j.biomaterials.2012.03.046

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Biomaterials 33 (2012) 4889e4906

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Biomaterials

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Review

Vitamin E TPGS as a molecular biomaterial for drug delivery

Zhiping Zhang a,b, Songwei Tan a,b, Si-Shen Feng c,d,e,*

a Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, PR Chinab National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, PR Chinac Department of Chemical & Biomolecular Engineering, National University of Singapore, Block E5, 02-11, 4 Engineering Drive 4, Singapore 117576, Singapored Department of Bioengineering, National University of Singapore, Block E5, 02-11, 4 Engineering Drive 4, Singapore 117576, Singaporee Nanoscience and Nanoengineering Initiative (NUSNNI), National University of Singapore, Block E5, 02-11, 4 Engineering Drive 4, Singapore 117576, Singapore

a r t i c l e i n f o

Article history:Received 21 February 2012Accepted 13 March 2012Available online 11 April 2012

Keywords:Cancer nanotechnologyBiodegradable polymersLiposomesMicellesNanoparticlesProdrugs

* Corresponding author. Department of ChemicalNational University of Singapore, Block E5, 02-11, 4 En117576, Singapore. Tel.: þ65 6874 3835; fax: þ65 677

E-mail address: [email protected] (S.-S. Feng).

0142-9612/$ e see front matter � 2012 Elsevier Ltd.doi:10.1016/j.biomaterials.2012.03.046

a b s t r a c t

D-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS, or simply TPGS) is a water-soluble deriv-ative of natural Vitamin E, which is formed by esterification of Vitamin E succinate with polyethyleneglycol (PEG). As such, it has advantages of PEG and Vitamin E in application of various nanocarriers fordrug delivery, including extending the half-life of the drug in plasma and enhancing the cellular uptake ofthe drug. TPGS has an amphiphilic structure of lipophilic alkyl tail and hydrophilic polar head witha hydrophile/lipophile balance (HLB) value of 13.2 and a relatively low critical micelle concentration(CMC) of 0.02% w/w, which make it to be an ideal molecular biomaterial in developing various drugdelivery systems, including prodrugs, micelles, liposomes and nanoparticles, which would be able torealize sustained, controlled and targeted drug delivery as well as to overcome multidrug resistance(MDR) and to promote oral drug delivery as an inhibitor of P-glycoprotein (P-gp). In this review, we brieflydiscuss its physicochemical and pharmaceutical properties and its wide applications in composition of thevarious nanocarriers for drug delivery, which we call TPGS-based drug delivery systems.

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1. Introduction

D-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS,or simply TPGS) (as shown in Scheme 1) is a water-soluble deriv-ative of natural Vitamin E, which is formed by esterification ofVitamin E succinate with polyethylene glycol (PEG). As such it hasadvantages of PEG and Vitamin E in application of various drugdelivery device, including extending the half-life of the drug inplasma and enhancing the cellular uptake of the drug. Typically, themolecular weight of TPGS with PEG1000 segment is 1513. TPGS hasamphiphilic structure of lipophilic alkyl tail and hydrophilic polarhead with a hydrophile-lipophile balance (HLB) value of 13.2 anda critical micelle concentration (CMC) of 0.02% w/w [1]. TPGS safetyissue has been investigated in details and it has been reported thatthe acute oral median lethal dose (LD50), which is defined as thequantity of an agent that will kill 50 percent of the test subjectswithin a designated period, is >/7 g/kg for young adult rats of bothsexes [2]. US FDA has approved TPGS as a safe pharmaceuticaladjuvant used in drug formulation.

& Biomolecular Engineering,gineering Drive 4, Singapore9 1936.

All rights reserved.

In recent years TPGS has been intensively applied in developingthe various drug delivery systems. TPGS has been used as anabsorption enhancer, emulsifier, solublizer, additive, permeationenhancer and stabilizer [3,4]. TPGS has also been served as theexcipient for overcoming multidrug resistance (MDR) and inhibitorof P-glycoprotein (P-gp) for increasing the oral bioavailability ofanticancer drugs [4e7]. TPGS has also been applied for prodrugdesign for enhanced chemotherapy [8,9]. Feng’s group has beenfocused in the past decade on various applications of TPGS innanomedicine, including TPGS-based prodrugs, micelles, lipo-somes, TPGS-emulsified PLGA nanoparticles and nanoparticles ofTPGS-based copolymers, which can significantly enhance thesolubility, permeability and stability of the formulated drug andrealize sustained, controlled and targeted drug delivery. TPGS hasbeen proved to be an efficient emulsifier for synthesis of nano-particles of biodegradable polymers, resulting in high drugencapsulation efficiency, high cellular uptake in vitro and hightherapeutic effects in vivo [10e12]. For example, TPGS may havemore than 77 times higher emulsification efficiency compared withthe traditional emulsifier polyvinyl alcohol (PVA), i.e. to producethe same amount of polymeric nanoparticles by the single emul-sion method, the needed TPGS amount can be only 1/77 than thatof PVA as the emulsifier used in the process. TPGS-emulsifiednanoparticles or TPGS-based nanoparticles have been found to

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Scheme 1. Chemical structure of TPGS.

Z. Zhang et al. / Biomaterials 33 (2012) 4889e49064890

increase the cell uptake efficiency on Caco-2, HT-29, MCF-7, C6glioma cells and thus enhance cancer cell cytotoxicity. The TPGS-based nanoparticles have been further found in resulting ina more desired pharmacokinetics of entrapped drug in vivo, whichcould significantly extend the half-life of the formulated drug in theplasma. Feng’s group has realized 168 h effective paclitaxel (PTX)chemotherapy by the TPGS-emulsified PLGA nanoparticles formu-lation in comparison with Taxol� of only 22 h effective chemo-therapy at the same 10 mg/kg body weight of rats. Moreover, theyhave found that 400% higher drug tolerance can be achieved, whichcould result in 360% AUC as a quantitative measurement of thein vivo chemotherapeutical effects. It means that the animalimmune system failed to recognize and thus eliminate the nano-particles. They proved in vivo the feasibility of nanomedicine, whichhad been one of the two major concerns for the newly emergingarea nanomedicine as future medicine. They then furtherconfirmed such advantages of nanomedicine that the PLA-TPGSnanoparticle formulation of PTX and docetaxel (DOC) can realize336 h and 360 h sustained effective chemotherapy respectively incomparison 23 h chemotherapy of Taxotere� at the same 10 mg/kgbody weight for rats. Also, a more desirable biodistribution of thedrug could be resulted with less drug in kidney, liver, heart andmore in blood and lung. Oral delivery and drug delivery across thebloodebrain barrier can also be achieved by further developmentof the nanoparticle technology with enhanced size and sizedistribution, surface functionalization, and copolymer synthesis[13e15].

In this review, we discuss in details the advantages of thevarious TPGS-based drug delivery systems such as prodrugs,micelles, liposomes, TPGS-emulsified PLGA nanoparticles andnanoparticles of TPGS copolymers such as PLA-TPGS, TPGS-COOH,PCL-TPGS, and so on.

2. TPGS as prodrug carrier

A prodrug is a pharmaceutical agent which is administered in aninactive form (say conjugated to a polymer) and then bioactivated(say released from the drug-polymer conjugate) into activemetabolites in vivo. The rationale behind a prodrug is generally toenhance the pharmacokinetics of a drug, i.e. to optimize the processof absorption, distribution, metabolism, and excretion (ADME).Prodrugs are usually designed to improve oral bioavailability of thedrug with poor absorption from the gastrointestinal tract [16,17].Among the conjugations discussed, conjugations between biode-gradable polymers such as polyethylene glycol (PEG), PLA-PEG, andpoly(L-glutamic acid) (PGA) and anticancer drugs such as DOX, PTX,and camptothecin have been intensively investigated [18e24].Among them, PEG-drug conjugation have been so widely used thatresulted in a special term called PEGylation, which means

conjugated to PEG [22e24]. Greenwald et al. discussed in detailsPEG-conjugation application in drug delivery of small moleculeanticancer drugs such as PTX as well as biological drugs such aspeptides and protein delivery [25,26].

2.1. TPGS-DOX conjugate

Doxorubicin (DOX), an anthracyclinic antibiotic, is a DNA inter-acting drug for treatment of various cancers especially breast,ovarian, prostate, brain, cervix and lung cancers. Clinical applica-tion of DOX was limited by its short half-life in the plasma andsevere gastrointestinal and cardiovascular toxicity. The drug resis-tance also limits its intracellular level. To reduce side effect fromDOX, evade drug resistance and enhance its therapeutic efficiency,DOX was conjugated to TPGS in Cao et al. studies (Scheme 2) [8].In vitro drug release from the conjugate was studied to show pHdependent favor with no burst release. After 10 days, there werearound 52.3%, 43.6% and 12.6% DOX released after incubatingconjugate at pH 3.0, 5.0 and 7.4, respectively. DOX conjugateexhibited higher cellular uptake of 1.7-, 1.3-, 1.2-, 1.2- fold for theMCF-7 cells and 5.4-, 5.9-, 1.3-, 1.1-fold for the glioma C6 cells after0.5, 1.5, 4, 6 h culture, respectively (p < 0.05), compared with thepristine DOX. The prodrug demonstrated 31.8, 69.6, 84.1% moreeffective with MCF-7 breast cancer cells and 43.9, 87.7, 42.2% moreeffective with C6 glioma cells than the parent drug after 24, 48, 72 hculture, respectively based on IC50 value. After i.v. administratedDOX pristine formulation or the prodrug at 5 mg/kg dose in rats, thet1/2 and MRT were increased from 2.53 h and 2.86 h to 9.65 h,10.9 h,respectively as seen in Fig. 1. The AUC0�N was also significantlyincreased from 288 ng-h/ml for DOX to 6812 ng-h/ml for the pro-drug. Biodistribution also exhibited the lower side effects of theconjugate compared with the DOX. The AUC value from heart,gastric, and intestine was decreased from 307, 313, and 246 mg-h/gtissue for the DOX to 155, 114.3 and 86.7 mg-h/g tissue, respectively.It seems that the TPGS-DOX prodrug demonstrated higher thera-peutic efficiency and lower side effects compared with the pristinedrug.

