemicallyanchored PEG chains can undergo spatial conformationsConsequently it is avoiding the opsonization of particles viathe macrophages of the RES and thus favors accumulationin liver and spleen Therefore PEG surface modificationenriches the circulation time of the colloidal particles in theblood [92 102 103]

The method of steric hindrance by the PEG modifiedsurface has been thoroughly inspected [93] A structuredshell is formed by the water molecules through hydrogenbonding to the ether oxygen molecules of PEG The proteininteractions are repelled by the strongly bound water thatforms a hydrated film around the particle [104] AdditionallyPEG surface modification also increases the hydrodynamicsize of the particle and reduces its clearance This process isdependent on the molecular size as well as particle volume[105] Eventually these assistants are greatly increasing circu-lation half-life of the particles [91 102 106] The technologyof PEG modification is readily in use for example manyPEG-modified nanocarrier products have been developed fortumor targeting which have been noted elsewhere [98]

Themolecular weight size and shape of the PEG segmentand the kind of linkage used to connect it to the entity ofinterest define the significances of PEGylation in relationto protein adsorption and pharmacokinetic properties likevolume distribution circulation half-life and renal clearanceThe required amount of PEG on the colloidal surface canbe adjusted by altering the molecular weight and molarratio (eg grafting efficiency) of PEG integration whenformulated into colloidal particles Longer PEG chains offerbetter steric influence around the colloidal entity and therelated phenomenon have been seen when the graftingdensity is increased in regard to the PEG chain lengthLonger PEG chainsmay also collapse against the nanoparticlesurface to provide a hydrophilic shield [107] But steric-shielding enhances therapeutics circulation time It is notastonishing that colloidal particles modified with 65molPEG that usually have a longer circulation time (half-life of170min) than particles changed with 25mol PEG (half-lifeof 80min)

RETRACTED


Remarkably branched derivatives of PEG usually havean increased half-life over unbranched PEG chains But at 7or greater mol surface modification both unbranched andbranched derivatives show a similar steric effect There existmany reports to support the pharmacokinetic enhancementsthat have been observed with the use of PEG-modifiednanocarriers over unmodified nanocarriers For examplegelatin nanoparticles which aremodified by PEG chains showincreased circulating half-life from 3 to 15 h over unmodifiedgelatin nanoparticles evidenced by a three-fold reductionin total body clearance [108] Nanocarriers with prolongedcirculation time and 29 to 38 h of half-life are considerablyrequired to enrich tumor tissue a significant enhancementof therapeutic efficacy Likewise a PLGA nanocarrier withPEG-modification also improves the circulation time Only5 of unchanged particles remains in circulation within5min of administration nonetheless as much as 25 of PEGof molecular weight of 5 kDa continues circulation [103]Remarkably PLGA particles that had been modified with20 kDa molecular weight of PEG were reserved up to 50of the circulation within first 5 minutes This observationsupports the increasing stealth properties and decreasingclearance for longer PEG chains

Some nanomaterials such as fractured dendrimer andpolyethyleneimine were also used through in vivo study andare shown to be active in brain and carotid artery [109110] The gene relocation by polyplexes and lipoplexes isless efficient in vivo than in vitro In vitro effects are notpredicted well in case of in vivo gene transfer [111 112]because of the different biological barriers in vivo factorsthat are not present in vitro cell culture systemsThe complexformation of cationic vehicle and DNAmay interact with theextracellular matrix materials after local gene administration(eg in arterial walls vitreous of the eye joints dermisextracellular matrix in tumor etc) and such communicationmay hinder the gene transfer to the targeted cells

Extracellular matrices comprise sulfated proteoglycansthat consist of a core protein covalently linked to one ormore sulfated or carboxylic glycosaminoglycans (GAGs)[113] Negatively charged GAGs such as hyaluronic acid andchondroitin sulfates are long unbranched polysaccharideswith repeated sulphated or carboxylic disaccharide units[112 113] Extracellular polyanionic GAGs might bind thepositively charged DNA complexes and thus disturb theirmobility in tissue as well as interaction with target cells

Previously Xu and Szoka [114] presented some polyan-ions (heparin and dextran sulfate) that release DNA fromDOTAP liposome by binding to the cationic lipids Var-ious polyplexes and lipoplexes are complexed with DNAdifferently and also their mechanisms and efficiencies ingene transfer are not alike [52 62 115ndash117] Consequentlyit has been demonstrated that the interactions betweenvarious DNA complexes and GAGs are far from identicalAdditionally inhibitory effects on transfection of cells are notdependent on DNA release or its relaxation in the complex

Nonviral gene delivery schemes for instance cationicliposomes [118] or synthetic gene carriers such as poly-L-lysine (PLL) [119ndash121] can overcome immunogenicity pro-duced by viral vectors in vitro However in vivo applications

of such gene delivery schemes are greatly destitute dueto poor biocompatibility and rapid degradation [122] TheLipofectin protocol is also one of the best dependable toolsin this category [123] nevertheless it also associated withhigh cytotoxicity [121] To overcome these problems PLLhas been modified by covalently attaching compounds liketyrosinamide triantennary oligosaccharide [124] asialoglyco-protein [118 125ndash127] N-glutarylphosphatidylethanolamine[128] transferrin [120 129] fusogenic peptide [129] antibody[130] lactose [131 132] ormannose [133] for the use as a genedelivery vector The terplex gene delivery system consistingof plasmid DNA low density lipoprotein and stearyl-PLLhas been reported to improve the transfection efficiency [134]Wolfert et al [135] and Kabanov et al [136] developed the A-B type block polycations as carriers for oligonucleotide andgene delivery For these carriers one hydrophilic polymerregion for example PEG is combined with PLL This blockcopolymer forms a complex with DNA maintaining a lowcytotoxicity comparable to the cation alone but with highsolubility It also increases the transfection efficiency in cellsfor example in 293 cells (human primary embryonal kidneycells) Such results are strongly motivating to develop anew series of polymer carriers like methoxy PEG-graftedPLL (PEG-g-PLL) carriers named comb-shaped PEG-g-PLLcopolymers Choi et al [137] found that the comb-shapedpolymer had a 5- to 30-fold increase in transfection efficiencycompared to PLL on Hep G2 cells They also found thatplasmid DNAPEG-g-PLL complexes enter the cells throughan endocytosis mechanism

4 Gene Delivery

41 Gene Delivery as a Whole Cationic polymers play acrucial role for the development of gene transfer agents dueto their extraordinarily good potential to condense DNA[138] The polycation-induced DNA condensation is usuallyexpected to be an entropy-driven process [139] The complexformation of high MW polycations with DNA is thermo-dynamically preferred over the complexation with low MWcationsThe change of the entropy during complex formationis much higher if new counterion of the DNA is large andreleases a huge number of low MW counterions As a resultthe development of liposome-based gene delivery systemsuses polycations to condense the DNA This polymerDNAcomplex is encapsulated by a liposome formulation leadingto a liposome entrapped polycation condensed DNA [140] Acomparable approach was to incorporate the polymerDNAcomplexes in biodegradable nanospheres and microspheresfor controlled release of the complex [141] Lipid moleculesare the conserved entities for the formation of liposomewhich has a head group and hydrophobic hydrocarbon tailregions linked through a backbone linker of glycerol [142]Cationic lipids generally interact with a positive chargethrough one or more amines which are present in thepolar head group The presence of positively charged aminesenables binding with anions for example those seen inDNAThus accumulations of energetic contribution by forces likeVan der Waals and electrostatic binding lead to the creation

RETRACTED


of liposome and also partially dictate the shapes attained bythem [43] Due to the polyanionic nature of DNA cationicand neutral lipids are usually used for gene delivery even ifthe application of anionic liposomes has been fairly limited tothe delivery of additional therapeutic macromolecules [143]

