J Biomaterials 2012 03 046

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 China
b
National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430030, PR China
c
Department of Chemical & Biomolecular Engineering, National University of Singapore, Block E5, 02-11, 4 Engineering Drive 4, Singapore 117576, Singapore
d
Department of Bioengineering, National University of Singapore, Block E5, 02-11, 4 Engineering Drive 4, Singapore 117576, Singapore
e
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 2012
Accepted 13 March 2012
Available online 11 April 2012
Keywords:
Cancer nanotechnology
Biodegradable polymers
Liposomes
Micelles
Nanoparticles
Prodrugs
a b s t r a c t
D-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS, or simply TPGS) is awater-soluble deriv-
ative of natural Vitamin E, which is formed by esterication of Vitamin E succinate with polyethylene
glycol (PEG). As such, it has advantages of PEG and Vitamin E in application of various nanocarriers for
drugdelivery, includingextendingthehalf-lifeof thedruginplasmaandenhancingthecellular uptakeof
the drug. TPGS has an amphiphilic structure of lipophilic alkyl tail and hydrophilic polar head with
a 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 drug
delivery systems, including prodrugs, micelles, liposomes and nanoparticles, which would be able to
realize sustained, controlled and targeted drug delivery as well as to overcome multidrug resistance
(MDR) andtopromoteoral drugdeliveryasan inhibitor of P-glycoprotein(P-gp). Inthisreview, webriey
discussitsphysicochemical andpharmaceutical propertiesanditswideapplicationsincompositionof the
various nanocarriers for drug delivery, which we call TPGS-based drug delivery systems.
2012 Elsevier Ltd. All rights reserved.
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 esterication of
Vitamin E succinate with polyethylene glycol (PEG). As such it has
advantages of PEG and Vitamin E in application of various drug
delivery device, including extending the half-life of the drug in
plasmaandenhancingthecellular uptakeof thedrug. Typically, the
molecular weight of TPGSwith PEG1000segment is1513. TPGShas
amphiphilic structure of lipophilic alkyl tail and hydrophilic polar
head with a hydrophile-lipophile balance (HLB) value of 13.2 and
acritical micelleconcentration (CMC) of 0.02%w/w [1]. TPGSsafety
issuehas been investigated in details and it has been reported that
the acute oral median lethal dose (LD50), which is dened as the
quantity of an agent that will kill 50 percent of the test subjects
within adesignated period, is >/7g/kgfor youngadult rats of both
sexes [2]. US FDA has approved TPGS as a safe pharmaceutical
adjuvant used in drug formulation.
In recent years TPGShas been intensivelyapplied in developing
the various drug delivery systems. TPGS has been used as an
absorption enhancer, emulsier, solublizer, additive, permeation
enhancer and stabilizer [3,4]. TPGS has also been served as the
excipient for overcomingmultidrugresistance(MDR) and inhibitor
of P-glycoprotein (P-gp) for increasing the oral bioavailability of
anticancer drugs [4e7]. TPGS has also been applied for prodrug
design for enhanced chemotherapy [8,9]. Fengs group has been
focused in the past decade on various applications of TPGS in
nanomedicine, including TPGS-based prodrugs, micelles, lipo-
somes, TPGS-emulsied PLGA nanoparticles and nanoparticles of
TPGS-based copolymers, which can signicantly enhance the
solubility, permeability and stability of the formulated drug and
realize sustained, controlled and targeted drug delivery. TPGS has
been proved to be an efcient emulsier for synthesis of nano-
particles of biodegradable polymers, resulting in high drug
encapsulation efciency, high cellular uptake in vitro and high
therapeutic effects in vivo [10e12]. For example, TPGS may have
morethan77timeshigher emulsicationefciencycomparedwith
the traditional emulsier polyvinyl alcohol (PVA), i.e. to produce
the same amount of polymeric nanoparticles by the single emul-
sion method, the needed TPGSamount can be only 1/77 than that
of PVA as the emulsier used in the process. TPGS-emulsied
nanoparticles or TPGS-based nanoparticles have been found to
* Corresponding author. Department of Chemical & Biomolecular Engineering,
National University of Singapore, Block E5, 02-11, 4 Engineering Drive 4, Singapore
117576, Singapore. Tel.: 65 6874 3835; fax: 65 6779 1936.
E-mail address: chefss@nus.edu.sg (S.-S. Feng).
Contents lists available at SciVerse ScienceDirect
Biomaterials
j ournal homepage: www. el sevi er. com/ l ocat e/ bi omat eri al s
0142-9612/$ e see front matter 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.biomaterials.2012.03.046
Biomaterials 33 (2012) 4889e4906
increase the cell uptake efciency on Caco-2, HT-29, MCF-7, C6
glioma cells and thus enhance cancer cell cytotoxicity. The TPGS-
based nanoparticles have been further found in resulting in
amore desired pharmacokinetics of entrapped drugin vivo, which
couldsignicantlyextendthehalf-lifeof theformulateddruginthe
plasma. Fengs group has realized 168 h effective paclitaxel (PTX)
chemotherapy by the TPGS-emulsied 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, they
havefoundthat 400%higher drugtolerancecanbeachieved, which
could result in 360%AUC as a quantitative measurement of the
in vivo chemotherapeutical effects. It means that the animal
immune system failed to recognize and thus eliminate the nano-
particles. Theyprovedinvivothefeasibilityof nanomedicine, which
had been one of the two major concerns for the newly emerging
area nanomedicine as future medicine. They then further
conrmed such advantages of nanomedicine that the PLA-TPGS
nanoparticle formulation of PTX and docetaxel (DOC) can realize
336 h and 360 h sustained effective chemotherapy respectively in
comparison 23 h chemotherapy of Taxotere
at thesame10 mg/kg
body weight for rats. Also, a more desirable biodistribution of the
drug could be resulted with less drug in kidney, liver, heart and
morein blood and lung. Oral delivery and drugdelivery across the
bloodebrain barrier can also be achieved by further development
of the nanoparticle technology with enhanced size and size
distribution, surface functionalization, and copolymer synthesis
[13e15].
In this review, we discuss in details the advantages of the
various TPGS-based drug delivery systems such as prodrugs,
micelles, liposomes, TPGS-emulsied PLGA nanoparticles and
nanoparticles of TPGS copolymers such as PLA-TPGS, TPGS-COOH,
PCL-TPGS, and so on.
2. TPGS as prodrug carrier
Aprodrugisapharmaceutical agent whichisadministeredinan
inactive form(say conjugated to a polymer) and then bioactivated
(say released from the drug-polymer conjugate) into active
metabolites in vivo. The rationale behind a prodrug is generally to
enhancethepharmacokineticsof adrug, i.e. tooptimizetheprocess
of absorption, distribution, metabolism, and excretion (ADME).
Prodrugs areusually designed toimproveoral bioavailability of the
drug with poor absorption from the gastrointestinal tract [16,17].
Among the conjugations discussed, conjugations between biode-
gradablepolymerssuch aspolyethyleneglycol (PEG), PLA-PEG, and
poly(L-glutamicacid) (PGA) andanticancer drugssuch asDOX, PTX,
and camptothecin have been intensively investigated [18e24].
Amongthem, PEG-drugconjugation havebeen so widely used that
resulted in a special term called PEGylation, which means
conjugated to PEG [22e24]. Greenwald et al. discussed in details
PEG-conjugation application in drug delivery of small molecule
anticancer drugs such as PTX as well as biological drugs such as
peptides 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 and
severe gastrointestinal and cardiovascular toxicity. The drug resis-
tance also limits its intracellular level. To reduce side effect from
DOX, evade drug resistance and enhance its therapeutic efciency,
DOX was conjugated to TPGS in Cao et al. studies (Scheme 2) [8].
In vitro drug release from the conjugate was studied to show pH
dependent favor with no burst release. After 10 days, there were
around 52.3%, 43.6%and 12.6%DOX released after incubating
conjugate at pH 3.0, 5.0 and 7.4, respectively. DOX conjugate
exhibited higher cellular uptake of 1.7-, 1.3-, 1.2-, 1.2- fold for the
MCF-7 cells and 5.4-, 5.9-, 1.3-, 1.1-fold for thegliomaC6 cells after
0.5, 1.5, 4, 6 h culture, respectively (p < 0.05), compared with the
pristine DOX. The prodrug demonstrated 31.8, 69.6, 84.1%more
effectivewith MCF-7 breast cancer cells and 43.9, 87.7, 42.2%more
effectivewithC6gliomacellsthantheparent drugafter 24, 48, 72h
culture, respectively based on IC
50
value. After i.v. administrated
DOXpristineformulationor theprodrugat 5mg/kgdoseinrats, the
t
1/2
andMRTwereincreasedfrom2.53hand2.86hto9.65h,10.9h,
respectively as seen in Fig. 1. The AUC
0N
was also signicantly
increased from288 ng-h/ml for DOX to 6812 ng-h/ml for the pro-
drug. Biodistribution also exhibited the lower side effects of the
conjugate compared with the DOX. The AUC value from heart,
gastric, and intestinewas decreased from307, 313, and 246 mg-h/g
tissuefor theDOX to155,114.3and 86.7mg-h/gtissue, respectively.
It seems that the TPGS-DOX prodrug demonstrated higher thera-
peutic efciency and lower sideeffects compared with thepristine
drug.
Anbharasi Vet al. further developedaTPGS-DOX-folicacid(FOL)
conjugate (TPGS-DOX-FOL) for targeted chemotherapy and
compared it with TPGS-DOX conjugate and pristine DOX [9]. Tar-
geting conjugate TPGS-DOX-FOL can be 45.0-fold effective than
DOX in cytotoxicityon MCF-7cellsjudged bytheIC
50
results, while
TPGS-DOX conjugate was only 1.19-fold effective than DOX. The
half-life (t
1/2
) of TPGSeDOX and TPGSeDOXeFOL were extended
from2.69h(DOX) to10.2hand10.5h, respectively. TheAUCvalues
of TPGS-DOX andTPGS-DOX-FOLwere19.2and14.5timesthan the
DOX, respectively. Conjugates also signicantly decreased thedrug
distribution 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
PTXisoneof thebest anticancer drug, whichprocessesexcellent
therapeutic effects against various cancers such as breast and
ovarian cancers. However, due to its extremely low solubility
(<0.03 mg/L in water), its clinical administration formulation
(Taxol
) has to usean adjuvant called Cremophor EL, which causes