Anbharasi V et al. further developed a TPGS-DOX-folic acid (FOL)conjugate (TPGS-DOX-FOL) for targeted chemotherapy andcompared it with TPGS-DOX conjugate and pristine DOX [9]. Tar-geting conjugate TPGS-DOX-FOL can be 45.0-fold effective thanDOX in cytotoxicity on MCF-7 cells judged by the IC50 results, whileTPGS-DOX conjugate was only 1.19-fold effective than DOX. Thehalf-life (t1/2) of TPGSeDOX and TPGSeDOXeFOL were extendedfrom 2.69 h (DOX) to 10.2 h and 10.5 h, respectively. The AUC valuesof TPGS-DOX and TPGS-DOX-FOL were 19.2 and 14.5 times than theDOX, respectively. Conjugates also significantly decreased the drugdistribution in gastric, intestine, and especially in heart. Indeed,TPGS conjugate, especially TPGS-DOX-FOL can deduce the gastro-intestinal side effect of the drug [9].

2.2. TPGS-paclitaxel conjugate

PTX is one of the best anticancer drug, which processes excellenttherapeutic effects against various cancers such as breast andovarian cancers. However, due to its extremely low solubility(<0.03 mg/L in water), its clinical administration formulation(Taxol�) has to use an adjuvant called Cremophor EL, which causessevere side effects including hyperaction, nephatoxocity, car-diotoxicity and neurotoxicity. In order to deal with this problem,various strategies were employed in seeking alternative formula-tion. Lee et al. presented a prodrug, formulated by conjugation ofPTX with TPGS [27]. The conjugate was expected to improve thecellular uptake and further increase the cancer cell cytotoxicity.Unfortunately, no further in vitro or in vivo data were published yet.

O

OO

OH

OO

n

H3C CH3

CH3CH3CH3CH3

CH3

CH3

OO O

O

O

OH

OHO OO

HO NH2

O OH

OH

O

O

OH

OHO OO

HO NH

O OH

OH

O

OOO O

O

nCH3

H3C CH3

CH3

CH3CH3 CH3 CH3O

O

Vintamin E TPGS Succinic Anhydride

DMAP100¡æ

TPGS-SA

NHS,DCC,TEADMSO

DoxorubicinTPGS-DOX

O

OO

O OO

n

CH3

CH3CH3CH3CH3

CH3

CH3

H3C

OH

O

O

Scheme 2. TPGS-DOX conjugate (reproduced from [8] with permission).

Z. Zhang et al. / Biomaterials 33 (2012) 4889e4906 4891

3. TPGS-based micelles

TPGS has micellar properties and can formulate micelles fordelivery of drug or imaging agent [28]. TPGS micelles were alsoused to encapsulate other functional materials like carbon nano-tubes [29], fullerenes or iron oxide [30]. It has been proved thatTPGS was a more effective dispersing agent of multi-wall andsingle-wall carbon nanotubes than the commonly used Triton X-100 in water. C60 was also solublized in TPGS aqueous solutionfrom fullerene. Highly ordered asymmetric nanoparticles, wherefullerene nanocrystals presented at the hydrophobic end of crys-talline TPGS nanobrushes, were found after drying these solutions[30]. Chandrasekharan et al. prepared superparamagnetic ironoxide (IOs) loaded TPGS micelles and compared them with F127micelles and the commercial Resovist� for thermotherapy andmagnetic resonance imaging (MRI). The IOs-loaded TPGS micellesshowed reduced toxic effect and enhanced uptake by the cancercells, thus resulted in a higher hyperthermia treatment efficient.

Fig. 1. Pharmacokinetic profile of the pristine DOX and the TPGSeDOX conjugate afteri.v. injection in rats at a single equivalent dose of 5 mg/kg (mean � SD, n ¼ 4). Triangle(:) for DOX-TPGS, diamond (-) for DOX and . for lowest effective level (reproducedfrom with [8] permission).

Due to the ability to escape from reticuloendothelial system (RES),the TPGS micelles are also more promising than the other two typesof micelles [31].

The CMC of TPGS is relatively high as mentioned above, whichmay make TPGS micelles dissociate in the plasma. Thus TPGS wasusually used together with other micellar materials to form mixedmicelles to increase the micelle stability and the drug solubilization[32]. Mu et al. prepared mixed micelles from poly(ethylene glycol)-phosphatidyl ethanolamine conjugate (PEG-PE) and TPGS witha molar ratio of 2:1 [33]. The CMC of the mixture was within 10�6 to10�5 M and the solubility of camptothecin (CPT) was improved atleast 50% compared to the PEGePE micelles due to the increasedinner micelle core volume through the big vitamin E head. Theanticancer efficiency of the mixed micelles was quite high becauseof their enhanced CPT solubility, permeability and stability as wellas improved cellular uptake ability [33]. This PEG-PE/TPGS systemwas further used to encapsulate anticancer drugs PTX and gossypolwith a 1:1 molar ratio (CMC 1.5 � 10�5 M) [34,35]. PTX-loadedTPGS-lipid mixed micelles were found quite stable with onlyabout 20% of drug release after 48 h at 37 �C. In addition, thesemixed micelles were stable in vitro under physiological modelingconditions and, especially at low pH values and with bile acids,which made them applicable for oral administration [34].

Chandran et al. used 1,2-distearoyl-sn-glycero-3-phosphoeth-anolamine-N- [methoxy(polyethylene glycol) 2000]/TPGS (DSPE-PEG/TPGS) for transportation of a potent anticancer agent 17-Allyamino-17-demethoxygeldanamycin (17-AAG), which has beenin phases I and II clinical trials [36]. TPGS was able to restrictmolecular motions of copolymers in both of the corona and coreregions of the micelles, thus controlling the release of 17-AAG. Themixed micelle also improved the cytotoxicity of 17-AAG towardsSKOV-3 cells compared with the free drug 17-AAG [36]. Co-deliveryof PTX and 17-AAG in PEG-DSPE/TPGS mixed micelles were alsorealized, which showed advantages in vitro compared with thePLA-PEG micelles and free drug [37].

Other TPGS mixed micelles, such as TPGS/oleic acid pluronic P105 [38], Pluronic P123 [39], PLGA-PEG-FOL, and Pluronic F127/


poly(butylcyanoacrylate) (PBCA) [40], have also been reported,which all showed a solublizing ability and/or enhanced cellularuptake. Quercetin (QT)-loaded micelles were fabricated in presenceof pluronic P123 (P123) and TPGS with proportion of 7:3 by thin-film hydration method. The size of the micelles was 18.43 nmwith 88.94% drug encapsulating efficiency for 10.59% drug loading.TPGS mixed micelles were found to increase the solubility of QT inQT-P/TPGS for about 2738-fold than that of crude QT in water andcan realize the sustained release and comparable in vitrocytotoxicity [39]. TPGS was also mixed with pluronic P105 or F127to increase the solubility and cytotoxicity of poorly soluble anti-cancer drug CPT. It was found to increase the drug loading up to0.0425 � 0.0011% w/w for 70% of TPGS compared to0.0254 � 0.0008% w/w for the micelles without TPGS. TPGS actedas stabilizer and got 10-fold lower of the CMC value than non TPGSstabilized micelles [40]. The mixed micelle formulation was foundto significantly increase the cytotoxicity of CPT against MCF-7cancer cell in vitro compared to the free drug [38,41].

Mi et al. synthesized TPGS2000 and TPGS3350-FOL conjugatesand mixed them to form micelles for targeted DOC delivery [42].TPGS2000 had a lower CMC (0.0219 mg/ml) than TPGS (0.2 mg/ml),which improves the stability of this drug-loading system. Thecellular uptake and cytotoxicity of MCF-7 cancer cells in vitro wereboth greatly enhanced compared with Taxotere�, especially afterconjugated with folate. More importantly, TPGS2000 is an analog ofTPGS, whose cytotoxicity for cancer cells was explored. There isa significant synergistic effect between TPGS2000 and DOC fromcytotoxicity assay as shown in Table 1. The work represents a newconcept in the design of drug delivery systems - the carrier mate-rials of the drug delivery system can also have therapeutic effects,which either modulate the side effects of, or promote a synergisticinteraction with the formulated drug. Such drug delivery systemmay need further investigation [42].

4. TPGS-based liposomes

TPGS can be used as a surfactant and/or component in liposomalformulation, which may bring some advantages for the sustainedand controlled drug delivery [43]. Muthu et al. prepared nano-sizednon-coated liposomes, PEG-DSPE coated liposomes and TPGScoated liposomes with DOC as the anticancer agent [44]. TPGScoated liposomes showed maximum DOC encapsulation efficiency(64%), higher cellular uptake and cytotoxicity (84.0% decrease in theIC50 value compared with that of Taxotere�). The liposomecomposed of 1,2-di-(9Z-octadecenoyl)-3-trimethylammo-nium-propane/egg phosphatidylcyoline/TPGS was fabricated for entrap-ping disulfide-linked oligodeoxyribonucleotide (ODN). The ODN-loaded liposome demonstrated superior colloidal stability, andefficient on cellular growth inhibition [45,46]. TPGS can act as thestabilizer of the liposomes which may be due to sterical hindranceof the pancreatic enzymes by the PEG chain. The delivery vesicle

Table 1IC50 of DOC formulated in Taxotere�, TPGS2k micelles and FA TPGS2k micelles after24, 48, 72 h incubation with MCF-7 breast cancer cells at 37 �C (reproduced from[42] with permission).