A large amount of effort has been made to delivercomplexes composed of nucleic acid and liposome to targetcells organs andor tissues accurately with different deliverysystem (Figure 1) Ligands (having affinity to cell surfacereceptors) are usually attached to PEG and then to thecationic or anionic carriers Owing to shielding the positivecharge of cationic complexes bymeans of PEG the delivery toa specific cell surface receptor is accomplished Neverthelessgene expression is usually lower in the target cell thanusing the nonspecific delivery of the cationic complex PEGis unable to ldquodeshieldrdquo upon contact with the target cellsurface although PEGylation shields the positive charge oncationic complexes Therefore the PEGylated complexes arenot capable of utilizing critical charge interactions for optimaltransfection into cells This loss of positive charge on thesurface causes transfection of fewer cells First the half-life of complexes was increased by the use of PEGylationfor the circulation and also to circumvent uptake in thelung Conversely this technology also abolishes the abilityto transfect efficiently to the cells The transfer of PEGylatedcomplexes into cells occurs predominantly through the endo-cytic pathway Subsequent deprivation of the DNA has beenobserved in lysosomes It is considered that maintenanceof sufficient positive charge on the surface of complexes isnecessary to drive cell entry by direct fusion Templeton[144] produced targeted delivery of the complexes withoutthe use of PEG and even tried to maintain the overall positivecharge It was achieved either through ionic interactions orcovalent attachments of Fab fragments monoclonal antibod-ies proteins partial proteins peptide mimetics peptidessmall molecules and drugs to the surface of the complexesafter mixing These ligands obviously enhanced the entryof complexes into the cell either by direct fusion or bycompetently binding to the targeted cell surface receptorsNovel approaches of adding ligands to the complexes fortargeted delivery may further increase the gene expressionlevels in the targeted cells after transfection For this reasonTempleton [144] designed targeted liposomal delivery sys-tems that could predominantly enter cells by direct fusionrather than endocytic pathway

42 Gene Delivery through Liposome Basis and Status Thereported lipid-polymer hybrid systems include DNA precon-densed with polycations followed by coating with cationicliposomes [145 146] anionic liposomes [147] or amphiphilicpolymers with or without helper lipids [148] Linear poly-L-lysine protamine histone and various synthetic polypep-tides have been used as the DNA condensation componentthe polyplexes formed are then coated with a lipid layer DNAis better protected in these lipid-wrapping polyplexes In vitro[145 146] the 3-part structure seems to be more efficientin transfection than lipid-DNA complexes and is true evenfor in vivo efficiency [149] An extensive reorganization of

the lipid membranes takes place following the initial contactwhen anionic complexes and DOPE-rich liposomes areadded to DNA polycation complexes which results in lipid-polymer-DNA complexes with anionic lipid coatings [147]This method overcomes the surface charge issue associatedwith cationic lipid-polymer-DNA complexes The receptor-mediated targeting is made possible by reducing cytotoxicityof the complexes without interferingwith nonspecific charge-charge interaction A parallel approach also resulted in afunctional complex that can be used for targeted gene deliv-ery using amphipathic peptide derivatives as DNA packingagents and a bulk of neutral helper lipid to prepare DNAcomplexes by the detergent dialysis method [150] Latelynumerous aspects related to lipid composition the presenceof shielding PEG-lipid conjugates and the nature of chemicalbonding that contributes to the biodegradability of the PEG-lipid conjugates in cells have been thoroughly studied [151152] Such ideas are significantly not the same from theoriginal lipid-DNA andor polymer-DNA complexes andcertainly deserve further exploration particularly in the areaof in vivo targeted gene delivery

Human telomeric DNA is composed of typical thousandsof TTAGGG repeats completed with 100ndash200 nucleotides at31015840-end overhang [153] These DNA sequences in vitro canform four-stranded helical structures called G-quadruplexes[154ndash157] assembled from the stacking of multiple G3G3G3Gtetrads [158] G-quadruplexes at telomeres have been noticedin vivo [159] and their presence in living cells can beregulated by a number of proteins [159 160] IntramolecularG-quadruplexes created by human telomeric DNA sequencesare promising anticancer targets [161 162] because the for-mation of such structures by the telomeric 31015840-end overhanginhibits the activity of telomerase [163 164] an enzymeessential for the proliferation of most human cancer cells[165] Biological macromolecules in living cells function ina crowded intracellular environment [166ndash168] Molecularcrowding may perhaps affect the structure stability andactivity of biomolecules [166ndash168]Many groups used circulardichroism (CD) spectra to interpret structural alterations ofG-quadruplexes under molecular crowding situations [169ndash175] Miyoshi et al [170] reported that molecular crowdingsimulated by PEG induces conformational development ofan Oxytricha telomeric sequence from an antiparallel to aparallel-stranded G-quadruplex Similarly PEG was shownto induce conformational development in a human telom-eric sequence [171 174] and it has been recommendedthat 40 (wv) PEG bring conformational switch of thissequence from an antiparallel to a parallel-stranded G-quadruplex [174] Under some circumstance such as undermolecular crowding the role of hydration onG-quadruplexeswas discussed in the work of Miyoshi et al [172] usingdifferent carbohydrate cosolutes and of Vorlıckova et al[173] using ethanol cosolute A recent work by Miller et al[176] showed that 50 (vv) of acetonitrile could induceconformational development in a human telomeric sequenceand hydration is necessary for determining the shape of G-quadruplex However the G-quadruplex conformationmadein this condition [176] was not identical to the parallel formobserved in the crystalline state [177] Heddi and Phan [178]

RETRACTED


(i) (ii)

Hydrophobic tail

Hydrophilic head

(a)

Gene added

Released genefrom liposome

Nucleus

Surface modified

Multiple copy preparation

(b)

Figure 1 Structure of liposome and schematic representation of the polymer modified liposomal gene delivery (a) structure of liposomeand its different phases (i) gel phase and (ii) liquid crystalline phase (b) schematic representation of the polymer modified liposomal genevehicle preparation and release process after the delivery in the cell

found that different G-quadruplex shape may change into apropeller-shaped G-quadruplex Study reported conversionof four different G-quadruplex conformations to a propeller-type parallel-stranded G-quadruplex in potassium- (K+-)containing crowded solution due to depletion of water Theyalso observed complex level of arrangement in extremelywater-depleted condition solutions containing high levels ofPEG concentration

Liang et al [179] prepared cationic polymeric liposomes(CPLs) with lipid bilayer structure having high thermalstability provided by polymeric surfactants of quaternized(carboxymethyl) chitosan attached to different carbon chains(namely dodecyl tetradecyl hexadecyl and octadecyl)

The gene delivery can be achieved through tetradecyl-quaternized (carboxymethyl) chitosan (TQCMC) CPLs hav-ing a suitable size of about 184 nm 120577 potentials of about27mV and productivity for synthesis of TQCMCwith weightyield of 131 in different cancer cell lines It is resolvedthat the CPLs are favorable gene delivery schemes thatmight be used to target different cancers The transfectionof internalized polyplexes depends on the cell type and thekind of polymer used It has been reported that the clathrin-coated pit pathway is the main route of transfection forlinear polyethylenimine (PEI) polyplexes [180] BranchedPEI polyplexes appear to facilitate transfection via boththe clathrin-dependent and lipid-raft-dependent pathways

RETRACTED


However both pathways are involved in HeLa cells with theformer being more pronounced [180] In A549 and HeLacells [181] PEI polyplexes are internalized by both pathwaysbut polyplexes taken up by clathrin-mediated endocytosisare degraded in lysosomes while those entering cells viacaveolae are successful in transfection [181] van der Aaet al [182] showed that in COS-7 cells blocking caveolae-mediated uptake causes an almost complete inhibition of PEIand pDMAEMA polyplex-mediated gene expression whileinternalization proceeds by both the clathrin and caveolae-mediated pathways However the use of a specific inhibitor offluid-phase endocytosis designated that this route is involvedin internalization of PEI-25-DNAcomplexes and transfectionin CHO-K1 and HeLa cells [183] Hatakeyama et al [184]recently found a multifunctional envelope-type nanodevice(MEND) to be used as a novel nonviral gene delivery systemThe modification of PEG that is PEGylation is an appropri-atemethod for attaining a longer passage time for the transferofMEND to a tumor through the improved permeability andretention (EPR) effect PEGylation helps to strongly inhibitcellular uptake and endosomal escape which could otherwiseresult in significant loss of activity of the delivery systemThisstudy described the developments and the applications ofMENDand various strategies based on the control of both thepharmacokinetics and cell trafficking basically intracellulartrafficking during the cellular uptake process and endosomaldischarge which occurred to overcome the PEG dilemmaIn response to the intracellular environment and the tumormicroenvironment the separation of PEG from carriers wasachieved to improve cellular uptake and endosomal escape