severe 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 of
PTX with TPGS [27]. The conjugate was expected to improve the
cellular uptake and further increase the cancer cell cytotoxicity.
Unfortunately, nofurther invitroor invivodatawerepublishedyet.
Scheme 1. Chemical structure of TPGS.
Z. Zhang et al. / Biomaterials 33 (2012) 4889e4906 4890
3. TPGS-based micelles
TPGS has micellar properties and can formulate micelles for
delivery of drug or imaging agent [28]. TPGS micelles were also
used to encapsulate other functional materials like carbon nano-
tubes [29], fullerenes or iron oxide [30]. It has been proved that
TPGS was a more effective dispersing agent of multi-wall and
single-wall carbon nanotubes than the commonly used Triton X-
100 in water. C60 was also solublized in TPGS aqueous solution
from fullerene. Highly ordered asymmetric nanoparticles, where
fullerene nanocrystals presented at the hydrophobic end of crys-
talline TPGSnanobrushes, were found after drying these solutions
[30]. Chandrasekharan et al. prepared superparamagnetic iron
oxide (IOs) loaded TPGS micelles and compared them with F127
micelles and the commercial Resovist
for thermotherapy and

magnetic resonance imaging (MRI). The IOs-loaded TPGS micelles
showed reduced toxic effect and enhanced uptake by the cancer
cells, thus resulted in a higher hyperthermia treatment efcient.
Due to the ability to escape fromreticuloendothelial system(RES),
theTPGSmicellesarealsomorepromisingthantheother twotypes
of micelles [31].
The CMC of TPGS is relatively high as mentioned above, which
may make TPGS micelles dissociate in the plasma. Thus TPGS was
usually used together with other micellar materials to formmixed
micellestoincreasethemicellestabilityandthedrugsolubilization
[32]. Mu et al. prepared mixed micelles frompoly(ethyleneglycol)-
phosphatidyl ethanolamine conjugate (PEG-PE) and TPGS with
amolar ratioof 2:1[33]. TheCMCof themixturewaswithin10
6
to
10
5
M and the solubility of camptothecin (CPT) was improved at
least 50%compared to the PEGePE micelles due to the increased
inner micelle core volume through the big vitamin E head. The
anticancer efciency of themixed micelles was quitehigh because
of their enhanced CPT solubility, permeability and stability as well
as improved cellular uptake ability [33]. This PEG-PE/TPGSsystem
wasfurther usedtoencapsulateanticancer drugsPTX andgossypol
with a 1:1 molar ratio (CMC 1.5 10
5
M) [34,35]. PTX-loaded
TPGS-lipid mixed micelles were found quite stable with only
about 20%of drug release after 48 h at 37