Incubationtime (h)

IC50 (mg/ml)

Taxotere� Micelleswithout DOCa

Micelleswith DOC

FA micelleswith DOC

24 103.4 1.350 0.526 0.17848 1.28 1.530 0.251 0.15272 0.148 7.58 0.233 0.114

a The value represents the concentration of DOC, that is equivalent to theconcentration of TPGS2k for 50% viability.

containing TPGS may be used for oral delivery of proteins or otherdrug substances with a low oral bioavailability due to gastrointes-tinal degradation and low permeation [43,47e49]. TPGS was alsoadded in fabrication of lipid nanoparticles, DOTAP/DDAB/Chol/TPGS/linoleic acid/hexadecenal at molar ratios of 30/30/34/1/5/0.2[50e52] and added as surfactant to fabricate liposomes encapsu-lated in polymeric microspheres fabricated by the double emulsionprocess [53]. It was also used as surfactant in fabricating solid lipidnanoparticles for MDR. IC50 of DOX-loaded SLN can be 9-fold lowerthan free DOX in cytotoxicity of resistant P388/ADR cell linewhereas there is not significant difference between idarubicin andthe particles. The DOX NP with TPGS was found to overcome P-gpmediated MDR both in P388/ADR leukemia cells and murineleukemia mouse model [54,55].

Recently, a drug carrier of lipidepolymer hybrid nanoparticle,where the polymeric core coated by a lipid layer, was developed tomerge the advantages of both liposomes and polymeric nano-particles. Zheng et al. prepared Transferrin-conjugated lipid-coated PLGA nanoparticles with egg PC and TPGS, which wasfound to increase the drug loading efficiency and the therapeuticefficiency [56]. Cheow et al. showed that TPGS was able to protectthe stability of hybrid nanoparticles by inclusion of TPGS in thesurface of nanoparticles in salt solutions. The polar PEG1000components of TPGS extend outwards into the aqueous phase,while the lipophilic end was adsorbed onto the hybrid nano-particles matrix. These structures thus realized the stability ofhybrid nanoparticles [57].

5. TPGS-emulsified nanoparticles

TPGS can be used as an emulsifier or an ideal coating moleculewhich can achieve high drug EE (up to 100%) and higher cellularuptake of the nanoparticles, and thus high therapeutic effectscompared with PVA emulsified nanoparticles [14]. Feng’s groupdid lots of works in this field and showed many impressive results[13,58e67]. They applied TPGS as a surfactant to fabricate PTX-loaded PLGA nanospheres in the solvent evaporation/extractiontechnique. Compared with PVA, TPGS significantly improved theencapsulation efficiency of the drug as high as 100% with size300e800 nm. TPGS-emulsified nanoparticles displayed a slowerrelease than that of PVA [58e60,67]. They fully investigatedinfluence of the different factors on the formation of nanoparticlesincluding ratios of oil phase, aqueous phase, polymer material andsurfactant by a modified solvent extraction/evaporation techniquewith TPGS as surfactant and additive of polymeric matrix. TPGSwas also used as a surfactant to emulsify PLGA, PCL, PLA-TPGS,PLGA-PEG and MPEG-SS-PLA NP [13,14,68e70]. TPGS as surfac-tant can be as low as 0.15%e0.06% but 0.02e0.03% showed the bestyield of nanoparticles. TPGS can have 67 times higher emulsifi-cation effects than PVA in the PLGA nanoparticle. Someresearchers still used 5% in fabricating cubic phase nanoparticlesfor rapamycin entrapment [71], 0.5% in fabricating PTX-loadedpoly(vl-evl-av-opd) NPs with size 57 nm by nanoprecipitationmethod [72], 15% TPGS for fabricating iron oxide nanocrystalsloaded PLA-TPGS NP [11,73]. In solvent extraction evaporationmethod, TPGS mainly was used as emulsifier/surfactant andcoating reagent [72,74]. It was distributed on the surface ofnanoparticles from XPS and FTIR-PAS investigation of the nano-spheres [58,59]. TPGS exhibited notable effect on the surfaceproperties of airewater interface as well as the lipid monolayer[75]. In nanoprecipitation method, TPGS mainly acted as stabilizer/surfactant [76e79]. TPGS coated on the surface of nanoparticlescan take advantage of P-gp inhibitor of TPGS, inhibiting the P-gp inMCF/ADR cells, delivery more drug into the cells and also the

Fig. 2. Plasma concentrationetime profiles of PTX formulated in Taxol�(10 mg/kg) orTPGS-emulsified PLGA nanoparticles (10 mg/kg as well as 40 mg/kg) after i.v. admin-istration to SD rats. The concentrations between the side-effect level (8540 ng/ml) andthe minimum-effective level (43 ng/ml) show the therapeutic window of the drug(reproduction from [64] with permission).

Fig. 3. Changes in the size of C6 tumor nodules after intratumoral injections on days11, 16 and 21 with saline, Taxol� and PTX formulated in TPGS-emulsified PLGA nano-particles at the same 10 mg/kg dose (mean � SD, n ¼ 5, p ¼ 0.05) (reproduction from[64] with permission).

Fig. 4. Pharmacokinetic profiles of PTX formulated in the TPGS-emulsified PLGA NPsversus Taxol� after oral or i.v. administration at the same 10 mg/kg PTX dose (datarepresent mean � SD, n ¼ 12) (reproduction from [65] with permission).


enhanced cell cytotoxicity [71,80]. It also enhanced free DOX tomove from the cytoplasm into the nucleus.

5.1. TPGS-emulsified PLGA NP for i.v. administration

TPGS-emulsified PLGA NPs demonstrated 5-fold more effectivethan Taxol� formulation from in vitro C6 cell mortality experi-ments. The NP can realize a comparable AUC value as Taxol�, butthe drug concentration was never exceeded the maximum toler-ance level, and hence should greatly reduce the side effects. In vivopharmacokinetics study also exhibited close to linear PK propertyfrom TPGS-emulsified nanoparticles (as seen in Fig. 2). Ratsreceiving Taxol� at doses higher than 20 mg/kg showed apathy anddied after 1 h injection whereas there is not any apathy from over40 mg/kg dosage of nanoparticles. It seems that nanoparticles cansignificantly increase the drug tolerance and realize sustainablechemotherapy. Furthermore, the particles formulation can realizea sustainable therapeutic time of 168 h in comparison with 22 h forTaxol� at a same dose of 10 mg/kg. The half life of Taxol� fora dosage of 10 mg/kg was 2.8 h only, which is much shorter than32.6 h for nanoparticles formulation. Moreover, the AUC of the40 mg/kg dose is about 3.6 times of that for the 10 mg/kg dose. Thetherapeutic effect was further evidenced from tumor xenograftresults which showed benefit on tumor inhibition from nano-particles compared with no treatment or clinical drug formulationtherapy (as seen in Fig. 3) [64,76,81].

From Fig. 2, we can conclude (1) PLGA nanoparticles of about200 nm size can successfully escape from recognition and elimi-nation by the reticuloendothelial system (RES). One dose of thePLGA nanoparticle formulation of PTX can realize a 168 h effectivechemotherapy in comparison with only 22 h for Taxol�. Moreover,the AUC is greatly increased by the PLGA NP formulation and thereis no AUC associated with drug concentration above the maximumtolerance level, which means much better therapeutic effects andmuch less side effects would be resulted.

5.2. TPGS-emulsified PLGA nanoparticles for oral delivery

Caco-2 cells were used as an in vitro model of GI barrier for oralchemotherapy and TPGS coated nanoparticles was found toincrease up to 1.4 folds cellular uptake than that of PVA-coated

PLGA nanoparticles and 4e6 folds higher than that of nude poly-styrene nanoparticles on Caco-2 cells [63]. HT-29, a colon cancercell line was incubated with placebo and PTX-loaded TPGS-emul-sified nanoparticles, and the clinical formulation, Taxol�, at thesame PTX concentration of 0.25 mg/ml. The mortalities of the HT-29cells were 1.88% and 7.13% for placebo nanoparticles, 3.19% and33.5% for Taxol� and 18.0% and 48.6% for TPGS-emulsified nano-particles after incubation for 24 and 96 h, respectively. Drug-loadedTPGS-emulsified NP exhibited 5.64, 5.36, 2.68, and 1.45 times moreeffective than Taxol� formulation after 24, 48, 72, 96 h treatment,respectively at 0.25 mg/ml drug concentration against HT-29 on cellviability [82]. TPGS-emulsified PLGA NP also exhibited 1.28, 1.38and 1.12-fold more effective than Taxol� after incubation NP withMCF-7 breast cancer cells for 24, 48, and 72 h, respectively. The NPat 10 mg/kg dose of PTX exhibited around 10-fold AUC comparedwith Taxol� (8510 ng-h/ml vs. 872 ng-h/ml for Taxol� by oral and35,500 ng-h/ml by i.v. administration)(as seen in Fig. 4). Sustainabletime also increased from 7.02 h for Taxol� to 88.2 h for NPformulation. The oral bioavailability of TPGS-emulsified NP wasincreased from 2.46% of Taxol to 24.0%. Our results exhibitedexcellent oral drug delivery formulation from TPGS-emulsified NP


[65]. The oral bioavailability of TPGS emulsified amphotericin Bloaded PLGA NP was also found to 8-fold than FungizoneA� [79].

5.3. TPGS-emulsified PLGA NP and further coated with tween 80 fordelivery to cross BBB

TPGS-coated PLGA NP can achieve 1.5-fold higher cellularuptake on MDCK cells. TPGS-emulsified NP demonstrated 4.2% ofthe injected dose to retain in brain tissue which is higher than2.59% for PVA-emulsified NP, but lower than 6.29% for F68-coatedPLGA NPs, 5.70% for F127-coated PLGA NPs, 4.26% for Tween 80-coated PLGA NPs. The distribution of the NPs within the liver,spleen, lungs and brain is significantly altered after surface coatingwith different surfactant [66].