5 Future Direction

The field gene therapy is making excellent progress Manygene therapies are showing very significant result and arein clinical trials Some instances of gene therapies are inthe management of haemophilia B and lipoprotein lipasescarcity [185 186] However there are some hazards asso-ciated with the polymer mediated liposomal gene deliveryvectors and thus future researches focused on making safergene delivery system are required More advanced polymermediated liposomal gene delivery vectors are required forsite specific deliveries So that it can be utilized for specificdiseases through definite routes as well as for exact tissuesStill some studies are needed to improve the efficacy of thepolymermediated liposomal gene delivery system for clinicalapplications Parallel to this a newer polymer mediatedliposomal gene delivery system is required for reducingobserved drug toxicities Finally a cost effective and cheapergene therapy can help maximize not only the people from thedeveloped countries but also the people from the developingworld

6 Conclusion

A wide variety of gene delivery systems has already beentechnologically advanced and many such systems are in thegrowing phases for the therapy of genetic diseases [187] It has

been observed that the polymer structure has a strong effecton the shape of the lipidDNA complexes The transfectionof polyplexes within the cell is influenced by the cell typeand the kind of polymer used Biological macromolecules inliving cells function in a crowded intracellular environmentand such crowding might affect the structure stabilityand activity of biomolecules Cationic polymer plays a keyrole in the development of gene transfer agents because oftheir well-defined potential to condense DNA Large anddiffusive complexes with positive surface charge are madeusing polymers with many short PEG blocks Such polymersusing a long PEG blocks can self-assemble into small andcompact condensates of lower surface charge Howevera high positive 120577-potential of the complexes can cause arobust erythrocyte aggregation and haemolysis Cytotoxicitymonitored with fibroblasts has a function of the degree ofPEGylation independent of the molecular weight of the PEGAppropriate in vitro gene expression is realized with thepolymer that created large complexes with a large surfacecharge and a low toxicity profile as it is found for the polymerwith several PEG blocks

Conflict of Interests

The authors declare no conflict of interests

Authorsrsquo Contribution

All authors contributed equally

Acknowledgments

This research was supported by a grant of the Korea HealthTechnology RampD Project through the Korea Health IndustryDevelopment Institute (KHIDI) funded by the Ministry ofHealth ampWelfare Republic of Korea (HI12C1265)

References

[1] E L Tatum ldquoMolecular biology nucleic acids and the futureof medicinerdquo Perspectives in Biology and Medicine vol 10 no 1pp 19ndash32 1966

[2] T Friedmann ldquoProgress toward human gene therapyrdquo Sciencevol 244 no 4910 pp 1275ndash1281 1989

[3] P L Felgner and G Rhodes ldquoGene therapeuticsrdquo Nature vol349 no 6307 pp 351ndash352 1991

[4] R C Mulligan ldquoThe basic science of gene therapyrdquo Science vol260 no 5110 pp 926ndash932 1993

[5] A D Bangham M M Standish and J C Watkins ldquoDiffusionof univalent ions across the lamellae of swollen phospholipidsrdquoJournal of Molecular Biology vol 13 no 1 pp 238ndash252 1965

[6] L D Mayer P R Cullis and M B Bally ldquoThe use oftransmembrane pH gradient-driven drug encapsulation inthe pharmacodynamic evaluation of liposomal doxorubicinrdquoJournal of Liposome Research vol 4 no 1 pp 529ndash553 1994

[7] D D Lasic ldquoRecent developments in medical applications ofliposomes sterically stabilized liposomes in cancer therapy andgene delivery in vivordquo Journal of Controlled Release vol 48 no2-3 pp 203ndash222 1997

RETRACTED


[8] A S Ulrich ldquoBiophysical aspects of using liposomes as deliveryvehiclesrdquo Bioscience Reports vol 22 no 2 pp 129ndash150 2002

[9] A Kidane G C Lantz S Jo and K Park ldquoSurface modificationwithPEO-containing triblock copolymer for improved biocom-patibility in vitro and ex vivo studiesrdquo Journal of BiomaterialsScience Polymer Edition vol 10 no 10 pp 1089ndash1105 1999

[10] C Monfardini and F M Veronese ldquoStabilization of substancesin circulationrdquo Bioconjugate Chemistry vol 9 no 4 pp 418ndash450 1998

[11] E T M Dams P Laverman W J G Oyen et al ldquoAcceleratedblood clearance and altered biodistribution of repeated injec-tions of sterically stabilized liposomesrdquo Journal of Pharmacologyand Experimental Therapeutics vol 292 no 3 pp 1071ndash10792000

[12] M T Peracchia E Fattal D Desmaele et al ldquoStealth PEGylatedpolycyanoacrylate nanoparticles for intravenous administra-tion and splenic targetingrdquo Journal of Controlled Release vol 60no 1 pp 121ndash128 1999

[13] M C Woodle ldquoControlling liposome blood clearance bysurface-grafted polymersrdquo Advanced Drug Delivery Reviewsvol 32 no 1-2 pp 139ndash152 1998

[14] C R OrsquoRiordan A Lachapelle C Delgado et al ldquoPEGylationof adenovirus with retention of infectivity and protectionfrom neutralizing antibody in vitro and in vivordquo Human GeneTherapy vol 10 no 8 pp 1349ndash1358 1999

[15] D Bhadra S Bhadra P Jain and N K Jain ldquoPegnology areview of PEG-ylated systemsrdquo Pharmazie vol 57 no 1 pp 5ndash29 2002

[16] A V Kabanov and V A Kabanov ldquoInterpolyelectrolyte andblock ionomer complexes for gene delivery physico-chemicalaspectsrdquo Advanced Drug Delivery Reviews vol 30 no 1ndash3 pp49ndash60 1998

[17] P Lemieux S V Vinogradov C L Gebhart et al ldquoBlock andgraft copolymers and Nanogel(TM) copolymer networks forDNA delivery into cellrdquo Journal of Drug Targeting vol 8 no2 pp 91ndash105 2000

[18] J M Metselaar P Bruin L W T De Boer et al ldquoA novel familyof L-amino acid-based biodegradable polymerlipid conjugatesfor the development of long-circulating liposomeswith effectivedrug-targeting capacityrdquo Bioconjugate Chemistry vol 14 no 6pp 1156ndash1164 2003

[19] M L Immordino F Dosio and L Cattel ldquoStealth liposomesreview of the basic science rationale and clinical applicationsexisting and potentialrdquo International Journal of Nanomedicinevol 1 no 3 pp 297ndash315 2006

[20] A D Bangham and R W Horne ldquoNegative staining ofphospholipids and their structural modification by surface-active agents as observed in the electron microscoperdquo Journalof Molecular Biology vol 8 no 5 pp 660ndash668 1964

[21] R W Horne A D Bangham and V P Whittaker ldquoNegativelystained lipoprotein membranesrdquo Nature vol 200 no 4913article 1340 1963

[22] A D Bangham and R W Horne ldquoAction of saponin onbiological cell membranesrdquo Nature vol 196 no 4858 pp 952ndash953 1962

[23] D-G Margineanu ldquoEquilibrium and non-equilibriumapproaches in biomembrane thermodynamicsrdquo Archives Inter-nationales de Physiologie et de Biochimie vol 95 no 5 pp381ndash422 1987

[24] S Svetina and B Zeks ldquoShape behavior of lipid vesicles as thebasis of some cellular processesrdquo Anatomical Record vol 268no 3 pp 215ndash225 2002

[25] M Shimomura and T Sawadaishi ldquoBottom-up strategy ofmaterials fabrication a new trend in nanotechnology of softmaterialsrdquoCurrent Opinion in Colloid and Interface Science vol6 no 1 pp 11ndash16 2001

[26] AM D Houslay and K K Stanley EdsDynamics of BiologicalMembranes Wiley Interscience Publications John Wiley ampSons New York NY USA 1982

[27] S K Kundu S G ChoeW Yamamoto R Kita and S YagiharaldquoDielectric relaxation and dynamic light scattering study ofliposome in the asqueous solutionrdquo inMaterial Research SocietySymposium Proceedings vol 1019 pp FF04ndashFF08 2007

[28] F Szoka Jr andD Papahadjopoulos ldquoProcedure for preparationof liposomes with large internal aqueous space and high captureby reverse-phase evaporationrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 75 no9 pp 4194ndash4198 1978

[29] R L Shew and D W Deamer ldquoA novel method for encapsula-tion of macromolecules in liposomesrdquo Biochimica et BiophysicaActa Biomembranes vol 816 no 1 pp 1ndash8 1985

[30] L D Mayer M B Bally and P R Cullis ldquoUptake of adriamycininto large unilamellar vesicles in response to a pH gradientrdquoBiochimica et Biophysica ActamdashBiomembranes vol 857 no 1pp 123ndash126 1986