C. In addition, these
mixed micelles were stable in vitro under physiological modeling
conditions and, especially at low pH values and with bile acids,
which made themapplicable 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 been
in phases I and II clinical trials [36]. TPGS was able to restrict
molecular motions of copolymers in both of the corona and core
regions of themicelles, thus controllingthereleaseof 17-AAG. The
mixed micelle also improved the cytotoxicity of 17-AAG towards
SKOV-3cellscomparedwith thefreedrug17-AAG[36]. Co-delivery
of PTX and 17-AAG in PEG-DSPE/TPGS mixed micelles were also
realized, which showed advantages in vitro compared with the
PLA-PEGmicelles and free drug [37].
Other TPGS mixed micelles, such as TPGS/oleic acid pluronic P
105 [38], Pluronic P123 [39], PLGA-PEG-FOL, and Pluronic F127/
Fig. 1. Pharmacokinetic prole of the pristine DOX and theTPGSeDOX conjugateafter
i.v. injection in rats at asingleequivalent dose of 5 mg/kg(mean SD, n 4). Triangle
(:) for DOX-TPGS, diamond (-) for DOX and .for lowest effective level (reproduced
fromwith [8] permission).
O
O
O
O
H
O
O
n
H
3
C
CH
3
CH
3
CH
3
CH
3 CH
3
CH
3
CH
3
O
O O
O
O
OH
OH O O
O
HO NH
2
O OH
OH
O
O
OH
OH O O
O
HO NH
O OH
OH
O
O
O
O
O
O
n
CH
3
H
3
C
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
O
O
Vintamin E TPGS Succinic Anhydride
DMAP
100
TPGS-SA
NHS,DCC,TEA
DMSO
Doxorubicin
TPGS-DOX
O
O
O
O O
O
n
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
H
3
C
OH
O
O
Scheme 2. TPGS-DOX conjugate (reproduced from [8] with permission).
poly(butylcyanoacrylate) (PBCA) [40], have also been reported,
which all showed a solublizing ability and/or enhanced cellular
uptake. Quercetin(QT)-loadedmicelleswerefabricatedinpresence
of pluronic P123 (P123) and TPGS with proportion of 7:3 by thin-
lm hydration method. The size of the micelles was 18.43 nm
with 88.94%drugencapsulatingefciency for 10.59%drugloading.
TPGSmixed micelles were found to increasethesolubility of QT in
QT-P/TPGSfor about 2738-fold than that of crude QT in water and
can realize the sustained release and comparable in vitro
cytotoxicity [39]. TPGSwas also mixed with pluronic P105 or F127
to increase the solubility and cytotoxicity of poorly soluble anti-
cancer drug CPT. It was found to increase the drug loading up to
0.0425 0.0011% w/w for 70% of TPGS compared to
0.0254 0.0008%w/w for the micelles without TPGS. TPGS acted
as stabilizer and got 10-fold lower of theCMCvaluethan non TPGS
stabilized micelles [40]. The mixed micelle formulation was found
to signicantly increase the cytotoxicity of CPT against MCF-7
cancer cell in vitro compared to the free drug [38,41].
Mi et al. synthesized TPGS2000 and TPGS3350-FOL conjugates
and mixed them to form micelles for targeted DOC delivery [42].
TPGS2000hadalower CMC(0.0219mg/ml) thanTPGS(0.2mg/ml),
which improves the stability of this drug-loading system. The
cellular uptakeand cytotoxicity of MCF-7 cancer cells in vitro were
both greatly enhanced compared with Taxotere
, especially after
conjugatedwithfolate. Moreimportantly, TPGS2000isananalogof
TPGS, whose cytotoxicity for cancer cells was explored. There is
a signicant synergistic effect between TPGS2000 and DOC from
cytotoxicity assay as shown in Table 1. The work represents a new
concept in the design of drug delivery systems - the carrier mate-
rials of the drug delivery systemcan also have therapeutic effects,
which either modulate thesideeffects of, or promoteasynergistic
interaction with the formulated drug. Such drug delivery system
may need further investigation [42].
4. TPGS-based liposomes
TPGScanbeusedasasurfactant and/or component inliposomal
formulation, which may bring some advantages for the sustained
andcontrolleddrugdelivery[43]. Muthuet al. preparednano-sized
non-coated liposomes, PEG-DSPE coated liposomes and TPGS
coated liposomes with DOC as the anticancer agent [44]. TPGS
coated liposomes showed maximumDOCencapsulation efciency
(64%), higher cellular uptakeandcytotoxicity(84.0%decreaseinthe
IC50 value compared with that of Taxotere
). The liposome
composed of 1,2-di-(9Z-octadecenoyl)-3-trimethylammo-nium-
propane/egg phosphatidylcyoline/TPGS was fabricated for entrap-
ping disulde-linked oligodeoxyribonucleotide (ODN). The ODN-
loaded liposome demonstrated superior colloidal stability, and
efcient on cellular growth inhibition [45,46]. TPGS can act as the
stabilizer of the liposomes which may bedueto sterical hindrance
of the pancreatic enzymes by the PEG chain. The delivery vesicle
containingTPGSmay be used for oral delivery of proteins or other
drug substances with a low oral bioavailability due to gastrointes-
tinal degradation and low permeation [43,47e49]. TPGS was also
added 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 polymericmicrospheresfabricated by thedoubleemulsion
process [53]. It was also used as surfactant in fabricatingsolid lipid
nanoparticles for MDR. IC
50
of DOX-loaded SLN can be9-fold lower
than free DOX in cytotoxicity of resistant P388/ADR cell line
whereas there is not signicant difference between idarubicin and
the particles. The DOX NP with TPGSwas found to overcome P-gp
mediated MDR both in P388/ADR leukemia cells and murine
leukemia mouse model [54,55].
Recently, a drug carrier of lipidepolymer hybrid nanoparticle,
wherethepolymeric corecoated byalipid layer, was developed to
merge 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 was
found to increase the drug loading efciency and the therapeutic
efciency [56]. Cheow et al. showed that TPGSwas able to protect
the stability of hybrid nanoparticles by inclusion of TPGS in the
surface of nanoparticles in salt solutions. The polar PEG1000
components 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 of
hybrid nanoparticles [57].
5. TPGS-emulsied nanoparticles
TPGScan be used as an emulsier or an ideal coating molecule
which can achieve high drug EE (up to 100%) and higher cellular
uptake of the nanoparticles, and thus high therapeutic effects
compared with PVA emulsied nanoparticles [14]. Fengs group
did lots of works in this eld and showed many impressive results
[13,58e67]. They applied TPGS as a surfactant to fabricate PTX-
loaded PLGA nanospheres in the solvent evaporation/extraction
technique. Compared with PVA, TPGS signicantly improved the
encapsulation efciency of the drug as high as 100%with size
300e800 nm. TPGS-emulsied nanoparticles displayed a slower
release than that of PVA [58e60,67]. They fully investigated
inuenceof thedifferent factors on theformation of nanoparticles
includingratios of oil phase, aqueous phase, polymer material and
surfactant by a modied solvent extraction/evaporation technique
with TPGS as surfactant and additive of polymeric matrix. TPGS
was 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 beas low as 0.15%e0.06%but 0.02e0.03%showed thebest
yield of nanoparticles. TPGS can have 67 times higher emulsi-
cation effects than PVA in the PLGA nanoparticle. Some
researchers still used 5%in fabricating cubic phase nanoparticles
for rapamycin entrapment [71], 0.5%in fabricating PTX-loaded
poly(vl-evl-av-opd) NPs with size 57 nm by nanoprecipitation
method [72], 15%TPGS for fabricating iron oxide nanocrystals
loaded PLA-TPGS NP [11,73]. In solvent extraction evaporation
method, TPGS mainly was used as emulsier/surfactant and
coating reagent [72,74]. It was distributed on the surface of
nanoparticles from XPS and FTIR-PAS investigation of the nano-
spheres [58,59]. TPGS exhibited notable effect on the surface
properties of airewater interface as well as the lipid monolayer
[75]. In nanoprecipitation method, TPGSmainly acted as stabilizer/
surfactant [76e79]. TPGS coated on the surface of nanoparticles
can takeadvantageof P-gp inhibitor of TPGS, inhibitingtheP-gp in
MCF/ADR cells, delivery more drug into the cells and also the
Table 1
IC
50
of DOCformulated in Taxotere
, TPGS2k micelles and FA TPGS2k micelles after