5.4. TPGS-emulsified nanoparticles for cardiovascular restenosistreatment

TPGS was also found to increase the coronary artery smoothmuscle cells (CASMC) uptake efficiency up to 38% compared with21% for PVA emulsified nanoparticles after 6 h incubation. The IC50of CASMC cells was decreased from 748 ng/ml for Taxol� to 708 ng/ml and 474 ng/ml for PVA and TPGS-emulsified nanoparticles,respectively. The arterial uptaken of nanoparticles was studied byconfocal microscope. The rabbits were injured by balloon catheterand then infused by coumarin 6-loaded nanoparticles suspension.Confocal image results demonstrated that fluorescence can beclearly observed in the carotid arteries walls and TPGS showedadvantages in the cell uptaken compared with PVA in emulsifica-tion of nanoparticles [64]. TPGS as emulsifier showed advantages inpreparing cardiovascular stents.

6. TPGS as additive for nanoparticles formulation

TPGS can be a matrix of micro-/nanoparticles after blendedTPGS with PLA, PLGA, poly (caprolactone) for anticancer drug,pacltiaxel, diphtheria toxoid and others, fabricated by dialysis,modified solvent extraction/evaporation, or spray drying methodwith increased encapsulation efficiency and sustained release[56,60,62,83,84]. TPGS as additive increased the drug encapsulationefficiency up to 75.9% compared to 69.0% for particles without TPGSfor 4.2% drug loading. 90.1% encapsulation efficiency was achievedwith 2% drug loading with blending 5% TPGS in matrix [85e88].TPGS was found to reduce the burst release and the lag-phase timein peptide loaded PLGA microparticles with 5% and 10% TPGS

OO

O

O

OO

O

O

CH3

H3C

R-OH

Catalyst

Cat.

TPGS

initiation

Propagation

Lactide monomer

+ R-OH

R O C

OHC O C C

H

O

CH3

H3C

CH3

C

Scheme 3. Schematic description of the synthesis mechanism of P

composition [89]. It was found to significantly enhance the cellularuptake and the cell cytotoxicity of entrapped drug against cancercells while mixed with PLGA in fabricating nanoparticles. It may bedue to TPGS can inhibit the P-gp activity and enhance the drugconcentration in cells and thus increase the cytotoxicity [90]. TPGSwas also added in folate conjugated PLGA-PEG NP with DOXloading and the formulation with TPGS was found to increase thecellular uptake of DOX, higher degree of DNA damage and apotosisand thus higher cytotoxicity on drug-resistant cancer cells. It maybe due to TPGS as a P-gp efflux pump inhibitor. Inducing TPGS inmicelle formulation can strengthen the therapeutic effect of themicelles [32]. Lipid-polymer hybrid nanoparticles, by fabricatingpolymer nanoparticles with lipid as surfactant and matrix, areunstable in salt solutions. TPGS with amphiphilic structure wasfound to protect the stability of hybrid nanoparticles by inclusion ofTPGS in the surface of nanoparticles. TPGS has polar PEG1000components, which extend outwards into the aqueous phase, whilelipophilic end was adsorbed onto the hybrid nanoparticles matrix,these structure thus realized the stability of hybrid nanoparticles[57]. However, TPGS has also been found to have negative effect onencapsulation efficiency of HSA entrapment and faster release infabricating PLGA or poly(lactide-co-ethylene glycol) (PELA) NP bywater-oil-water emulsion method with 2% or 10% TPGS. Low TPGSconcentration of 2% can form porous morphology of microparticlesand 10% of TPGS resulted in denser morphology of the micro-spheres [91].

7. Biodegradable PLA-TPGS copolymers in drug delivery

7.1. Polymer synthesis

Zhang et al. synthesized PLA-TPGS copolymers in 2006 andapplied this copolymer in anticancer drugs delivery includingpaclitaxel, DOX and also protein BSA. The copolymers weresynthesized with various lactide and TPGS ratios by ring openingpolymerization with stannous octoate as catalyst (Scheme 3) [12].Molecular structure of the copolymer was characterized by FTIRspectrophotometer and 1H NMR in CDCl3. The weight-averagedmolecular weight and molecular weight distribution were deter-mined by gel permeation chromatography which demonstratedsingle narrow peak from the copolymer and significant peak shiftcompared with TPGS. It confirmed the copolymer is not the phys-ical mix of reactants. The thermal properties of the samples werestudied by using thermogravimetric analysis. TPGS exhibits singlecombustion zone located the range 315e450 �C. The copolymer

OO

O

CH3

H3C(m-1)

where R-OH : TPGS

Cat.O OR

H+

OH

R O C

OHC O C C

H

O

OH

m

OO

O

O

H3

CH3

CH3

CH3

H3C+

LA-TPGS copolymer (reproduction from [12] with permission).


exhibits two combustion zones at 200-315 and 315e450 �C,respectively. TPGS composition was calculated from TGA resultsshowed well match with NMR measurement. Ha at al also usedstannous octoate as catalyst to synthesis PLA-TPGS 50:50 copol-ymer [92]. Zhang ZP et al. and Mei L et al. further synthesized PLGA-TPGS copolymer by the similar way [93e95]. The component ratioof lactide:glycolide:TPGS in the PLA-TPGS copolymer was 60:27:13with molecular weight 11,900 which was calculated by the ratio ofpeak integration area at 5.21 ppm (-CH protons of PLA), 4.87 ppm(-CH protons of PGA) and 3.60 ppm (-CH2 protons of PEO part ofTPGS). PCL-TPGS [96], PCL-PGA-TPGS [97] and PCL-PLA-TPGScopolymers were also synthesized with the similar method asZhang ZP et al.

Li et al. modified the PLLA-TPGS copolymer synthesis with L-lactide/TPGS 30/1 or 40/1 ratio by bidentate sulfonamide zinc ethylcomplex as catalyst [98]. Compared with catalyst stannous octoate,they got much uniform polydispersity around 1.11e1.12 and alsoreduced reaction time from 8e12 h to 3.5 h with 96e97% conver-sion rate. Critical aggregation concentration (CAC) were measuredas 7.29 � 10�5 and 2.06 � 10�5 g/ml for PLA30-TPGS and PLA40-TPGS copolymer, respectively.

7.2. Nanoparticles fabrication

PLA-TPGS copolymers with various PLA/TPGS ratio were used toentrap different drugs, protein or medical imaging agent. Nano-precipitation method can realize smaller particles size with goodencapsulation efficiency for hydrophobic anticancer drugs ormedical imaging agent such as iron oxide nanocrystals (IOs) ororganic quantumn dots (QDs). Single emulsion method can realizemuch higher entrapment compared with nanoprecipitationmethod but the particles size was normally 100 nm larger. Doubleemulsion method can be used to entrap hydrophilic drug, protein orhydrophilic coated medical agents. No matter the fabricationprocess, PLA-TPGS NP exhibited enhanced encapsulation efficiency,cellular uptake and the cytotoxicity of the payload on cancer cellscompared with normally used PLGA NP in entrapping payloads [76].

7.2.1. Nanoprecipitation methodDocetaxel loaded nanoparticles was fabricated by nano-

precipitation method [99]. Dong et al. developed nanoprecipitationmethod for PLA-PEG NP fabrication with particles size less than100 nm and XPS measurement demonstrated PEG layer present onthe surface of nanoparticles [100]. Nanoprecipitation method is thebetter way to realize PEG layer cover the surface of nanoparticleswith smaller size compared with solvent extraction/evaporationmethod but the drug loading would be relative lower, around 1e3%for PTX. The method is also not easy to realize hydrophilic drugencapsulation and the controlled release is much faster comparedwith solvent extraction/evaporation method. The particles size ofPLA-TPGS NP was around 121 nm with 80% encapsulation efficiencyfor DOC [99]. In fabrication, polymer and drug were dissolved inacetone, vortexed and ethanol added in. The organic phase wasthen mixed with the aqueous phase containing 0.1% TPGS at650 rpm stirring rate on magnetic stirrer plate. The particles wasthen centrifuged at 15,000 rpm at 4 �C and washed three times.Prashant et al. fabricated iron oxide nanocrystals loaded PLA-TPGSNP by nanoprecipitation method with 256 nm, 64% encapsulationefficiency and nanocrystals were monodispersed in nanoparticles.Tetrahydrofuran (THF) was used as solvent and 15% TPGS wasapplied as stablisier [73].

7.2.2. Solvent extraction/evaporation (single emulsion) methodPTX can be entrapped in PLA-TPGS NPs by solvent extraction/

evaporation method and the copolymer itself can be acted as

surfactant so it can be self-emulsified. Particles size from PLA-TPGS88:12 (weight ratio) was around 280 nm with 90% encapsulationefficiency for 5% PTX loading. The atom composition of the copol-ymer nanoparticles was determined by X-ray photoelectron scope.XPS can quantitatively determine the chemical composition of the5e10 nm depth of nanoparticles surface. From XPS nitrogen anal-ysis, there was not any nitrogen signal from particles which meansPTX distributed inside of nanoparticles. There is only nitrogen atomsignal from PTX in the nanoparticles fabrication. The C1s spectra ofthe copolymer and copolymer nanoparticles exhibited increasingC-O-C peak ratio from 18.5% for the pure copolymer to 27.8% for thePTX-loaded PLA-TPGS copolymer nanoparticles. It demonstratedthat the copolymer nanoparticles can realize TPGS coating on thesurface of nanoparticles and thus achieve desired advantages ofTPGS from TPGS coated nanoparticles [101]. The TPGS coating ratiowas also affected by the TPGS composition of the copolymers. Thedrug release of copolymer nanoparticles was relative to the TPGScomposition ratios in the copolymers. The higher TPGS ratio in thecopolymers, the faster drug release from the copolymers nano-particles [10,102]. The copolymers demonstrated the advantages inthe cell uptake efficiency of the fabricated nanoparticles. Thecellular uptake was increased with increased composition ratio ofTPGS in the copolymers. The cell uptake efficiency of PLA-TPGS NPwas 2.05-, 1.69-, and 1.35-fold higher than PVA-emulsified PLGA NPand 1.23-,1.16-, and 1.12-fold higher than TPGS-emulsified PLGA NP,after incubating HT-29 cells with coumarin 6-loaded NP at theconcentration of 100, 250, 500 mg/ml, respectively. The similartendency was seen as Caco-2 cells and as shown in confocal images[102]. The fluorescent NPs are located inside of cells but not withinthe cell membranes. The copolymers also showed significantadvantages in cancer cell cytotoxicity. The IC50 value of PTX-loadedPLA-TPGS NP was much lower than Taxol� after 48 h incubationwith HT-29 (103 ng/ml vs. 117 ng/ml) and Caco-2 cells (16.270 vs.18.49 mg/ml). Li et al. also fabricated DOX-loaded PLA-TPGS NP withTHF as solvent. Compared with Feng’s group nanoparticles fabri-cation, they got much smaller particles around 127 nm with 98.5%encapsulation efficiency for DOX which may be due to the lowerpolydispersity of the copolymer synthesized as lower as 1.1 [98].Furthermore, DOC, iron oxide nanocrystals and QDs were alsoloaded by single emulsion method with size around 200e350 nmand up to 99% encapsulation efficiency for 10% DOC loading[11,94,103e105]