[31] S H Hwang Y Maitani X Qi K Takayama and T NagaildquoRemote loading of diclofenac insulin and fluorescein isoth-iocyanate labeled insulin into liposomes by pH and acetategradient methodsrdquo International Journal of Pharmaceutics vol179 no 1 pp 85ndash95 1999

[32] E M Bolotin R Cohen L K Bar et al ldquoAmmonium sulfategradients for efficient and stable remote loading of amphipathicweak bases into liposomes and ligandoliposomesrdquo Journal ofLiposome Research vol 4 no 1 pp 455ndash479 1994

[33] A Jesorka and O Orwar ldquoLiposomes technologies and analyt-ical applicationsrdquoAnnual Review of Analytical Chemistry vol 1no 1 pp 801ndash832 2008

[34] D Lasic Liposomes From Physics to Applications ElsevierAmsterdam The Netherlands 1993

[35] V P Torchilin ldquoRecent advances with liposomes as pharmaceu-tical carriersrdquo Nature Reviews Drug Discovery vol 4 no 2 pp145ndash160 2005

[36] S Svetina ldquoShape behavior of lipid vesicles as the basis of somecellular processesrdquo Anatomical Record vol 268 no 3 pp 215ndash225 2002

[37] C Tros de Ilarduya Y Sun andN Duzgunes ldquoGene delivery bylipoplexes and polyplexesrdquo European Journal of PharmaceuticalSciences vol 40 no 3 pp 159ndash170 2010

[38] I Koltover T Salditt and C Safinya ldquoPhase diagram sta-bility and overcharging of lamellar cationic lipid- DNA self-assembled complexesrdquo Biophysical Journal vol 77 no 2 pp915ndash924 1999

[39] B Sternberg ldquoNew structures in complex formation betweenDNA and cationic liposomes visualized by freeze-fractureelectron microscopyrdquo FEBS Letters vol 356 no 2-3 pp 361ndash366 1994

[40] I Koltover T Salditt J O Radler andC R Safinya ldquoAn invertedhexagonal phase of cationic liposome-DNA complexes relatedto DNA release and deliveryrdquo Science vol 281 no 5373 pp 78ndash81 1998

[41] J O Radler I Koltover T Salditt and C R Safinya ldquoStruc-ture of DNA-cationic liposome complexes DNA intercalationin multilamellar membranes in distinct interhelical packingregimesrdquo Science vol 275 no 5301 pp 810ndash814 1997

RETRACTED


[42] J Gustafsson G Arvidson G Karlsson and M AlmgrenldquoComplexes between cationic liposomes andDNAvisualized bycryo-TEMrdquo Biochimica et Biophysica ActamdashBiomembranes vol1235 no 2 pp 305ndash312 1995

[43] J N Israelachvili Intermolecular and Surface Forces AcademicPress London UK 2nd edition 1991

[44] V P Torchilin ldquoLiposomes as targetable drug carriersrdquo CriticalReviews in Therapeutic Drug Carrier Systems vol 2 no 1 pp65ndash115 1985

[45] A L Klibanov K Maruyama V P Torchilin and L HuangldquoAmphipathic polyethyleneglycols effectively prolong the circu-lation time of liposomesrdquo The FEBS Letters vol 268 no 1 pp235ndash237 1990

[46] G Blume and G Cevc ldquoMolecular mechanism of the lipid vesi-cle longevity in vivordquo Biochimica et Biophysica Acta Biomem-branes vol 1146 no 2 pp 157ndash168 1993

[47] A A Gabizon ldquoPegylated liposomal doxorubicin metamor-phosis of an old drug into a new form of chemotherapyrdquo CancerInvestigation vol 19 no 4 pp 424ndash436 2001

[48] FMartin andD Lasic Eds Stealth Liposomes CRC Press BocaRaton Fla USA 1995

[49] V P Torchilin V G Omelyanenko M I Papisov et al ldquoPoly(ethylene glycol) on the liposome surface on the mechanism ofpolymer-coated liposome longevityrdquo Biochimica et BiophysicaActa vol 1195 no 1 pp 11ndash20 1994

[50] V P Torchilin and V S Trubetskoy ldquoWhich polymers canmakenanoparticulate drug carriers long-circulatingrdquo AdvancedDrug Delivery Reviews vol 16 no 2-3 pp 141ndash155 1995

[51] T M Allen and C Hansen ldquoPharmacokinetics of stealth versusconventional liposomes effect of doserdquoBiochimica et BiophysicaActamdashBiomembranes vol 1068 no 2 pp 133ndash141 1991

[52] J Zabner A J Fasbender T Moninger K A Poellinger andMJ Welsh ldquoCellular and molecular barriers to gene transfer by acationic lipidrdquo Journal of Biological Chemistry vol 270 no 32pp 18997ndash19007 1995

[53] M E Dowty P Williams G Zhang J E Hagstrom and J AWolff ldquoPlasmid DNA entry into postmitotic nuclei of primaryrat myotubesrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 92 no 10 pp 4572ndash45761995

[54] P Hug and R G Sleight ldquoLiposomes for the transformationof eukaryotic cellsrdquo Biochimica et Biophysica ActamdashMolecularBasis of Disease vol 1097 no 1 pp 1ndash17 1991

[55] J A Wolff R W Malone P Williams G Acsadi A Jani andP L Felgner ldquoDirect gene transfer into mouse muscle in vivordquoScience vol 247 no 4949 pp 1465ndash1468 1990

[56] J A Wolff M E Dowty S Jiao et al ldquoExpression of nakedplasmids by cultured myotubes and entry of plasmids into Ttubules and caveolae of mammalian skeletal musclerdquo Journal ofCell Science vol 103 no 4 pp 1249ndash1259 1992

[57] M Yoshida R I Mahato K Kawabata Y Takakura and MHashida ldquoDisposition characteristics of plasmid DNA in thesingle-pass rat liver perfusion systemrdquoPharmaceutical Researchvol 13 no 4 pp 599ndash603 1996

[58] M A Hickman R W Malone K Lehmann-Bruinsma et alldquoGene expression following direct injection of DNA into liverrdquoHuman Gene Therapy vol 5 no 12 pp 1477ndash1483 1994

[59] M van Borssum-Waalkes M van Galen H Morselt B Stern-berg and G L Scherphof ldquoIn vitro stability and cytostaticactivity of liposomal formulations of 5-fluoro-29-deox-yuridineand its diacylated derivativesrdquo Biochimica et Biophysica Actavol 1148 no 1 pp 161ndash172 1993

[60] O Zelphati E Wagner and L Leserman ldquoSynthesis and anti-HIV activity of thiocholesteryl-coupled phosphodiester anti-sense oligonucleotides incorporated into immunoliposomesrdquoAntiviral Research vol 25 no 1 pp 13ndash25 1994

[61] L D Mayer T M Madden M B Bally and P R Cullis ldquopHgradient-mediated drug entrapment in liposomesrdquo in LiposomeTechnology G Gregoriadis Ed vol 2 CRC Press Boca RatonFla USA 2nd edition 1993

[62] P L Felgner and G M Ringold ldquoCationic liposome-mediatedtransfectionrdquo Nature vol 337 no 6205 pp 387ndash388 1989

[63] R Leventis and J R Silvius ldquoInteractions of mammalian cellswith lipid dispersions containing novel metabolizable cationicamphiphilesrdquoBiochimica et BiophysicaActa Biomembranes vol1023 no 1 pp 124ndash132 1990

[64] J P Behr B Demeneix J P Loeffler and J Perez-Mutul ldquoEffi-cient gene transfer into mammalian primary endocrine cellswith lipopolyamine-coated DNArdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 86 no18 pp 6982ndash6986 1989

[65] I Jaaskelainen J Monkkonen and A Urtti ldquoOligonucleotide-cationic lipid interactions a physicochemical studyrdquoBiochimicaet Biophysica Acta vol 1195 no 1 pp 115ndash123 1994

[66] J Zabner A J Fasbender T Moninger K A Poellinger andMJ Welsh ldquoCellular and molecular barriers to gene transfer by acationic lipidrdquoThe Journal of Biological Chemistry vol 270 no32 pp 18997ndash19007 1995

[67] I Jaaskelainen B Sternberg J Monkkonen and A UrttildquoPhysicochemical and morphological properties of complexesmade of cationic liposomes and oligonucleotidesrdquo InternationalJournal of Pharmaceutical vol 167 no 1-2 pp 191ndash203 1998

[68] G J Nabel E G Nabel Z Yang et al ldquoDirect gene transfer withDNA-liposome complexes in melanoma expression biologicactivity and lack of toxicity in humansrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 90 no 23 pp 11307ndash11311 1993