24, 48, 72 h incubation with MCF-7 breast cancer cells at 37

C (reproduced from
[42] with permission).
Incubation
time (h)
IC
50
(mg/ml)
Taxotere
Micelles
without DOC
a
Micelles
with DOC
FA micelles
with DOC
24 103.4 1.350 0.526 0.178
48 1.28 1.530 0.251 0.152
72 0.148 7.58 0.233 0.114
a
The value represents the concentration of DOC, that is equivalent to the
concentration of TPGS2k for 50%viability.
enhanced cell cytotoxicity [71,80]. It also enhanced free DOX to
move from the cytoplasm into the nucleus.
5.1. TPGS-emulsied PLGA NP for i.v. administration
TPGS-emulsied PLGA NPs demonstrated 5-fold more effective
than Taxol
formulation from in vitro C6 cell mortality experi-

ments. The NP can realize a comparable AUC value as Taxol
, but
the drug concentration was never exceeded the maximum toler-
ancelevel, and henceshould greatly reducethesideeffects. Invivo
pharmacokinetics study also exhibited close to linear PK property
from TPGS-emulsied nanoparticles (as seen in Fig. 2). Rats
receivingTaxol
at doseshigher than 20mg/kgshowedapathyand

died after 1 h injection whereas there is not any apathy fromover
40 mg/kg dosage of nanoparticles. It seems that nanoparticles can
signicantly increase the drug tolerance and realize sustainable
chemotherapy. Furthermore, the particles formulation can realize
asustainabletherapeutictimeof 168h in comparisonwith 22h for
Taxol
at a same dose of 10 mg/kg. The half life of Taxol
for
a dosage of 10 mg/kg was 2.8 h only, which is much shorter than
32.6 h for nanoparticles formulation. Moreover, the AUC of the
40mg/kgdoseis about 3.6times of that for the10mg/kgdose. The
therapeutic effect was further evidenced from tumor xenograft
results which showed benet on tumor inhibition from nano-
particles compared with no treatment or clinical drug formulation
therapy (as seen in Fig. 3) [64,76,81].
From Fig. 2, we can conclude (1) PLGA nanoparticles of about
200 nm size can successfully escape from recognition and elimi-
nation by the reticuloendothelial system (RES). One dose of the
PLGA nanoparticle formulation of PTX can realize a 168 h effective
chemotherapy in comparison with only 22 h for Taxol
. Moreover,
theAUCis greatly increased by thePLGA NP formulation and there
is no AUCassociated with drugconcentration abovethemaximum
tolerance level, which means much better therapeutic effects and
much less side effects would be resulted.
5.2. TPGS-emulsied PLGA nanoparticles for oral delivery
Caco-2cells wereused as an in vitro model of GI barrier for oral
chemotherapy and TPGS coated nanoparticles was found to
increase 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 cancer
cell line was incubated with placebo and PTX-loaded TPGS-emul-
sied nanoparticles, and the clinical formulation, Taxol
, at the
samePTX concentration of 0.25mg/ml. Themortalitiesof theHT-29
cells were 1.88%and 7.13%for placebo nanoparticles, 3.19%and
33.5%for Taxol
and 18.0%and 48.6%for TPGS-emulsied nano-

particlesafter incubationfor 24and96h, respectively. Drug-loaded
TPGS-emulsied NP exhibited 5.64, 5.36, 2.68, and 1.45times more
effective than Taxol
formulation after 24, 48, 72, 96 h treatment,

respectivelyat 0.25mg/ml drugconcentration against HT-29on cell
viability [82]. TPGS-emulsied PLGA NP also exhibited 1.28, 1.38
and 1.12-fold more effective than Taxol
after incubation NP with

MCF-7 breast cancer cells for 24, 48, and 72 h, respectively. TheNP
at 10 mg/kg dose of PTX exhibited around 10-fold AUC compared
with Taxol
(8510 ng-h/ml vs. 872 ng-h/ml for Taxol
by oral and
35,500ng-h/ml byi.v. administration)(asseeninFig. 4). Sustainable
time also increased from 7.02 h for Taxol
to 88.2 h for NP
formulation. The oral bioavailability of TPGS-emulsied NP was
increased from 2.46%of Taxol to 24.0%. Our results exhibited
excellent oral drug delivery formulation fromTPGS-emulsied NP
Fig. 2. Plasma concentrationetime proles of PTX formulated in Taxol
(10 mg/kg) or
TPGS-emulsied PLGA nanoparticles (10 mg/kg as well as 40 mg/kg) after i.v. admin-
istration to SDrats. Theconcentrations between theside-effect level (8540 ng/ml) and
the 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 days
11, 16 and 21 with saline, Taxol
and PTX formulated in TPGS-emulsied PLGA nano-