7.2.3. Dialysis methodPTX-loaded PLA-TPGS NP was fabricated by dialysis method.

PTX and the copolymer were dissolved into a suitable solvent andthen dialyzed against millipore water for 30e40 h with changingwater every 3e6 h. The particles fabrication was optimized onsolvent, theoretical drug loading, polymer concentration, and thecomponent ratio of the copolymer. Among the solvent selectedfrom DMSO, DMF, THF, 1,4-dioxane, acetone and acetonitrile, DMFachieved smallest particles size with suitable encapsulation effi-ciency 54% while copolymer concentration of 12.5 mg/ml, 10% drugloading and PLA-TPGS 92:8 copolymer. As copolymer concentrationin organic solvent increased, the particles size was increased from367 to 475 nm and drug loading efficiency decreased from 48.8% to35.5% for copolymer concentration increased from 2.5 mg/ml to12.5 mg/ml. Theoretical drug loading did not affect the particlessize but significant increased the size from 356 nm (5% drugloading) to 452 nm (20% drug loading). Especially when the drugloading was as high as 20%, the particles size significantly increasedbut the encapsulation efficiency was sharply decreased from 60.2%to 24.6% for 20% drug loading. Compared with PLGA in fabricatingNP, the copolymer increased drug loading efficiency and smallerparticles size was achieved for more hydrophilic copolymer.

Table 2Mean non-compartmental pharmacokinetic parameters of SD rats for intravenousadministration of Taxotere� and TPGS-emulsified DOC-loaded PLA-TPGS nano-particles at a dose of 10 mg/kg (reproduction from [107] with permission).

Parameter Taxotere� NPs

tmax (h) 0.5 3.0Cmax (ng/ml) 14,990 � 4800 7250 � 1120AUC0�N (ng-h/ml) 1.14 � 105 � 7.13 � 104 3.92 � 105 � 9.72 � 104

t1/2 (h) 4.17 � 1.92 83.87 � 9.61MRT (h) 3.69 � 1.42 73.89 � 10.39CL (ml/h/kg) 111.51 � 63.97 23.46 � 5.84AUCtoxic/AUC0�N 0.84 0.19


Dialysis method does not need much severe experiment conditions.Furthermore, the fabricating process is self-dialysis and the fabri-cation process may easily promote TPGS to distribute on the surfaceof the nanoparticles as seen from XPS analysis [10]. The hydro-philicity of the copolymers from TPGS also affected the entrappeddrug release. The initial burst release in the first day was up to24.0%, 23.0%, 29.7% and 31.1% for PTX-loaded PLGA, PLA-TPGS 98:2,92:8, and 88:12 NPs, respectively. After 30 days, 63.6%, 60.7%, 77.7%and 80.3% of entrapped PTX was released from the copolymersnanoparticles, respectively.

7.2.4. Double emulsion methodProtein can be entrapped in the PLA-TPGS NP by the double

emulsion method. Different compositions of TPGS in the copoly-mers were studied on the encapsulation efficiency, in vitro drugrelease and degradation of BSA-loaded NPs [106]. The copolymerscan achieve 75.6% encapsulation efficiency for 16.7% theoreticalBSA loading with size around 320 nm. The effect of theoreticalprotein loading on the encapsulation efficiency and particles sizewas studied on various PLA-TPGS copolymers and PLGA NP. PLA-TPGS can realize much higher encapsulation efficiency comparedwith 64.5% for PLGA NP at 16.7% theoretical protein loading. Besidesthese, PLA-TPGS was found to protect BSA from aggregation anddeterioration by stable degradation microenvironment.

7.3. Drug or imaging agent encapsulation

7.3.1. DocetaxelGan CW et al. fabricated DOC-loaded PLA-TPGS nanoparticles

with desired size and pharmaceutical properties. NPs demon-strated the higher cellular uptake and therapeutic effects in MCF-7cancer cells compared with normal PLGA NP formulation. NPformulation can achieve a 360-h effective chemotherapy with 3.44-fold higher therapeutic effect and 4.42-fold lower side effect thanthat of Taxotere� at the same dose of 10 mg/kg (as seen in Fig. 5 andTable 2). There are different biodistribution from NP compared withcommercial drug formulation (as seen in Fig. 6). Accumulation ofthe drug in various important organs, except lungs was relativelylower for the NPs formulation, thus reducing the side effects

Fig. 5. In vivo pharmacokinetics profiles of DOC plasma concentration vs. time after i.v. aSpragueeDawley rats at the same DOC dose of 10 mg/kg (n ¼ 5) (reproduction from [107]

from toxic adjuvant used in Taxotere�. Moreover, there is drugdistributed in the brain which may provide the drug-loadednanoparticles to deliver drug across the bloodebrain barrier [107].

Feng et al. fabricated DOC-loaded PLA-TPGS NP or PLA-TPGS/MMT NP with sustained release [105]. TPGS was used to takeadvantages of high emulsification effects and high drug encapsu-lation efficiency, and those in drug formulation such as high cellularadhesion and adsorption. MMT of similar effects is also a detoxifier,which may cure some side effects caused by the formulated drug.The particles released loaded drug around 28.6% and 21% for PLA-TPGS NP and PLA-TPGS/MMT NP, respectively in the first 5 daysand after 28 days, 40.7% and 28.4% loaded drug were released,respectively. PLA-TPGS NP and PLA-TPGS/MMT NP enhancedcellular uptake on Caco-2 cells 1.48-, 1.62-, 1.68-fold and 1.78-,2.28-, 2.59-fold respectively than the PLGA NP at the incubationconcentration of 100, 250, 500 mg/ml, respectively. There are similartendency for MCF breast cancer cells. The cell cytotoxicity of theformulations were ranged as PLA-TPGS/MMT NP formulation>PLA-TPGS NP formulation >Taxotere�. Considered about IC50value, PLAeTPGS/MMT NP formulation was found 2.89, 3.98, 2.12-fold more effective and the PLAeTPGS NP formulation could be1.774, 2.58, 1.58-fold more effective than the Taxotere� after 24, 48,72 h treatment, respectively. PLAeTPGS/MMT NP formulation andthe PLAeTPGS NP formulation were found to increase the half-lifeof formulated drug up to 26.4 and 20.6-fold, respectively afteroral administration compared to 22 h for i.v. administration of

dministration of Taxotere� and the TPGS-emulsified PLA-TPGS NPs formulation usingwith permission).

Fig. 6. Biodistribution of DOC formulated in (A) Taxotere� and (B) PLA-TPGS NPs after i.v. administration at the same DOC dose of 10 mg/kg to SD rats. (C) DOC content in the brain at1, 5, 10 and 24 h after i.v. administration (n ¼ 3) (reproduction from [107] with permission).


Taxotere at the same 10 mg/kg dose (as seen in Fig. 7 and Table 3).Furthermore, the PLAeTPGS/MMT NP formulation and PLAeTPGSNP formulation exhibited significantly increase of oral bioavail-ability up to 78% and 91%, respectively compared to that of 3.59% forTaxotere�, 16% for normal PLGA NP and 21% for PLGA/MMT NP. PLA-TPGS or PLA-TPGS/MMT NP provided great potential for oralchemotherapy.

Sun BF et al. fabricated targeted delivery of DOC NP with PLA-TPGS NP as matrix [108]. The particles surface was conjugated

with trastuzumab for realizing targeting for HER2-over expressedcancer cells. DOC-loaded PCL-PLA-TPGS NP and PLGA-TPGS NPwere also exhibited increased drug encapsulation efficiency up to99% for 10% DOC, internalization by human cervix carcinoma cells(HeLa) and increased cell cytotoxicity on MCF-7 and HeLa cellscompared with commercial Taxotere� [94e96]. DOC-loaded TPGS-PCL-PGA NP could effectively inhibit the growth of MCF-7 tumorover a longer period of time than Taxotere� at the same dose onSCID mice [97].

Fig. 7. Plasma concentrationetime profiles of DOC after oral administration to SD rats at 10 mg/kg dose formulated in the PLAeTPGS NPs or Taxotere�, compared with the i.v.administration of Taxotere� (n ¼ 5). The therapeutic window is defined as the drug concentration in plasma between the maximum tolerated level (2700 ng/ml) and the minimum-effective level (35 ng/ml), which are calculated from the in vitro cytotoxicity.