[69] O Boussif F LezoualCrsquoH M A Zanta et al ldquoA versatile vectorfor gene and oligonucleotide transfer into cells in culture and invivo polyethyleniminerdquo Proceedings of the National Academy ofSciences of the United States of America vol 92 no 16 pp 7297ndash7301 1995

[70] M X Tang C T Redemann and F C Szoka Jr ldquoIn vitro genedelivery by degraded polyamidoamine dendrimersrdquo Bioconju-gate Chemistry vol 7 no 6 pp 703ndash714 1996

[71] J Haensler and F C Szoka Jr ldquoPolyamidoamine cascadepolymers mediate efficient transfection of cells in culturerdquoBioconjugate Chemistry vol 4 no 5 pp 372ndash379 1993

[72] M X Tang and F C Szoka ldquoThe influence of polymerstructure on the interactions of cationic polymers with DNAandmorphology of the resulting complexesrdquoGeneTherapy vol4 no 8 pp 823ndash832 1997

[73] D Needham T J McIntosh and D D Lasic ldquoRepulsiveinteractions and mechanical stability of polymer-grafted lipidmembranesrdquo Biochimica et Biophysica Acta vol 1108 no 1 pp40ndash48 1992

[74] M DeCastro Y Saijoh and G C Schoenwolf ldquoOptimizedcationic lipid-based gene delivery reagents for use in developingvertebrate embryosrdquo Developmental Dynamics vol 235 no 8pp 2210ndash2219 2006

[75] F Shi L Wasungu A Nomden et al ldquoInterference of poly(eth-ylene glycol)-lipid analogues with cationic-lipid-mediateddelivery of oligonucleotides role of lipid exchangeability and

RETRACTED


non-lamellar transitionsrdquo Biochemical Journal vol 366 no 1pp 333ndash341 2002

[76] H Maeda T Sawa and T Konno ldquoMechanism of tumor-targeted delivery of macromolecular drugs including the EPReffect in solid tumor and clinical overview of the prototypepolymeric drug SMANCSrdquo Journal of Controlled Release vol74 no 1ndash3 pp 47ndash61 2001

[77] S Zalipsky M Qazen J A Walker II N Mullah Y P Quinnand S K Huang ldquoNew detachable poly(ethylene glycol) con-jugates Cysteine-cleavable lipopolymers regenerating naturalphospholipid diacyl phosphatidylethanolaminerdquo BioconjugateChemistry vol 10 no 5 pp 703ndash707 1999

[78] Z Symon A Peyser D Tzemach et al ldquoSelective delivery ofdoxorubicin to patients with breast carcinoma metastases bystealth liposomesrdquo Cancer vol 86 no 1 pp 72ndash78 1999

[79] A T Perez G H Domenech C Frankel and C L VogelldquoPegylated liposomal doxorubicin (Doxil) for metastatic breastcancer the Cancer Research Network Inc experiencerdquo CancerInvestigation vol 20 supplement 2 pp 22ndash29 2002

[80] J A OShaughnessy ldquoPegylated liposomal doxorubicin in thetreatment of breast cancerrdquo Clinical Breast Cancer vol 4 no 5pp 318ndash328 2003

[81] M Schwonzen C M Kurbacher and P Mallmann ldquoLiposomaldoxorubicin andweekly paclitaxel in the treatment ofmetastaticbreast cancerrdquo Anti-Cancer Drugs vol 11 no 9 pp 681ndash6852000

[82] A Goncalves A C Braud F Viret et al ldquoPhase I study ofpegylated liposomal doxorubicin (Caelyx) in combination withcarboplatin in patients with advanced solid tumorsrdquoAnticancerResearch vol 23 no 4 pp 3543ndash3548 2003

[83] K J Harrington C Lewanski A D Northcote et al ldquoPhase IIstudy of pegylated liposomal doxorubicin (Caelyx) as inductionchemotherapy for patients with squamous cell cancer of thehead and neckrdquo European Journal of Cancer vol 37 no 16 pp2015ndash2022 2001

[84] S R D Johnston and M E Gore ldquoCaelyx phase II studiesin ovarian cancerrdquo European Journal of Cancer vol 37 nosupplement 9 pp S8ndashS14 2001

[85] M Schmidinger C Wenzel G J Locker et al ldquoPilot study withpegylated liposomal doxorubicin for advanced or unresectablehepatocellular carcinomardquoTheBritish Journal of Cancer vol 85no 12 pp 1850ndash1852 2001

[86] U Wollina R Dummer N H Brockmeyer et al ldquoMulticenterstudy of pegylated liposomal doxorubicin in patients withcutaneous T-cell lymphomardquo Cancer vol 98 no 5 pp 993ndash1001 2003

[87] K M Skubitz ldquoPhase II trial of pegylated-liposomal doxoru-bicin (Doxil) in sarcomardquo Cancer Investigation vol 21 no 2pp 167ndash176 2003

[88] M V Seiden F Muggia A Astrow et al ldquoA phase II studyof liposomal lurtotecan (OSI-211) in patients with topotecanresistant ovarian cancerrdquo Gynecologic Oncology vol 93 no 1pp 229ndash232 2004

[89] S Sundar T K Jha C PThakur M Mishra V P Singh and RBuffels ldquoSingle-dose liposomal amphotericin B in the treatmentof visceral leishmaniasis in India a multicenter studyrdquo ClinicalInfectious Diseases vol 37 no 6 pp 800ndash804 2003

[90] G J Grant Y Barenholz E M Bolotin et al ldquoA novelliposomal bupivacaine formulation to produce ultralong-actinganalgesiardquo Anesthesiology vol 101 no 1 pp 133ndash137 2004

[91] D E Owens III and N A Peppas ldquoOpsonization biodis-tribution and pharmacokinetics of polymeric nanoparticlesrdquoInternational Journal of Pharmaceutics vol 307 no 1 pp 93ndash102 2006

[92] F M Veronese and G Pasut ldquoPEGylation successful approachto drug deliveryrdquoDrug Discovery Today vol 10 no 21 pp 1451ndash1458 2005

[93] J M Harris Poly(ethylene glycol) Chemistry Biotechnical andBiomedical Applications Plenum Press New York NY USA1992

[94] M L Adams A Lavasanifar and G S Kwon ldquoAmphiphilicblock copolymers for drug deliveryrdquo Journal of PharmaceuticalSciences vol 92 no 7 pp 1343ndash1355 2003

[95] N KumarM N V Ravikumar and A J Domb ldquoBiodegradableblock copolymersrdquoAdvancedDrugDelivery Reviews vol 53 no1 pp 23ndash44 2001

[96] M Yokoyama ldquoBlock copolymers as drug carriersrdquo CriticalReviews inTherapeutic Drug Carrier Systems vol 9 no 3-4 pp213ndash248 1992

[97] D B Shenoy and M M Amiji ldquoPoly(ethylene oxide)-modifiedpoly(120576-caprolactone) nanoparticles for targeted delivery oftamoxifen in breast cancerrdquo International Journal of Pharmaceu-tics vol 293 no 1-2 pp 261ndash270 2005


[99] United States Food and Drug Administration httpwwwfdagovDrugsdefaulthtm

[100] T Yamaoka Y Tabata and Y Ikada ldquoDistribution and tissueuptake of poly(ethylene glycol) with differentmolecular weightsafter intravenous administration to micerdquo Journal of Pharma-ceutical Sciences vol 83 no 4 pp 601ndash606 1994

[101] C Monfardini O Schiavon P Caliceti M Morpurgo JM Harris and F M Veronese ldquoA branched monomethoxy-poly(ethylene glycol) for protein modificationrdquo BioconjugateChemistry vol 6 no 1 pp 62ndash69 1995

[102] M Hamidi A Azadi and P Rafiei ldquoPharmacokinetic conse-quences of pegylationrdquo Drug Delivery vol 13 no 6 pp 399ndash409 2006

[103] R Gref R Gref Y Minamitake et al ldquoBiodegradable long-circulating polymeric nanospheresrdquo Science vol 263 no 5153pp 1600ndash1603 1994

[104] R Gref A Domb P Quellec et al ldquoThe controlled intra-venous delivery of drugs using PEG-coated sterically stabilizednanospheresrdquo Advanced Drug Delivery Reviews vol 16 no 2-3pp 215ndash233 1995