particles at the same 10 mg/kg dose (mean SD, n 5, p 0.05) (reproduction from
[64] with permission).
Fig. 4. Pharmacokinetic proles of PTX formulated in the TPGS-emulsied PLGA NPs
versus Taxol
after oral or i.v. administration at the same 10 mg/kg PTX dose (data
represent mean SD, n 12) (reproduction from [65] with permission).
[65]. The oral bioavailability of TPGS emulsied amphotericin B
loaded PLGA NP was also found to 8-fold than FungizoneA
[79].
5.3. TPGS-emulsiedPLGANP andfurther coatedwith tween 80for
delivery to cross BBB
TPGS-coated PLGA NP can achieve 1.5-fold higher cellular
uptake on MDCK cells. TPGS-emulsied NP demonstrated 4.2%of
the injected dose to retain in brain tissue which is higher than
2.59%for PVA-emulsied NP, but lower than 6.29%for F68-coated
PLGA 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 signicantly altered after surfacecoating
with different surfactant [66].
5.4. TPGS-emulsied nanoparticles for cardiovascular restenosis
treatment
TPGS was also found to increase the coronary artery smooth
muscle cells (CASMC) uptake efciency up to 38%compared with
21%for PVA emulsied nanoparticles after 6 h incubation. TheIC
50
of CASMCcells was decreased from748ng/ml for Taxol
to708ng/
ml and 474 ng/ml for PVA and TPGS-emulsied nanoparticles,
respectively. The arterial uptaken of nanoparticles was studied by
confocal microscope. The rabbits were injured by balloon catheter
and then infused by coumarin 6-loaded nanoparticles suspension.
Confocal image results demonstrated that uorescence can be
clearly observed in the carotid arteries walls and TPGS showed
advantages in the cell uptaken compared with PVA in emulsica-
tionof nanoparticles[64]. TPGSasemulsier showedadvantagesin
preparing cardiovascular stents.
6. TPGS as additive for nanoparticles formulation
TPGS can be a matrix of micro-/nanoparticles after blended
TPGS with PLA, PLGA, poly (caprolactone) for anticancer drug,
pacltiaxel, diphtheria toxoid and others, fabricated by dialysis,
modied solvent extraction/evaporation, or spray drying method
with increased encapsulation efciency and sustained release
[56,60,62,83,84]. TPGSasadditiveincreasedthedrugencapsulation
efciencyupto75.9%comparedto69.0%for particleswithout TPGS
for 4.2%drugloading. 90.1%encapsulation efciency was achieved
with 2%drug loading with blending 5%TPGS in matrix [85e88].
TPGSwas found to reducetheburst releaseand thelag-phasetime
in peptide loaded PLGA microparticles with 5%and 10%TPGS
composition [89]. It was found to signicantly enhancethecellular
uptake and the cell cytotoxicity of entrapped drug against cancer
cells whilemixed with PLGA in fabricatingnanoparticles. It may be
due to TPGS can inhibit the P-gp activity and enhance the drug
concentration in cells and thus increasethecytotoxicity [90]. TPGS
was also added in folate conjugated PLGA-PEG NP with DOX
loading and the formulation with TPGS was found to increase the
cellular uptakeof DOX, higher degreeof DNA damageand apotosis
and thus higher cytotoxicity on drug-resistant cancer cells. It may
be due to TPGS as a P-gp efux pump inhibitor. Inducing TPGS in
micelle formulation can strengthen the therapeutic effect of the
micelles [32]. Lipid-polymer hybrid nanoparticles, by fabricating
polymer nanoparticles with lipid as surfactant and matrix, are
unstable in salt solutions. TPGS with amphiphilic structure was
foundtoprotect thestabilityof hybridnanoparticlesbyinclusionof
TPGS in the surface of nanoparticles. TPGS has polar PEG1000
components, whichextendoutwardsintotheaqueousphase, while
lipophilic end was adsorbed onto the hybrid nanoparticles matrix,
these structure thus realized the stability of hybrid nanoparticles
[57]. However, TPGShas also been found to havenegativeeffect on
encapsulation efciency of HSA entrapment and faster release in
fabricating PLGA or poly(lactide-co-ethylene glycol) (PELA) NP by
water-oil-water emulsion method with 2%or 10%TPGS. Low TPGS
concentration of 2%can formporousmorphology of microparticles
and 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 and
applied this copolymer in anticancer drugs delivery including
paclitaxel, DOX and also protein BSA. The copolymers were
synthesized with various lactide and TPGS ratios by ring opening
polymerization with stannous octoate as catalyst (Scheme 3) [12].
Molecular structure of the copolymer was characterized by FTIR
spectrophotometer and
1
H NMR in CDCl
3
. The weight-averaged
molecular weight and molecular weight distribution were deter-
mined by gel permeation chromatography which demonstrated
single narrow peak from the copolymer and signicant peak shift
compared with TPGS. It conrmed the copolymer is not the phys-
ical mix of reactants. The thermal properties of the samples were
studied by using thermogravimetric analysis. TPGS exhibits single
combustion zone located the range 315e450

C. The copolymer
O
O
O
O
O
O
O
CH
3
H
3
C
O
O
O
O
CH
3
H
3
C
R-OH
Catalyst
Cat.
TPGS
initiation
(m-1)
Propagation
where R-OH : TPGS
Lactide monomer
Cat.
O
OR
H
+
+
R-OH
R O C
O
H
C O C C
H
O
OH
R O C
O
H
C O C C
H
O
OH
m
O
O
O
O
CH
3
H
3
C
CH
3
CH
3
CH
3
CH
3
CH
3
H
3
C
+
Scheme 3. Schematic description of the synthesis mechanism of PLA-TPGS copolymer (reproduction from [12] with permission).
exhibits two combustion zones at 200-315 and 315e450

C,
respectively. TPGS composition was calculated from TGA results
showed well match with NMR measurement. Ha at al also used
stannous octoate as catalyst to synthesis PLA-TPGS 50:50 copol-
ymer [92]. ZhangZPet al. andMei Let al. further synthesizedPLGA-
TPGScopolymer by the similar way [93e95]. The component ratio
of lactide:glycolide:TPGSin thePLA-TPGScopolymer was 60:27:13
with molecular weight 11,900 which was calculated by theratio of
peak integration area at 5.21 ppm(-CH protons of PLA), 4.87 ppm
(-CH protons of PGA) and 3.60 ppm (-CH
2
protons of PEO part of
TPGS). PCL-TPGS [96], PCL-PGA-TPGS [97] and PCL-PLA-TPGS
copolymers were also synthesized with the similar method as
Zhang ZP et al.
Li et al. modied the PLLA-TPGS copolymer synthesis with L-
lactide/TPGS30/1or 40/1ratio by bidentatesulfonamidezincethyl
complex as catalyst [98]. Compared with catalyst stannous octoate,
they got much uniform polydispersity around 1.11e1.12 and also
reduced reaction time from8e12 h to 3.5 h with 96e97%conver-
sion rate. Critical aggregation concentration (CAC) were measured
as 7.29 10
5
and 2.06 10
5
g/ml for PLA30-TPGS and PLA40-
TPGScopolymer, respectively.
7.2. Nanoparticles fabrication
PLA-TPGScopolymerswith variousPLA/TPGSratiowereused to
entrap different drugs, protein or medical imaging agent. Nano-
precipitation method can realize smaller particles size with good
encapsulation efciency for hydrophobic anticancer drugs or
medical imaging agent such as iron oxide nanocrystals (IOs) or
organic quantumn dots (QDs). Single emulsion method can realize
much higher entrapment compared with nanoprecipitation
method but the particles size was normally 100 nmlarger. Double
emulsionmethodcanbeusedtoentraphydrophilicdrug, proteinor
hydrophilic coated medical agents. No matter the fabrication
process, PLA-TPGSNP exhibitedenhanced encapsulation efciency,
cellular uptake and the cytotoxicity of the payload on cancer cells
comparedwithnormallyusedPLGANPinentrappingpayloads[76].
7.2.1. Nanoprecipitation method
Docetaxel loaded nanoparticles was fabricated by nano-
precipitation method[99]. Donget al. developed nanoprecipitation
method for PLA-PEG NP fabrication with particles size less than
100 nmand XPSmeasurement demonstrated PEGlayer present on
thesurfaceof nanoparticles[100]. Nanoprecipitation methodisthe
better way to realize PEG layer cover the surface of nanoparticles
with smaller size compared with solvent extraction/evaporation
methodbut thedrugloadingwould berelativelower, around 1e3%
for PTX. The method is also not easy to realize hydrophilic drug
encapsulation and the controlled release is much faster compared
with solvent extraction/evaporation method. The particles size of
PLA-TPGSNPwasaround121nmwith80%encapsulationefciency
for DOC [99]. In fabrication, polymer and drug were dissolved in
acetone, vortexed and ethanol added in. The organic phase was
then mixed with the aqueous phase containing 0.1% TPGS at
650 rpm stirring rate on magnetic stirrer plate. The particles was
then centrifuged at 15,000 rpm at 4