7.3.2. PaclitaxelPTX-loaded PLA-TPGS copolymers nanoparticles with various

TPGS component in the copolymers were fabricated by solventextraction/evaporation method as discussed in fabrication methodpart. The copolymers nanoparticles demonstrated higher cellularuptake compared to normal PVA emulsified PLGA formulation andhigher cell cytotoxicity of drug nanoparticles formulationcompared to commercial Taxol� [12,102]. Paclitaxel-loaded variousPLA-TPGS copolymer NP was fabricated by dialysis method withoptimization [10,109]. Cellular uptake on HT-29 cells was enhanced1.6-fold for PLA-TPGS 92:8 copolymer NP and 1.8-fold for PLA-TPGS88:12 copolymer NP (PLA-TPGS 88:12 means the weight ratio ofPLA/TPGS in the copolymer) compared with PLGA NP after incu-bating with coumarin-loaded NP at 250 mg/ml NP concentration for2 h. PLA-TPGS 98:2 copolymer NP did not show any significantenhancement which may attribute to not enough TPGS amountdistribute on the surface of NP. Caco-2 cell uptake efficiency alsoexhibited the similar enhancement from PLA-TPGS NP. The cellularuptake was more confirmed form confocal microscopic images.In vivo pharmaceutical and biodistribution study demonstratedgreat potential of the copolymer for cancer therapy. After i.v.administration, most of rats showed weak life signal and even deadwhile we increased dosage of Taxol� for more than 10 mg/kg bodyweight of rats. However, more than 80 mg/kg PTX amount loaded inNP can be injected to rats without losing or sick from rats.

Table 3Pharmacokinetics in SD rats after i.v. administration of Taxotere� and oral DOC formulatesame 10 mg/kg drug dose (reproduction from [105] with permission).

PK parameters Taxotere� (i.v.) Taxotere� (oral) PLGA NPs (oral)

Cmax (ng/ml) 15,500 � 3420 604 � 110.6 450 � 94.6tmax (h) 0.5 2.5 2AUC0�N (ng-h/ml) 116,600 � 1722 4192 � 852 19,010 � 1530t1/2 (h) 4.5 � 2.85 6.9 � 2.1 114.3 � 21.3MRT (h) 5.86 � 3.64 8.56 � 1.56 126 � 28.9Absolute bioavailability e 3.5% 16%

Furthermore, 39% of AUC value from clinical administrationformulation Taxol� was distributed above the toxic drug level8540 ng/ml which may cause toxic to rats. Compared with Taxol�,the copolymer NP exhibited sustained release the drug in vivo andno toxic level demonstrated from drug concentration vs. timecurve. The circulation time was also significantly increased from thecopolymer NP. PLA-TPGS 88:12 NP achieved 76.8 h of t1/2 and 69.0 hof MRT compared with Taxol�, 2.8 h and 2.6 h, respectively. AUCvalue of drug loaded copolymer NP was 1.6-fold of Taxol�. NPaffected in vivo distribution of the drug after administrationcompared with Taxol� and may have potential to use for deliveringdrug to cross BBB in future. Xenograft results after inoculated HT-29cells to SCID mice further confirmed drug loaded NP advantagescompared with Taxol� formulation. After 35 days, only one third ofmice were survived from treatment compared with 100% from NPtreatment.

7.3.3. DoxorubicinDOX-loaded PLGA-TPGS NP was fabricated by solvent extrac-

tion/evaporation method with particles size 350 nm [93]. In thefabrication, DOX was conjugated with PLGA-TPGS or loaded in theparticles by physical form (DOX was dissolved in acetone in thepresence of TEA as molar ratio 1:2). The particles can realize tar-geting effect for folate-receptor rich tumors by including TPGS-FOLin fabricating NP. In the blending for fabricating NP, 0%, 20%, 33%

d in the Taxotere�, PLGA NPs, PLGA/MMT, PLAeTPGS NPs and PLAeTPGS/MMT at the

PLGA/MMT NPs (oral) PLA-TPGS NPs (oral) PLA-TPGS/MMT NPs (oral)

567 � 103.5 919 � 148.5 1012 � 4004 2.5 4.524,400 � 2310 106,420 � 5930 90,900 � 320060 � 19.7 92.6 � 13.4 118.8 � 24.578.9 � 20.1 167.2 � 20.9 171.8 � 35.821% 91% 78%


and 50% TPGS-FOL was added and denoted the NP as 0% TPGS-FOLNP, 20%TPGS-FOL NP, 33% TPGS-FOL NP and 50% TPGS-FOL NP,respectively. NP can realize around 80% drug loading for3.47e4.96% DOX drug loading (2% physical drug loading) with sizearound 320e350 nm. After 30 days, 48.3%, 50.3%, 52.1% and 65.1% ofthe entrapped drug was released from the 0%, 20%, 33% and 50%TPGS-FOL NPs, respectively. TPGS-FOL affect the drug release whichcan be attributed to the smaller molecular weight of TPGS-FOL,hydrophilicity and increased TPGS-FOL content occupied thesurface of NP. Folate was decorated on the surface of NP was seenfrom XPS analysis. The cell viability was decreased from 51% for 0%TPGS-FOL NP to 8.2% for 50% TPGS-FOL NP for MCF-7 cells and49.6%e30.6% for C6 cells. 50% TPGS-FOL NP with 50% TPGS-FOL inblend of fabricating NP enhanced the cellular uptake up to 1.4-foldfor MCF-7 cells and 1.3-fold for C6 cells.

Li et al. fabricated DOX-loaded PLLA40-TPGS NP with 98.5%encapsulation efficiency. When changed polymer/drug ratio from5/2 to 15/1 in the nanoprecipitation method, the particles can beoptimized from 275 nm to 131 nm with encapsulation efficiencyincrease from 69% to 98.5% [98]. The particles released entrappedDOX much faster in pH 5.0 compared with pH7.4 from vitro drugrelease experiment. PLA-TPGS NP was found to inhibit the P-gpactivity without changing its expression and enhanced intracellulardrug accumulation in MCF-7/ADR cells from calcein AM experi-ment, cellular uptake study by flow cytometry and intracellularlocalization by confocal results. PLA-TPGS NP promoted trans-location of DOX into the nucleus and enhanced the cellular uptakeof DOX by MCF-7/ADR cells. Furthermore NP also significantlyenhanced the loaded drug cytotoxicity at the incubated concen-tration of 20 mM. The cell viability of cells treated with drug loadednanoparticles was decreased to 37.6% from 66% for the free drug.PLA-TPGS nanoparticles carrying DOX can result in combinationeffect of P-gp efflux pump inhibition and increase of drug enteringinto nucleus of drug-resistant MCF/ADR cells. It was demonstratedthe increased cell mortality of drug loaded nanoparticles, cellularuptake and nuclear accumulation of drug on MCF/ADR cells[98,110].

7.3.4. Curcumin and RisperidoneCurcumin is a natural substance applying in inhibiting and/or

treating carcinogenesis, however, its poor solubility limited itstreatment efficacy and application. Ha et al fabricated curcumin-loaded PLA-TPGS NP [92]. In this research the researcher usedPLA-TPGS 50:50 copolymer to fabricate drug loaded micelles.Curcumin-loaded PLA-TPGS micelles were fabricated by dissolvingdrug in methanol and copolymer in DCM and then after solventevaporation, the mixture was mixed with PBS. The particles wereformed with size 100e400 nm and also tinny particles with size20e40 nm. Risperidone-loaded PCL-TPGS microparticles werefabricated by a modified solvent extraction/evaporation methodwithout extra emulsifier. The copolymer MP was found to signifi-cantly increase the drug release than PCL MP [111].

7.3.5. Protein deliveryLee et al. investigated PLA-TPGS copolymers for protein delivery

[106]. The protein-loaded nanoparticles were fabricated by doubleemulsion method with higher encapsulation efficiency. As theincreasing of TPGS composition in the copolymers, the BSAencapsulation efficiency was decreased from 75.6% for PLA-TPGS97:3 copolymer to 68.8% for PLA-TPGS 94:6 and 44.3% for PLA-TPGS 88:12 copolymer NP for 16.7% BSA theoretical loading. It isattributed to the higher TPGS composition, the lower copolymermolecular weight and higher hydrophilicity from the copolymersand thus higher hydrophilicity of copolymers NPs. The particles sizewas also decreased from 362 nm for PLA-TPGS 97:3 copolymer NP

to 274 nm for PLA-TPGS 88:12 NP. PLA-TPGS degradation wasaffected by the molecular weight and TPGS content in the copoly-mers. The higher hydrophilicity for higher TPGS content of copol-ymers led to faster erosion of polymer matrix. After 35 days, therewas around 16%, 27.2% and 51.5% weight loss happened for PLA-TPGS 97:3, 94:6 and 88:12 copolymers. However, the degradationof BSA-loaded nanoparticles was accelerated which may beattributed to the acidic byproducts during degradation catalyzedthe degradation of copolymers [112,113]. The acidic byproducts cancause a decrease in the pH value and acidic microenvironmentwhich cause the denature of protein drugs. Compared with PLGANP, PLA-TPGS showed much smaller and slower pH change duringdegradation. After 35 days, the pH value was changed from 7.4 to6.3 for BSA-loaded PLGA NP but there was less 0.1 change from PLA-TPGS series NPs. It seems that copolymers NP can protect proteindrugs more efficiently compared with PLGA NP. BSA-loaded PLGANP showed a initial burst release followed by a slow and non-release profile which may be attributed to the non-covalentprotein aggregation happened due to the acidic microenviron-ment from the degradation of PLGA. PLA-TPGS copolymer NPsshowed a biphasic BSA release profile and the release rate depen-ded on the TPGS compositions in the copolymers. After initial burstrelease, 80%, 55% and 43% of entrapped BSA released from PLA-TPGS 88:12, 94:6 and 97:3 copolymers nanoparticles after 30days incubation in PBS at 37 �C, respectively. The release was alsoaffected by the BSA loading. The higher BSA loading, the fasterin vitro release happened from the similar PLA-TPGS NPs. To furtherstudy the advantages of PLA-TPGS copolymers, the BSA integritywas studied by SDS-PAGE for released BSA from NPs. The primarystructure of BSA can be retained more than 5 weeks for PLA-TPGS94:6 NPs. However, the protein aggregation happened after firstday release from the presence of higher molecular weight band.There were not significant alterations in the CD spectra of BSAreleased from copolymers NPs but decrease in the alfa-helixcontent presented from PLGA NP. The copolymer nanoparticleshave great potential to protein drug delivery.