[105] S M Moghimi H Hedeman I S Muir L Illum and S SDavis ldquoAn investigation of the filtration capacity and the fateof large filtered sterically-stabilized microspheres in rat spleenrdquoBiochimica et Biophysica Acta vol 1157 no 3 pp 233ndash240 1993

[106] S M Moghimi A C Hunter and J C Murray ldquoLong-circulating and target-specific nanoparticles theory to prac-ticerdquo Pharmacological Reviews vol 53 no 2 pp 283ndash318 2001

[107] S Mao M Neu O Germershaus et al ldquoInfluence of polyethy-lene glycol chain length on the physicochemical and biologicalproperties of poly(ethylene imine)-graft-poly(ethylene glycol)block copolymerSiRNA polyplexesrdquo Bioconjugate Chemistryvol 17 no 5 pp 1209ndash1218 2006

RETRACTED


[108] S Kommareddy and M Amiji ldquoBiodistribution and pharma-cokinetic analysis of long-circulating thiolated gelatin nanopar-ticles following systemic administration in breast cancer-bearing micerdquo Journal of Pharmaceutical Sciences vol 96 no2 pp 397ndash407 2007

[109] B Abdallah A Hassan C Benoist D Goula J P Behr andB A Demeneix ldquoA powerful nonviral vector for in vivo genetransfer into the adult mammalian brain polyethyleniminerdquoHuman Gene Therapy vol 7 no 16 pp 1947ndash1954 1996

[110] M P Turunen M O Hiltunen M Ruponen et al ldquoEfficientadventitial gene delivery to rabbit carotid artery with cationicpolymer-plasmid complexesrdquoGeneTherapy vol 6 no 1 pp 6ndash11 1999

[111] N K Egilmez Y Iwanuma and R B Bankert ldquoEvaluationand optimization of different cationic liposome formulationsfor in vivo gene transferrdquo Biochemical and Biophysical ResearchCommunications vol 221 no 1 pp 169ndash173 1996

[112] S Yla-Herttuala H Sumuvuori K Karkola M Mottonen andT Nikkari ldquoGlycosaminoglycans in normal and atherosclerotichuman coronary arteriesrdquo Laboratory Investigation vol 54 no4 pp 402ndash407 1986

[113] T NWight D K Heinegard andV C Hascall ldquoProteoglycansstructure and functionrdquo in Cell Biology of Extracellular MatrixE D Hay Ed pp 45ndash78 Plenum Press New York NY USA1991

[114] Y Xu and F C Szoka Jr ldquoMechanism of DNA release fromcationic liposomeDNA complexes used in cell transfectionrdquoBiochemistry vol 35 no 18 pp 5616ndash5623 1996

[115] J-P Behr B Demeneix J-P Loeffler and J Perez-Mutul ldquoEffi-cient gene transfer into mammalian primary endocrine cellswith lipopolyamine-coated DNArdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 86 no18 pp 6982ndash6986 1989

[116] O Boussif F Lezoualch M A Zanta et al ldquoA versatile vectorfor gene and oligonucleotide transfer into cells in culture and invivo polyethyleniminerdquo Proceedings of the National Academy ofSciences of the United States of America vol 92 no 16 pp 7297ndash7301 1995


[118] H M Temin ldquoSafety considerations in somatic gene therapy ofhuman disease with retrovirus vectorsrdquo Human Gene Therapyvol 1 no 2 pp 111ndash123 1990

[119] G Y Wu and C H Wu ldquoReceptor-mediated gene delivery andexpression in vivordquoThe Journal of Biological Chemistry vol 263no 29 pp 14621ndash14624 1988

[120] E Wagner M Zenke M Cotten H Beug and M L BirnstielldquoTransferrin-polycation conjugates as carriers for DNA uptakeinto cellsrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 87 no 9 pp 3410ndash3414 1990

[121] H Farhood R Bottega R M Epand and L HuangldquoEffect of cationic cholesterol derivatives on gene transfer andprotein kinase C activityrdquo Biochimica et Biophysica ActamdashBiomembranes vol 1111 no 2 pp 239ndash246 1992

[122] N J Caplen EW FWAlton PGMiddleton et al ldquoLiposome-mediatedCFTR gene transfer to the nasal epitheliumof patientswith cystic fibrosisrdquo Nature Medicine vol 1 no 3 pp 39ndash461995

[123] J H Felgner R Kumar C N Sridhar et al ldquoEnhanced genedelivery and mechanism studies with a novel series of cationic

lipid formulationsrdquo Journal of Biological Chemistry vol 269 no4 pp 2550ndash2561 1994

[124] M S Wadhwa D L Knoell A P Young and K G Rice ldquoTar-geted gene delivery with a low molecular weight glycopeptidecarrierrdquo Bioconjugate Chemistry vol 6 no 3 pp 283ndash291 1995

[125] G Y Wu and C H Wu ldquoReceptor-mediated in vitro genetransformation by a soluble DNA carrier systemrdquo The Journalof Biological Chemistry vol 262 no 10 pp 4429ndash4432 1987

[126] C H Wu J M Wilson and G Y Wu ldquoTargeting genesdelivery and persistent expression of a foreign gene drivenby mammalian regulatory elements in vivordquo The Journal ofBiological Chemistry vol 264 no 29 pp 16985ndash16987 1989

[127] H C Chiou M V Tangco S M Levine et al ldquoEnhancedresistance to nuclease degradation of nucleic acids complexed toasialoglycoprotein-polylysine carriersrdquo Nucleic Acids Researchvol 22 no 24 pp 5439ndash5446 1994

[128] X Zhou A L Klibanov and L Huang ldquoLipophilic polylysinesmediate efficient DNA transfection in mammalian cellsrdquoBiochimica et Biophysica Acta vol 1065 no 1 pp 8ndash14 1991

[129] E Wagner C Plank K Zatloukal M Cotten and M L Birn-stiel ldquoInfluenza virus hemagglutinin HA-2 N-terminal fuso-genic peptides augment gene transfer by transferrin-polylysine-DNA complexes toward a synthetic virus-like gene-transfervehiclerdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 89 no 17 pp 7934ndash7938 1992

[130] V S Trubetskoy V P Torchilin S J Kennel and L HuangldquoUse ofN-terminalmodified poly(L-lysine)-antibody conjugateas a carrier for targeted gene delivery in mouse lung endothelialcellsrdquo Bioconjugate Chemistry vol 3 no 4 pp 323ndash327 1992

[131] P Midoux C Mendes A Legrand et al ldquoSpecific gene transfermediated by lactosylated poly-L-lysine into hepatoma cellsrdquoNucleic Acids Research vol 21 no 4 pp 871ndash878 1993

[132] D Martinez-Fong J E Mullersman A F Purchio J Armen-dariz-Borunda and A Martinez-Hernandez ldquoNonenzymaticglycosylation of poly-L-lysine a new tool for targeted genedeliveryrdquo Hepatology vol 20 no 6 pp 1602ndash1608 1994

[133] P Erbacher M Bousser J Raimond M Monsigny PMidoux and A C Roche ldquoGene transfer by DNAglycosylatedpolylysine complexes into human blood monocyte-derivedmacrophagesrdquo Human Gene Therapy vol 7 no 6 pp 721ndash7291996

[134] J Kim A Maruyama T Akaike and S W Kim ldquoIn vitrogene expression on smoothmuscle cells using a terplex deliverysystemrdquo Journal of Controlled Release vol 47 no 1 pp 51ndash591997

[135] M A Wolfert E H Schacht V Toncheva K Ulbrich ONazarova and L W Seymour ldquoCharacterization of vectors forgene therapy formed by self-assembly of DNA with syntheticblock co-polymersrdquo Human Gene Therapy vol 7 no 17 pp2123ndash2133 1996

[136] A V Kabanov S V Vinogradov Y G Suzdaltseva and VY Alakhov ldquoWater-soluble block polycations as carriers foroligonucleotide deliveryrdquo Bioconjugate Chemistry vol 6 no 6pp 639ndash643 1995

[137] Y H Choi F Liu J Kim Y K Choi J S Park and S W KimldquoPolyethylene glycol-grafted poly-L-lysine as polymeric genecarderrdquo Journal of Controlled Release vol 54 no 1 pp 39ndash481998

[138] M Ruponen S Yla-Herttuala and A Urtti ldquoInteractions ofpolymeric and liposomal gene delivery systems with extra-cellular glycosaminoglycans Physicochemical and transfection

RETRACTED


studiesrdquo Biochimica et Biophysica Acta Biomembranes vol 1415no 2 pp 331ndash341 1999