C and washed three times.
Prashant et al. fabricated iron oxide nanocrystals loaded PLA-TPGS
NP by nanoprecipitation method with 256 nm, 64%encapsulation
efciency and nanocrystals were monodispersed in nanoparticles.
Tetrahydrofuran (THF) was used as solvent and 15%TPGS was
applied as stablisier [73].
7.2.2. Solvent extraction/evaporation (single emulsion) method
PTX can be entrapped in PLA-TPGS NPs by solvent extraction/
evaporation method and the copolymer itself can be acted as
surfactant so it can beself-emulsied. Particles sizefromPLA-TPGS
88:12 (weight ratio) was around 280 nm with 90%encapsulation
efciency for 5%PTX loading. The atom composition of the copol-
ymer nanoparticles was determined by X-ray photoelectron scope.
XPScan quantitatively determine the chemical composition of the
5e10 nm depth of nanoparticles surface. From XPS nitrogen anal-
ysis, therewas not any nitrogen signal fromparticles which means
PTXdistributedinsideof nanoparticles. Thereisonlynitrogenatom
signal fromPTX in thenanoparticles fabrication. TheC1s spectraof
the copolymer and copolymer nanoparticles exhibited increasing
C-O-Cpeak ratiofrom18.5%for thepurecopolymer to27.8%for the
PTX-loaded PLA-TPGS copolymer nanoparticles. It demonstrated
that the copolymer nanoparticles can realize TPGS coating on the
surface of nanoparticles and thus achieve desired advantages of
TPGSfromTPGScoated nanoparticles [101]. TheTPGScoatingratio
was also affected by the TPGScomposition of the copolymers. The
drug release of copolymer nanoparticles was relative to the TPGS
composition ratios in thecopolymers. Thehigher TPGSratio in the
copolymers, the faster drug release from the copolymers nano-
particles [10,102]. Thecopolymers demonstrated theadvantages in
the cell uptake efciency of the fabricated nanoparticles. The
cellular uptake was increased with increased composition ratio of
TPGSin thecopolymers. The cell uptakeefciency of PLA-TPGSNP
was2.05-,1.69-, and1.35-foldhigher than PVA-emulsiedPLGANP
and1.23-,1.16-, and1.12-foldhigher thanTPGS-emulsiedPLGANP,
after incubating HT-29 cells with coumarin 6-loaded NP at the
concentration of 100, 250, 500 mg/ml, respectively. The similar
tendency wasseen asCaco-2cellsandasshown in confocal images
[102]. Theuorescent NPs arelocated insideof cells but not within
the cell membranes. The copolymers also showed signicant
advantages in cancer cell cytotoxicity. TheIC
50
valueof PTX-loaded
PLA-TPGS NP was much lower than Taxol
after 48 h incubation
with HT-29 (103 ng/ml vs. 117 ng/ml) and Caco-2 cells (16.270 vs.
18.49mg/ml). Li et al. alsofabricatedDOX-loadedPLA-TPGSNP with
THF as solvent. Compared with Fengs group nanoparticles fabri-
cation, they got much smaller particles around 127 nmwith 98.5%
encapsulation efciency for DOX which may be due to the lower
polydispersity of the copolymer synthesized as lower as 1.1 [98].
Furthermore, DOC, iron oxide nanocrystals and QDs were also
loaded by single emulsion method with size around 200e350 nm
and up to 99% encapsulation efciency for 10% DOC loading
[11,94,103e105]
7.2.3. Dialysis method
PTX-loaded PLA-TPGS NP was fabricated by dialysis method.
PTX and the copolymer were dissolved into a suitable solvent and
then dialyzed against millipore water for 30e40 h with changing
water every 3e6 h. The particles fabrication was optimized on
solvent, theoretical drug loading, polymer concentration, and the
component ratio of the copolymer. Among the solvent selected
fromDMSO, DMF, THF, 1,4-dioxane, acetone and acetonitrile, DMF
achieved smallest particles size with suitable encapsulation ef-
ciency 54%whilecopolymer concentration of 12.5mg/ml,10%drug
loadingandPLA-TPGS92:8copolymer. Ascopolymer concentration
in organic solvent increased, the particles size was increased from
367to 475nmand drugloadingefciency decreased from48.8%to
35.5%for copolymer concentration increased from 2.5 mg/ml to
12.5 mg/ml. Theoretical drug loading did not affect the particles
size but signicant increased the size from 356 nm (5%drug
loading) to 452 nm (20%drug loading). Especially when the drug
loadingwasashigh as20%, theparticlessizesignicantlyincreased
but theencapsulation efciency was sharply decreased from60.2%
to 24.6%for 20%drug loading. Compared with PLGA in fabricating
NP, the copolymer increased drug loading efciency and smaller
particles size was achieved for more hydrophilic copolymer.
Dialysismethoddoesnot needmuchsevereexperiment conditions.
Furthermore, the fabricating process is self-dialysis and the fabri-
cationprocessmayeasilypromoteTPGStodistributeonthesurface
of the nanoparticles as seen from XPS analysis [10]. The hydro-
philicity of the copolymers fromTPGS also affected the entrapped
drug release. The initial burst release in the rst day was up to
24.0%, 23.0%, 29.7%and 31.1%for PTX-loaded PLGA, PLA-TPGS98:2,
92:8, and 88:12NPs, respectively. After 30days, 63.6%, 60.7%, 77.7%
and 80.3%of entrapped PTX was released from the copolymers
nanoparticles, respectively.
7.2.4. Double emulsion method
Protein 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 efciency, in vitro drug
release and degradation of BSA-loaded NPs [106]. The copolymers
can achieve 75.6%encapsulation efciency for 16.7%theoretical
BSA loading with size around 320 nm. The effect of theoretical
protein loading on the encapsulation efciency and particles size
was studied on various PLA-TPGS copolymers and PLGA NP. PLA-
TPGS can realize much higher encapsulation efciency compared
with64.5%for PLGANPat 16.7%theoretical proteinloading. Besides
these, PLA-TPGS was found to protect BSA from aggregation and
deterioration by stable degradation microenvironment.
7.3. Drug or imaging agent encapsulation
7.3.1. Docetaxel
Gan CW et al. fabricated DOC-loaded PLA-TPGS nanoparticles
with desired size and pharmaceutical properties. NPs demon-
strated thehigher cellular uptakeand therapeutic effects in MCF-7
cancer cells compared with normal PLGA NP formulation. NP
formulationcanachievea360-heffectivechemotherapywith3.44-
fold higher therapeutic effect and 4.42-fold lower side effect than
that of Taxotere
at thesamedoseof 10mg/kg(asseen inFig. 5and