7.3.6. Supraparamagnetic iron oxidesSuperparamagnetic iron oxide nanocrystals are developed for

assessing and treating diseases in humans. Prashant C et al devel-oped PLA-TPGS NP for SPIOs encapsulation for medical imaging bymagnetic resonance imaging (MRI) [11,73]. IO nanoparticles werewell dispersed within PLA-TPGS NP as visualized from TEM imagesand the nanoparticles were prepared by single emulsion method ornanoprecipitation method with optimization. The biocompatibilityand cellular uptake of IOs-PLA-TPGS NP were studied on MCF-7breast cancer cells and NIH-3T3 mouse fibroblast cells withcomparison to commercial formulation, Resovist�. The copolymerNP can achieve 256 nm with 64% encapsulation efficiency for 1.2%Fe loaded in nanoparticles with monodisperse nature. Nanocrystalswas distributed uniformly in the matrix with enhanced biocom-patibility of the nanocrystals as cell toxicity study [73]. Comparedwith commercial particles, PLA-TPGS NP was w10 fold less toxic toNIH-3T3 mouse fibroblast cell line. PLA-TPGS NP formulated IOswere good contrast agent for T2 weighted imaging using MRI andcan be cleared in liver within 24 h compared with several weeks forResovist� [73]. Nanoparticles formulation demonstrated theenhanced permeation and retention (EPR) effect of the tumorvasculature compared with commercial Resovist� from xenografttumor model MRI study [11].

7.3.7. Quantum dotsQDs have been widely studied as luminescence probes in

medical images in recent years which may be due to its broadexcitation spectra, high quantum yield of fluorscence, strong


brightness, excellent photostability and high resistance to photo-bleaching. To reduce its toxicity, recent strategy was used to loadQDs in polymeric NP which could greatly improve its biocompati-bility, stability and realize a controlled and sustained release. Tofurther reduce the toxicity and increase the efficiency in medicalimaging. QDs-loaded PLA-TPGS NP was fabricated by modifiedsolvent extraction evaporation method with PVA as surfactant.0.15 ml 1 mM organic QDs was mixed with PLA-TPGS DCM solutionand poured into water phase with 0.5% PVA. After sonicated for3 min at 20W output, the NP was collected as normal singleemulsion method. MAA-coated QDs was also fabricated ascomparison on side effects and imaging effect with NP. PLA-TPGS88:12 (weight ratio, Mw ¼ 23,072) was used in NP fabrication.The particles size was around 200 nm with no QDs located in thesurface of NP from XPS analysis. QDs were confirmed in the NP fromTEM images and XPS analysis and NP was covered by TPGS on thesurface which can realized advantages of TPGS in NP. PLA-TPGS NPachieved better photostability by protecting QDs emission inten-sities after irradiation. For free QDs, the relative emission intensitywere almost decreased to zero at 12 h, whereas, NP can still keepthe intensity even after 30 days irradiation process. NP entrappedQDs exhibited higher cell viability compared with MAA-coated QDson MCF-7 cells. In summary, PLA-TPGS copolymer can entrap QDsin the NP with relative small size, realized protection effect on QDsfrom long term irradiation, reduced its side effects and improvedthe biocompatibility compared with free QDs. It has potential to useNP entrap QDs as cell imaging which may promote QDs applicationin medical imaging without serious side effects [104]. Foliate-decorated QDs-loaded PLA-TPGS NP was further formulated withtargeting cancer diagnosis [103].

7.3.8. Multimodal imaging systemCo-delivery of IOs and QDs in PLA-TPGS NP was fabricated by

modified nanoprecipitation method for concurrent imaging of themagnetic resonance imaging (MRI) and the fluorescence imaging.These multimodal imaging will combine their advantages, over-come their disadvantages, promote a sustained and controlledimaging with passive targeting effects to the diseased cells. Thetransmission electron microscopy (TEM) images exhibited directevidence that QDs and IOs well dispersed and distributed withinthe PLA-TPGS NPs (as seen in Fig. 8). These multimodal imagingexhibited great advantages of both contrast agents making theresultant probe highly sensitive with good depth penetration (asseen in Figs. 9e11). The copolymer PLA-TPGS can realize the PLA forthe needed mechanical strength and biodegradability, and TPGScomponent for enhancing the biocompatibility and providingstealth from RES as well as inhibits the multiple drug resistance(MDR) [114e116].

Fig. 8. TEM Images of A: the IOs-loaded PLA-TPGS NPs, B: the QDs-loaded PLA-TPGS NPs andwith permission).

8. Targeting strategies

Although TPGS itself cannot realize targeting effect but it can beused as the linking agent for realizing different targeting effect innanoparticles fabrication. Foliate was widely studied on targetingdrug delivery because most of tumor cells overexpressed foliatereceptor on the tumor cell surface compared with normal cells.Foliate has small molecular weight and is not easy to apply asmatrix of nanoparticles or without effect after directly added todrug solution. There are two ways for targeting delivery from TPGSin NP until now developed, one way was to use TPGS-COOH as theblend matrix with polymer to fabricate polymer NP and then tar-geting agent was post-conjugated to the surface with TPGS-COOHdecorated NP. Another way was to synthesis TPGS-Folate or othertargeting agent and then as blend matrix to fabricate NP withfolate-decorated NP. Until now there was not report on thecomparison with these two kinds of targeting strategies.

8.1. TPGS-FOL conjugate

Zhang ZP et al. synthesized TPGS-Folate polymer and appliedthis polymer for targeting delivery of copolymer NP. TPGS-FOLsynthesis was shown as Scheme 4. TPGS-NHS was synthesized byreacting TPGS, glutaric acid and DCC at molar ratio 1:1:1 in DMSOunder nitrogen at room temperature for 24 h the product wasfiltered, dialyzed against DMSO for 24 h, dialyzed against water for24 h and then freeze-dried. The product was further reacted withNHS/DCC for 6 h at 50 �C at molar ratio 1:2:2. FOL-NH2 wasproduced by reacting folate with DCC/NHS in DMSO for 6 h at 50 �Cand then reacted with excess ethylene diamine in the presence ofpyridine as catalyst. TPGS-NHS and FOL-NH2 was reacted in DMSOat molar ratio 1:2 for 2 days at room temperature and then dialyzedand freeze-dried to get yellowish product TPGS-FOL [93]. DifferentTPGS-FOL blend component with PLGA-TPGS was utilized tofabricate targeting NP for folate-receptor rich tumors. XPS imagesexhibited folate decorated on the surface of NP. NP realized tar-geting effect from in vitro cellular uptake and cell viability results.Compared with no TPGS-FOL NP, 50% TPGS-FOL NP increased celluptake efficiency up to 1.5-fold and 1.6-fold for MCF-7 and C6 cellsafter incubated with cells for 1.5 h, respectively. IC50 value of MCF7cells was decreased from >100uM for 0% TPGS-FOL NP to 39.8, 28.5,19.4 mM for 20%, 33% and 50% TPGS-FOL NP, respectively which wasalso lower than 43.7 mM for free drug. For C6 cells, the value wasdecreased from 95.9 mM for 0% TPGS-FOL NP to 12.6, 7.47, and3.25 mM for TPGS decorated NP. Confocal images results alsodemonstrated the targeting effect from TPGS-FOL decorated NPand folate-receptor mediate endocytosis was exhibited [93]. TPGS-FOL was also added in fabricating PTX-loaded PLA-MPEG

C: the QDs and IOs-loaded PLA-TPGS NPs (scale bar ¼ 200 nm) (Reproduced from [114]

Fig. 9. Axial MRI image sections of the MCF-7 grafted tumor bearing mice. Images A and B show the part of the tumor (shown by the arrow) before and after 6 h of administration ofthe QDs and IOs-loaded PLA-TPGS NPs into the mice. Images C and D show the kidney (K) and liver (L) part of the mice before and 6 h after the administration of the PLA-TPGS NPsformulation of QDS and IOs (dosage: 1.5 mg of Cd/kg of body weight or equivalent of 6.0 mg of Fe/kg body weight). The decrease in intensity in the regions of the tumor and liver canbe noticed in comparison with the color scale aside (reproduction from [114] with permission).


nanoparticles with 50% TPGS-FOL, which increased cellular uptakefor tumor HeLa and glioma C6 cells but no difference on NIH3T3cells [117].

Foliate targeting strategy was also developed in the DOX pro-drug by conjugating foliate with TPGS-DOX conjugate, TPGS-DOX-FOL. The TPGS-DOX conjugate increased the cellular uptake ofDOX by 15.2% compared with free drug and further increased 6.3%for TPGS-DOX-FOL for 0.5 h cell culture. Also the IC50 value for 24 hcell culture with MCF-7 cells exhibited 1.19 and 45.0-fold moreeffective than the free drug for the prodrug and TPGS-DOX-FOL,respectively. The prodrug and the targeted formulation of pro-drug showed 3.79- and 3.9-fold higher half life and 19.2- and 14.5-fold of AUC than DOX, respectively. The targeting formulation alsofurther reduced the cardiotoxicity and gastrointestinal side effectby changing the in vivo biodistribution of the drug to heart andgastrointestinal tract [9].