[139] T Bronich A V Kabanov and L A Marky ldquoA thermodynamiccharacterization of the interaction of a cationic copolymer withDNArdquo Journal of Physical Chemistry B vol 105 no 25 pp6042ndash6050 2001

[140] S Chesnoy and L Huang ldquoDNA condensed by polycations andlipids for gene transferrdquo STP Pharma Sciences vol 9 no 1 pp5ndash12 1999

[141] Y Capan B H Woo S Gebrekidan S Ahmed and P PdeLuca ldquoPreparation and characterization of poly (DL-lactide-co-glycolide) microspheres for controlled release of poly(L-lysine) complexed plasmidDNArdquoPharmaceutical Research vol16 no 4 pp 509ndash513 1999

[142] P P Karmali and A Chaudhuri ldquoCationic liposomes as non-viral carriers of genemedicines resolved issues open questionsand future promisesrdquoMedicinal Research Reviews vol 27 no 5pp 696ndash722 2007

[143] E Mayhew and D Papajadjopoulos ldquoTherapeutic applicationsof liposomesrdquo in Liposomes M J Ostro Ed pp 289ndash341Marcel Dekker New York NY USA 1983

[144] N S Templeton ldquoCationic liposome-mediated gene delivery invivordquo Bioscience Reports vol 22 no 2 pp 283ndash295 2002

[145] X Gao and L Huang ldquoPotentiation of cationic liposome-mediated gene delivery by polycationsrdquo Biochemistry vol 35no 3 pp 1027ndash1036 1996

[146] F L Sorgi S Bhattacharya and L Huang ldquoProtamine sulfateenhances lipid-mediated gene transferrdquoGeneTherapy vol 4 no9 pp 961ndash968 1997

[147] R J Lee and L Huang ldquoFolate-targeted anionic liposome-entrapped polylysine-condensed DNA for tumor cell-specificgene transferrdquo Journal of Biological Chemistry vol 271 no 14pp 8481ndash8487 1996

[148] L K Lee C L Williams D Devore and C M RothldquoPoly(propylacrylic acid) enhances cationic lipid-mediateddelivery of antisense oligonucleotidesrdquo Biomacromolecules vol7 no 5 pp 1502ndash1508 2006

[149] S Li and L Huang ldquoIn vivo gene transfer via intravenousadministration of cationic lipid-protamine-DNA (LPD) com-plexesrdquo Gene Therapy vol 4 no 9 pp 891ndash900 1997

[150] E A Murphy A J Waring S M Haynes and K J LongmuirldquoCompaction of DNA in an anionic micelle environment fol-lowed by assembly into phosphatidylcholine liposomesrdquoNucleicAcids Research vol 28 no 15 pp 2986ndash2992 2000

[151] E A Murphy A J Waring J C Murphy R C Willson andK J Longmuir ldquoDevelopment of an effective gene deliverysystem a study of complexes composed of a peptide-basedamphiphilic DNA compaction agent and phospholipidrdquoNucleicAcids Research vol 29 no 17 pp 3694ndash3704 2001

[152] K J Longmuir S M Haynes M E Dickinson J C Murphy RC Willson and A J Waring ldquoOptimization of a peptidenon-cationic lipid gene delivery system for effective microinjectioninto chicken embryo in vivordquo Molecular Therapy vol 4 no 1pp 66ndash74 2001

[153] V L Makarov Y Hirose and J P Langmore ldquoLong G tailsat both ends of human chromosomes suggest a C stranddegradation mechanism for telomere shorteningrdquo Cell vol 88no 5 pp 657ndash666 1997

[154] F W Smith and J Feigon ldquoQuadruplex structure of Oxytrichatelomeric DNA oligonucleotidesrdquoNature vol 356 no 6365 pp164ndash168 1992

[155] J T Davis ldquoG-quartets 40 years later from 51015840-GMP to molecu-lar biology and supramolecular chemistryrdquoAngewandte ChemieInternational Edition vol 43 no 6 pp 668ndash698 2004

[156] D J Patel A T Phan andVKuryavyi ldquoHuman telomere onco-genic promoter and 51015840-UTR G-quadruplexes diverse higherorder DNA and RNA targets for cancer therapeuticsrdquo NucleicAcids Research vol 35 no 22 pp 7429ndash7455 2007

[157] S Neidle ldquoThe structures of quadruplex nucleic acids and theirdrug complexesrdquo Current Opinion in Structural Biology vol 19no 3 pp 239ndash250 2009

[158] M Gellert M N Lipsett and D R Davies ldquoHelix formation byguanylic acidrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 48 no 12 pp 2013ndash20181962

[159] K Paeschke T Simonsson J Postberg D Rhodes and H JLipps ldquoTelomere end-binding proteins control the formation ofG-quadruplex DNA structures in vivordquo Nature Structural andMolecular Biology vol 12 no 10 pp 847ndash854 2005

[160] N Maizels ldquoDynamic roles for G4 DNA in the biology ofeukaryotic cellsrdquo Nature Structural and Molecular Biology vol13 no 12 pp 1055ndash1059 2006

[161] D Sun BThompson B E Cathers et al ldquoInhibition of humantelomerase by a G-Quadruplex-Interactive compoundrdquo Journalof Medicinal Chemistry vol 40 no 14 pp 2113ndash2116 1997

[162] J L Mergny and C Helene ldquoG-quadruplex DNA a target fordrug designrdquoNatureMedicine vol 4 no 12 pp 1366ndash1367 1998

[163] A M Zahler J R Williamson T R Cech and D MPrescott ldquoInhibition of telomerase by G-quartet DNA struc-turesrdquo Nature vol 350 no 6320 pp 718ndash720 1991

[164] L Oganesian I K Moon T M Bryan and M B JarstferldquoExtension of G-quadruplexDNAby ciliate telomeraserdquo EMBOJournal vol 25 no 5 pp 1148ndash1159 2006

[165] N W Kim M A Piatyszek K R Prowse et al ldquoSpecificassociation of human telomerase activity with immortal cellsand cancerrdquo Science vol 266 no 5193 pp 2011ndash2015 1994

[166] S B Zimmerman and S O Trach ldquoEstimation of macro-molecule concentrations and excluded volume effects for thecytoplasm of Escherichia colirdquo Journal ofMolecular Biology vol222 no 3 pp 599ndash620 1991

[167] R J Ellis and A P Minton ldquoCell biology join the crowdrdquoNature vol 425 pp 27ndash28 2003

[168] H Zhou G Rivas and A P Minton ldquoMacromolecular crowd-ing and confinement biochemical biophysical and potentialphysiological consequencesrdquo Annual Review of Biophysics vol37 pp 375ndash397 2008

[169] D Miyoshi and N Sugimoto ldquoMolecular crowding effects onstructure and stability of DNArdquo Biochimie vol 90 no 7 pp1040ndash1051 2008

[170] D Miyoshi A Nakao and N Sugimoto ldquoMolecular crowdingregulates the structural switch of the DNA G-quadruplexrdquoBiochemistry vol 41 no 50 pp 15017ndash15024 2002

[171] J Li J J Correia L Wang J O Trent and J B Chaires ldquoNot socrystal clear the structure of the human telomereG-quadruplexin solution differs from that present in a crystalrdquo Nucleic AcidsResearch vol 33 no 14 pp 4649ndash4659 2005

[172] D Miyoshi H Karimata and N Sugimoto ldquoHydration reg-ulates thermodynamics of G-quadruplex formation undermolecular crowding conditionsrdquo Journal of the AmericanChem-ical Society vol 128 no 24 pp 7957ndash7963 2006

[173] M Vorlıckova K Bednarova I Kejnovska and J KyprldquoIntramolecular and intermolecular guanine quadruplexes of

RETRACTED


DNA in aqueous salt and ethanol solutionsrdquo Biopolymers vol86 no 1 pp 1ndash10 2007

[174] Y Xue Z Kan Q Wang et al ldquoHuman telomeric DNA formsparallel-stranded intramolecular G-quadruplex in K+ solutionunder molecular crowding conditionrdquo Journal of the AmericanChemical Society vol 129 no 36 pp 11185ndash11191 2007

[175] P Balagurumoorthy S K Brahmachari DMohantyM BansalandV Sasisekharan ldquoHairpin and parallel quartet structures fortelomeric sequencesrdquo Nucleic Acids Research vol 20 no 15 pp4061ndash4067 1992