Table2). Therearedifferent biodistributionfromNPcomparedwith
commercial drug formulation (as seen in Fig. 6). Accumulation of
the drug in various important organs, except lungs was relatively
lower for the NPs formulation, thus reducing the side effects
from toxic adjuvant used in Taxotere
. Moreover, there is drug

distributed in the brain which may provide the drug-loaded
nanoparticles to deliver drugacross 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 take
advantages of high emulsication effects and high drug encapsu-
lationefciency, andthoseindrugformulationsuchashighcellular
adhesion and adsorption. MMTof similar effects isalso adetoxier,
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 rst 5 days
and after 28 days, 40.7%and 28.4%loaded drug were released,
respectively. PLA-TPGS NP and PLA-TPGS/MMT NP enhanced
cellular 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 incubation
concentrationof 100, 250, 500mg/ml, respectively. Therearesimilar
tendency for MCF breast cancer cells. The cell cytotoxicity of the
formulations were ranged as PLA-TPGS/MMT NP formulation
>PLA-TPGS NP formulation >Taxotere
. Considered about IC
50
value, PLAeTPGS/MMT NP formulation was found 2.89, 3.98, 2.12-
fold more effective and the PLAeTPGS NP formulation could be
1.774, 2.58,1.58-fold moreeffectivethan theTaxotere
after 24, 48,

72 h treatment, respectively. PLAeTPGS/MMT NP formulation and
the PLAeTPGSNP formulation were found to increase the half-life
of formulated drug up to 26.4 and 20.6-fold, respectively after
oral administration compared to 22 h for i.v. administration of
Fig. 5. In vivo pharmacokinetics proles of DOC plasma concentration vs. time after i.v. administration of Taxotere
and the TPGS-emulsied PLA-TPGS NPs formulation using

SpragueeDawley rats at the same DOC dose of 10 mg/kg (n 5) (reproduction from [107] with permission).
Table 2
Mean non-compartmental pharmacokinetic parameters of SD rats for intravenous
administration of Taxotere
and TPGS-emulsied DOC-loaded PLA-TPGS nano-

particles at a dose of 10 mg/kg (reproduction from[107] with permission).
Parameter Taxotere
NPs
t
max
(h) 0.5 3.0
C
max
(ng/ml) 14,990 4800 7250 1120
AUC
0N
(ng-h/ml) 1.14 10
5
7.13 10
4
3.92 10
5
9.72 10
4
t
1/2
(h) 4.17 1.92 83.87 9.61
MRT (h) 3.69 1.42 73.89 10.39
CL (ml/h/kg) 111.51 63.97 23.46 5.84
AUC
toxic
/AUC
0N
0.84 0.19
Taxotere at thesame 10 mg/kgdose (as seen in Fig. 7 and Table 3).
Furthermore, the PLAeTPGS/MMT NP formulation and PLAeTPGS
NP formulation exhibited signicantly increase of oral bioavail-
abilityupto78%and91%, respectivelycomparedtothat of 3.59%for
Taxotere
,16%for normal PLGANPand21%for PLGA/MMTNP. PLA-

TPGS or PLA-TPGS/MMT NP provided great potential for oral
chemotherapy.
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 expressed
cancer cells. DOC-loaded PCL-PLA-TPGS NP and PLGA-TPGS NP
were also exhibited increased drug encapsulation efciency up to
99%for 10%DOC, internalization by human cervix carcinoma cells
(HeLa) and increased cell cytotoxicity on MCF-7 and HeLa cells
compared with commercial Taxotere
[94e96]. DOC-loaded TPGS-

PCL-PGA NP could effectively inhibit the growth of MCF-7 tumor
over a longer period of time than Taxotere
at the same dose on

SCID mice [97].
Fig. 6. Biodistribution of DOCformulatedin (A) Taxotere
and(B) PLA-TPGSNPsafter i.v. administration at thesameDOCdoseof 10mg/kgtoSDrats. (C) DOCcontent in thebrain at

1, 5, 10 and 24 h after i.v. administration (n 3) (reproduction from [107] with permission).
7.3.2. Paclitaxel
PTX-loaded PLA-TPGS copolymers nanoparticles with various
TPGS component in the copolymers were fabricated by solvent
extraction/evaporation method as discussed in fabrication method
part. The copolymers nanoparticles demonstrated higher cellular
uptake compared to normal PVA emulsied PLGA formulation and
higher cell cytotoxicity of drug nanoparticles formulation
compared to commercial Taxol
[12,102]. Paclitaxel-loaded various

PLA-TPGS copolymer NP was fabricated by dialysis method with
optimization [10,109]. Cellular uptakeon HT-29cellswasenhanced
1.6-fold for PLA-TPGS92:8copolymer NPand 1.8-fold for PLA-TPGS
88:12 copolymer NP (PLA-TPGS 88:12 means the weight ratio of
PLA/TPGS in the copolymer) compared with PLGA NP after incu-
batingwith coumarin-loadedNPat 250mg/ml NP concentration for
2 h. PLA-TPGS 98:2 copolymer NP did not show any signicant
enhancement which may attribute to not enough TPGS amount
distribute on the surface of NP. Caco-2 cell uptake efciency also
exhibited thesimilar enhancement fromPLA-TPGSNP. Thecellular
uptake was more conrmed form confocal microscopic images.
In vivo pharmaceutical and biodistribution study demonstrated
great potential of the copolymer for cancer therapy. After i.v.
administration, most of ratsshowed weak lifesignal andeven dead
whileweincreased dosageof Taxol
for morethan 10 mg/kgbody

weight of rats. However, morethan80mg/kgPTXamount loadedin
NP can be injected to rats without losing or sick from rats.
Furthermore, 39% of AUC value from clinical administration
formulation Taxol
was distributed above the toxic drug level