8.2. TPGS-COOH

Pan et al. fabricated PLGA NP with TPGS-COOH as co-matrix.Foliate was activated to foliate-NH2 by DCC/NHS method and canbe reacted with TPGS-COOH group in the nanoparticles by EDC/NHS method (as seen in Scheme 5) [103,118]. The researchers usedpost-conjugation method to induce targeting agent foliate andconsidered targeted NP effect on MCF-7 cells which overexpressfoliate receptors and NIH313 cells with few foliate receptors.Compared with non-targeted NP, foliate conjugated NP exhibitsmuch higher cellular uptaken on MCF-7 cells which not shown inNIH313 cells. Foliate-conjugated TPGS-COOH co-matrix PLGAnanoparticles achieved 11.22-fold decrease in IC50 value ofentrapped DOC which is much higher than 7.58-fold decrease inIC50 for non-targeted nanoparticles after 48 h incubation with MCF-

7 breast cancer cells. Foliate post-conjugated TPGS-COOH/PLGAnanoparticles was also showed better imaging effects. 16.7% foliate-decorated NPs achieved 1.03-, 1.12-, 1.12-, and 1.25-fold highercellular uptake efficiency than non-targeted TPGS-COOH/PLGA NPsafter 0.5,1.0, 2.0 and 4.0 h incubation with MCF-7 cells, respectively.It seems that introducing TPGS-COOH in the fabrication of nano-particles can realize post-conjugating of targeting agents and evenprecise controlling on targeting agents on the surface of nano-particles by controlling TPGS amount in fabricating nanoparticles.The targeting effect was affected by TPGS amount and post-conjugation. Pan et al also used this post-conjugation methodfabricated quantum dots-loaded PLA-TPGS NP. From XPS images wecan see, the weight percentages of nitrogen on the particles surfacewere 3.62% and 4.33% for NP with 11.1% and 16.7% TPGS-COOH inthe blend of matrix while fabricating NP, respectively [103]. Tar-geting delivery of PTX was realized by using TPGS-COOH blendedwith PLA-TPGS in matrix fabricating NP. NP contained 9.1%, 16.7%and 33.3% TPGS-COOH in the fabricating mixture was studied toanalyze foliate amount effect on cellular uptake and cytotoxicity.16% FD NP (containing 16.7% TPGS-COOH in fabricating NP andfoliate conjugated, FC NP means non foliate conjugated) demon-strated 1.5 and 1.6-fold higher cellular uptake than FC NP after 4 hincubation with MCF-7 cells and the glioma C6 cells, respectively.Cell viability on MCF cells was decreased from 53.0% for Taxol�, to48.4% for 0% FC NP, 36.6% 16.7% FD NP and 33.4% for 33.3% FD NPafter incubated 24 h with 25 mg/ml drug concentration. As thesimilar way, FD NP also enhanced cell cytotoxicity on C6 cells. After24 h incubating with the formulations, the cell viability wasdecreased from 43.8% for Taxol� to 38.6% for 0% FC NP, 29.2% and27.9% for 16.7% and 33.3% FD NP, respectively [119].

Trastuzumab, a humanized monoclonal antibody directedagainst the human epidermal growth factor receptor-2 (HER2), is

Fig. 10. Confocal laser scanning microscopy sections of the mouse tumor sections. Images A, B and C show the tumor sections of the control with no treatment (scale bar 30 mm). A:Blue coded DAPI stained nuclei. B: Red channel detection showing no signal due to absence of QDs. C: Complete overlapped image of A and B. Images D, E and F show the tumorsections of the mouse treated with the QDs and IOs-loaded PLA-TPGS NPs (scale bar 20 mm). D: Blue coded DAPI stained nuclei. E: Red coded QD from NPs in cytoplasm. F: Completeoverlapped image (reproduction from [114] with permission). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of thisarticle.)


overexpressed in 25e30% breast cancers. There has been syner-gistic effects while combination therapy of trastuzumab and PTX.Sun BF et al fabricated PLA-TPGS NP loaded DOC or PTX withtrastuzumab functionalized [108,120]. NPs were fabricated by usingTPGS-COOH and PLA-TPGS as matrix and emulsified with TPGS.Trastuzumab can be conjugated to the surface of NP by EDC/NHSmethod. The in vitro targeting effect was studied by SK-BR-3(higher HER2 overexpression) and MCF-7 cells (moderate HER2overexpression) after incubated with 125 mg/ml coumarin-loadedtargeted nanoparticles or non-targeting conjugated nanoparticlesat 37 �C. Trastuzumab-conjugated nanoparticles exhibited 1.36-,1.33-, 1.31-, and 1.28-fold higher for SK-BR-3 cells and 1.21-, 1.17-,

Fig. 11. Field emission transmission electron microscope (FETEM) image of immunog

1.15-, 1.17-fold higher for MCF-7 cells after incubated for 0.5, 1, 2,and 4 h, respectively compared with non-conjugated nanoparticles.The cell mortality also demonstrated the advantages oftrastuzumab-conjugated nanoparticles. Targeting nanoparticlesshowed 1.22-fold and 1.70-fold more effective for MCF-7 and SK-BR-3 cells, respectively. It also shows evidence that targetingeffect of nanoparticles depend on the HER2 receptor expression onthe cells. It seems that TPGS-COOH can be acted as targeting agentlinker and co-matrix for fabricating nanoparticles. There iscombinational effect from anticancer drug DOC and antibodytherapy, trastuzumab [108,121]. Zhao J et al further realizedprecisely control the targeting effects by adjusting PLA-TPGS:TPGS-

old labeled PLAS-TPGS nanoparticles (reproduction from [121] with permission).

Scheme 4. Synthetic scheme of TPGS-FOL conjugate (reproduction from [93] with permission).


COOH copolymer blend ratio for coarse control in the NP formu-lation process and feeding concentration of the ligand in the her-ceptin conjugation process for fine control [121].

8.3. Antibody coated on the surface of nanoparticles

Transferrin (Tf), a single polypeptide glycoprotein with about679 amino acids, is a co-factor in DNA replication, iron transport forcellular growth or differentiation. Tf conjugated PLA-TPGS NP(simply PLA-TPGS/Tf-NP) loaded DOC exhibited great advantagesover PLA-TPGS NP or Taxotere� formulation. The particles size wasaround 160 nm with 79% encapsulation efficiency to DOC. Tf wasadsorbed on the surface of NPs from N atom signal from XPS resultson the N binding energy scan region. There was not any N signal inPLA-TPGS NP or PLGA NP XPS results but the obvious N signaldemonstrated in Tf conjugated PLA-TPGS NP XPS image. The signalattributed to the N-glycosidic chains of the Tf, which allows thatthe Tf on the surface of nanoparticles can interact with Tf receptoron the cell surface and achieve targeting effect. In vitro cellularuptake and confocal images after coumarin 6-loaded nanoparticleswere incubated with glioma C6 cells also exhibited the targetingeffect. Tf conjugated targeting nanoparticles exhibited strongerintensity compared with PLA-TPGS NP or PLGA NP or extra Tfconjugated NP with extra Tf reagent in culture medium to compete

with NP. Tf conjugated NP demonstrated higher cellular uptakewas attributed to Tf conjugated on the surface of nanoparticles andthe activity would be blocked after including extra Tf. IC50 dataafter formulations were incubated with C6 cells 24 h also showedthat the advantages of Tf-conjugated PLA-TPGS NPs formulation ofDOC. The IC50 of Tf conjugated NPs was lower as 5.10 mg/mlcompared with 6.53 mg/ml, 5.96 mg/ml and 16.77 mg/ml for PLGANP, PLA-TPGS NP and clinical formulation, respectively. The parti-cles formulation exhibited 23.4%, 16.9% and 229% more efficientthan the PLGA NPs, the PLA-TPGS NPs formulations and Taxotere�

after 24 h treatment, respectively. Coumarin-loaded Tf conjugatedPLA-TPGS NP also demonstrated significant higher ex vivo distri-bution in brain and benefit to be developed to deliver imaging/therapeutic agents across the blood brain barrier for furtherdevelopment [99].

9. Advantages of the PLA-TPGS series copolymer

PLA-TPGS has been shows as potential candidate for drugdelivery carrier as exhibited above. It can be developed to deliveranticancer reagent such as pacltiaxel, DOC, DOX, protein BSA, andimaging reagent QDs and iron nanoparticles and so on with higherencapsulation efficiency compared with commonly used PLGA. Theamphiphilic structure of the polymer can promote nanoparticles

Scheme 5. Preparation scheme for folic acid-conjugated PLGA/TPGS-COOH nanoparticles loaded with quantum dots, a model imaging agent and DOC, a model drug (reproductionfrom [118] with permission).


increased the cellular uptake of NPs and cell cytotoxicity of payload,extended much longer circulation time in vivo, across some barriersuch as blood brain barrier. Li et al found the PLA-TPGS NP caninhibit P-gp activity without changing P-gp expression [98]. PLA-TPGS NP may inhibit the efflux pump and increase the entry ofDOX into the nucleus in drug-resistant MCF7/ADR cells. It seemsthat the copolymer NP may have great potential for i.v. or oral andcross blood brain barrier drug delivery of protein or anticancerdrugs. The oral bioavailability of DOC was increased from 3.59% forTaxotere� (10 mg/kg drug dose) to 16%, 21%, 91% and 78% for PLGANP, PLGA/MMT NP, PLA-TPGS NP and PLA-TPGS/MMT NP, respec-tively [105]. Furthermore, the polymer can be mixed with TPGS-foliate or other targeting agent to realize targeting effect of nano-particles or conjugated with targeted agent such as Tf. Nano-particles encapsulated imaging agent can be developed as imagingnanoparticles in further development. The recent developmentmay be due to the amphiphilic structure from the polymer and thepolymer NP can realize TPGS bound to the surface of nanoparticles,which is much stronger and stable than TPGS-emulsified PLA orPLGA nanoparticles. Until now we need more data to support thecopolymer application. There was not data exhibited the compar-ison between PLA-MPEG and PLA-TPGS polymers. Still there ismore space for in vivo experiment need to be developed on thiskind of polymers.

Acknowledgments

The work was financially supported jointly by National BasicResearch Program of China (973 Program, 2012CB932500) and theSingapore-China Collaborative Grant, A*STAR, Singapore (R-398-000-077-305, PI: SS Feng) and NUS FRC R-397-000-136-731 (Co-PI:SS Feng).

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