[176] M C Miller R Buscaglia J B Chaires A N Lane andJ O Trent ldquoHydration is a major determinant of the G-quadruplex stability and conformation of the human telomere31015840 sequence of d(AG 3(TTAG3)3)rdquo Journal of the AmericanChemical Society vol 132 no 48 pp 17105ndash17107 2010

[177] G N Parkinson M P H Lee and S Neidle ldquoCrystal structureof parallel quadruplexes from human telomeric DNArdquo Naturevol 417 no 6891 pp 876ndash880 2002

[178] B Heddi and A T Phan ldquoStructure of human telomeric DNAin crowded solutionrdquo Journal of the American Chemical Societyvol 133 no 25 pp 9824ndash9833 2011

[179] X Liang X Li J Chang Y Duan and Z Li ldquoPropertiesand evaluation of quaternized chitosanlipid cation polymericliposomes for cancer-targeted gene deliveryrdquo Langmuir vol 29no 27 pp 8683ndash8693 2013

[180] K von Gersdorff N N Sanders R Vandenbroucke S C deSmedt E Wagner and M Ogris ldquoThe internalization routeresulting in successful gene expression depends on both cell lineandpolyethylenimine polyplex typerdquoMolecularTherapy vol 14no 5 pp 745ndash753 2006

[181] J Rejman A Bragonzi and M Conese ldquoRole of clathrin- andcaveolae-mediated endocytosis in gene transfer mediated bylipo- and polyplexesrdquoMolecularTherapy vol 12 no 3 pp 468ndash474 2005

[182] M A E M van der Aa U S Huth S Y Hafele et al ldquoCellularuptake of cationic polymer-DNA complexes via caveolae plays apivotal role in gene transfection in COS-7 cellsrdquo PharmaceuticalResearch vol 24 no 8 pp 1590ndash1598 2007

[183] H Hufnagel P Hakim A Lima and F Hollfelder ldquoFluid phaseendocytosis contributes to transfection of DNA by PEI-25rdquoMolecular Therapy vol 17 no 8 pp 1411ndash1417 2009

[184] H Hatakeyama H Akita and H Harashima ldquoThe polyethyl-eneglycol dilemma advantage and disadvantage of PEGylationof liposomes for systemic genes and nucleic acids delivery totumorsrdquo Biological and Pharmaceutical Bulletin vol 36 no 6pp 892ndash899 2013

[185] C S Manno V R Arruda G F Pierce et al ldquoSuccessfultransduction of liver in hemophilia by AAV-Factor IX andlimitations imposed by the host immune responserdquo NatureMedicine vol 12 no 3 pp 342ndash347 2006

[186] F Mingozzi J J Meulenberg D J Hui et al ldquoAAV-1-mediatedgene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cellsrdquo Blood vol 114no 10 pp 2077ndash2086 2009

[187] A R Sharma S K Kundu J S Nam et al ldquoNext generationdelivery system for proteins and genes of therapeutic purposewhy and howrdquoBioMedResearch International vol 2014 ArticleID 327950 11 pages 2014

RETRACTEDReview Article

Recent Trends of Polymer Mediated LiposomalGene Delivery System

Shyamal Kumar Kundu12 Ashish Ranjan Sharma3 Sang-Soo Lee3

Garima Sharma3 C George Priya Doss4 Shin Yagihara2 Do-Young Kim3

Ju-Suk Nam3 and Chiranjib Chakraborty35

1 Department of Physics School of Basic and Applied Sciences Galgotias University Greater Noida 203201 India2Department of Physics Tokai University Hiratsuka-Shi Kanagawa 259-1292 Japan3 Institute for Skeletal Aging amp Orthopedic Surgery Hallym University-Chuncheon Sacred Heart HospitalChuncheon 200704 Republic of Korea

4Medical Biotechnology Division School of Biosciences and Technology VIT University Vellore Tamil Nadu 632014 India5 Department of Bioinformatics School of Computer Sciences Galgotias University Greater Noida 203201 India

Correspondence should be addressed to Ju-Suk Nam jsnam88hallymackr and Chiranjib Chakraborty drchiranjibyahoocom

Received 9 May 2014 Revised 15 July 2014 Accepted 15 July 2014 Published 27 August 2014

Academic Editor Nagendra K Kaushik

Copyright copy 2014 Shyamal Kumar Kundu et alThis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Advancement in the gene delivery systemhave resulted in clinical successes in gene therapy for patientswith several genetic diseasessuch as immunodeficiency diseases X-linked adrenoleukodystrophy (X-ALD) blindness thalassemia and many more Amongvarious delivery systems liposomal mediated gene delivery route is offering great promises for gene therapy This review is anattempt to depict a portrait about the polymer based liposomal gene delivery systems and their future applications Herein wehave discussed in detail the characteristics of liposome importance of polymer for liposome formulation gene delivery and futuredirection of liposome based gene delivery as a whole

1 Introduction

The gene therapy has shown great promise for the potentialcure of several genetic disorders and appears to possessenormous therapeutic potential Although this news mightseem fresh and innovative the transfer of genetic materialsinto living cells has been tested around the decades In1966 Tatum [1] predicted that the transfection techniquesfor mammalian cells will be advertised as part of the futuremedicine After over 30 years of research the field of genetherapy is offering an acceptable treatment protocol for thecure for human diseases

Studying the basic structure of genes into cells of differentorigins has been a major practice in cellular biology investi-gation In addition to being a powerful research implementgene transfer is a novel idea for gene therapy and is amolecular therapeutic approach for curing inherited and

several other diseases [2 3] Diseases developed because of agenetic constituent can theoretically be corrected by geneticrefinement based on the addition of needed genes Amongthe genetic diseases muscular dystrophy cystic fibrosis andfamilial hypercholesteremia have been studied so far As forcancer most of the mutations acquired are not inherited butare a result of cumulative effect of various external factorsTherefore it is a great challenge in the area of gene therapyto correct these mutations and to repair the gene A geneitself is not able to enter into a cell as it is a large portionof DNA that is bound by several anionic charges A widerange of artificial techniques has been developed and utilizedtime to time for in vitro gene transfer Some techniques ofgene transfer are membrane perturbation by chemicals (ieorganic solvents and detergents) direct DNAmicroinjectionphysical methods (ie mechanical or osmotic method andelectric shocks) and liposomes

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 934605 15 pageshttpdxdoiorg1011552014934605

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4 Gene Delivery


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(i) (ii)

Hydrophobic tail

Hydrophilic head

(a)

Gene added


Nucleus

Surface modified


(b)





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5 Future Direction


6 Conclusion







Acknowledgments


References








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4 Gene Delivery


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(i) (ii)

Hydrophobic tail

Hydrophilic head

(a)

Gene added


Nucleus

Surface modified


(b)





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5 Future Direction


6 Conclusion







Acknowledgments


References








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RETRACTED






































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4 Gene Delivery


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(i) (ii)

Hydrophobic tail

Hydrophilic head

(a)

Gene added


Nucleus

Surface modified


(b)





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5 Future Direction


6 Conclusion







Acknowledgments


References








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4 Gene Delivery


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RETRACTED


(i) (ii)

Hydrophobic tail

Hydrophilic head

(a)

Gene added


Nucleus

Surface modified


(b)





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5 Future Direction


6 Conclusion







Acknowledgments


References








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4 Gene Delivery


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RETRACTED


(i) (ii)

Hydrophobic tail

Hydrophilic head

(a)

Gene added


Nucleus

Surface modified


(b)





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5 Future Direction


6 Conclusion







Acknowledgments


References








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RETRACTED






































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4 Gene Delivery


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RETRACTED


(i) (ii)

Hydrophobic tail

Hydrophilic head

(a)

Gene added


Nucleus

Surface modified


(b)





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5 Future Direction


6 Conclusion







Acknowledgments


References








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RETRACTED






































RETRACTED

















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RETRACTED


(i) (ii)

Hydrophobic tail

Hydrophilic head

(a)

Gene added


Nucleus

Surface modified


(b)





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5 Future Direction


6 Conclusion







Acknowledgments


References








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(i) (ii)

Hydrophobic tail

Hydrophilic head

(a)

Gene added


Nucleus

Surface modified


(b)





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5 Future Direction


6 Conclusion







Acknowledgments


References








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5 Future Direction


6 Conclusion







Acknowledgments


References








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Retracted: Recent Trends of Polymer Mediated Liposomal Gene … · 2020. 1. 14. · 3&53"$5&%...

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Transcript of Retracted: Recent Trends of Polymer Mediated Liposomal Gene … · 2020. 1. 14. · 3&53"$5&%...