8540 ng/ml which may cause toxic to rats. Compared with Taxol
,
the copolymer NP exhibited sustained release the drug in vivo and
no toxic level demonstrated from drug concentration vs. time
curve. Thecirculationtimewasalsosignicantlyincreasedfromthe
copolymer NP. PLA-TPGS88:12NPachieved76.8hof t
1/2
and69.0h
of MRT compared with Taxol
, 2.8 h and 2.6 h, respectively. AUC

value of drug loaded copolymer NP was 1.6-fold of Taxol
. NP
affected in vivo distribution of the drug after administration
compared with Taxol
and mayhavepotential to usefor delivering

drugtocrossBBBinfuture. Xenograft resultsafter inoculatedHT-29
cells to SCID mice further conrmed drug loaded NP advantages
compared with Taxol
formulation. After 35days, only onethird of

mice were survived fromtreatment compared with 100%fromNP
treatment.
7.3.3. Doxorubicin
DOX-loaded PLGA-TPGS NP was fabricated by solvent extrac-
tion/evaporation method with particles size 350 nm [93]. In the
fabrication, DOX was conjugated with PLGA-TPGSor loaded in the
particles by physical form (DOX was dissolved in acetone in the
presence of TEA as molar ratio 1:2). The particles can realize tar-
getingeffect for folate-receptor rich tumors by includingTPGS-FOL
in fabricating NP. In the blending for fabricating NP, 0%, 20%, 33%
Fig. 7. Plasma concentrationetime proles 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 5). Thetherapeuticwindow is dened as thedrugconcentration in plasmabetween themaximumtolerated level (2700ng/ml) and theminimum-
effective level (35 ng/ml), which are calculated from the in vitro cytotoxicity.
Table 3
Pharmacokinetics in SDratsafter i.v. administration of Taxotere
and oral DOCformulated in theTaxotere
, PLGA NPs, PLGA/MMT, PLAeTPGSNPsand PLAeTPGS/MMTat the

same 10 mg/kg drug dose (reproduction from[105] with permission).
PK parameters Taxotere
(i.v.) Taxotere
(oral) PLGA NPs (oral) PLGA/MMT NPs (oral) PLA-TPGSNPs (oral) PLA-TPGS/MMT NPs (oral)
C
max
(ng/ml) 15,500 3420 604 110.6 450 94.6 567 103.5 919 148.5 1012 400
t
max
(h) 0.5 2.5 2 4 2.5 4.5
AUC
0N
(ng-h/ml) 116,600 1722 4192 852 19,010 1530 24,400 2310 106,420 5930 90,900 3200
t
1/2
(h) 4.5 2.85 6.9 2.1 114.3 21.3 60 19.7 92.6 13.4 118.8 24.5
MRT (h) 5.86 3.64 8.56 1.56 126 28.9 78.9 20.1 167.2 20.9 171.8 35.8
Absolute bioavailability e 3.5% 16% 21% 91% 78%
and 50%TPGS-FOL was added and denoted theNP as 0%TPGS-FOL
NP, 20%TPGS-FOL NP, 33%TPGS-FOL NP and 50%TPGS-FOL NP,
respectively. NP can realize around 80% drug loading for
3.47e4.96%DOX drug loading (2%physical drug loading) with size
around320e350nm. After 30days, 48.3%, 50.3%, 52.1%and65.1%of
the entrapped drug was released from the 0%, 20%, 33%and 50%
TPGS-FOLNPs, respectively. TPGS-FOLaffect thedrugreleasewhich
can be attributed to the smaller molecular weight of TPGS-FOL,
hydrophilicity and increased TPGS-FOL content occupied the
surface of NP. Folate was decorated on the surface of NP was seen
fromXPSanalysis. Thecell viability was decreased from51%for 0%
TPGS-FOL NP to 8.2%for 50%TPGS-FOL NP for MCF-7 cells and
49.6%e30.6%for C6 cells. 50%TPGS-FOL NP with 50%TPGS-FOL in
blend of fabricatingNP enhanced thecellular uptakeup to 1.4-fold
for MCF-7 cells and 1.3-fold for C6 cells.
Li et al. fabricated DOX-loaded PLLA40-TPGS NP with 98.5%
encapsulation efciency. When changed polymer/drug ratio from
5/2 to 15/1 in the nanoprecipitation method, the particles can be
optimized from 275 nm to 131 nm with encapsulation efciency
increase from 69%to 98.5%[98]. The particles released entrapped
DOX much faster in pH 5.0 compared with pH7.4 fromvitro drug
release experiment. PLA-TPGS NP was found to inhibit the P-gp
activitywithout changingitsexpressionandenhancedintracellular
drug accumulation in MCF-7/ADR cells from calcein AM experi-
ment, cellular uptake study by ow cytometry and intracellular
localization by confocal results. PLA-TPGS NP promoted trans-
location of DOX into the nucleus and enhanced thecellular uptake
of DOX by MCF-7/ADR cells. Furthermore NP also signicantly
enhanced the loaded drug cytotoxicity at the incubated concen-
tration of 20 mM. Thecell viability of cells treated with drugloaded
nanoparticles was decreased to 37.6%from 66%for the free drug.
PLA-TPGS nanoparticles carrying DOX can result in combination
effect of P-gp efux pump inhibition and increaseof drugentering
into nucleus of drug-resistant MCF/ADRcells. It was demonstrated
the increased cell mortality of drug loaded nanoparticles, cellular
uptake and nuclear accumulation of drug on MCF/ADR cells
[98,110].
7.3.4. Curcumin and Risperidone
Curcumin is a natural substance applying in inhibiting and/or
treating carcinogenesis, however, its poor solubility limited its
treatment efcacy and application. Ha et al fabricated curcumin-
loaded PLA-TPGS NP [92]. In this research the researcher used
PLA-TPGS 50:50 copolymer to fabricate drug loaded micelles.
Curcumin-loaded PLA-TPGSmicelles werefabricated by dissolving
drug in methanol and copolymer in DCM and then after solvent
evaporation, the mixture was mixed with PBS. The particles were
formed with size 100e400 nm and also tinny particles with size
20e40 nm. Risperidone-loaded PCL-TPGS microparticles were
fabricated by a modied solvent extraction/evaporation method
without extra emulsier. The copolymer MP was found to signi-
cantly increase the drug release than PCL MP [111].
7.3.5. Protein delivery
Leeet al. investigated PLA-TPGScopolymersfor protein delivery
[106]. The protein-loaded nanoparticles were fabricated by double
emulsion method with higher encapsulation efciency. As the
increasing of TPGS composition in the copolymers, the BSA
encapsulation efciency was decreased from 75.6%for PLA-TPGS
97:3 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 is
attributed to the higher TPGS composition, the lower copolymer
molecular weight and higher hydrophilicity from the copolymers
andthushigher hydrophilicityof copolymersNPs. Theparticlessize
was also decreased from362 nmfor PLA-TPGS97:3 copolymer NP
to 274 nm for PLA-TPGS 88:12 NP. PLA-TPGS degradation was
affected 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, there
was around 16%, 27.2%and 51.5%weight loss happened for PLA-
TPGS 97:3, 94:6 and 88:12 copolymers. However, the degradation
of BSA-loaded nanoparticles was accelerated which may be
attributed to the acidic byproducts during degradation catalyzed
thedegradation of copolymers [112,113]. Theacidicbyproducts can
cause a decrease in the pH value and acidic microenvironment
which cause the denature of protein drugs. Compared with PLGA
NP, PLA-TPGSshowed much smaller and slower pH change during
degradation. After 35 days, the pH value was changed from 7.4 to
6.3for BSA-loadedPLGANPbut therewasless0.1changefromPLA-
TPGS series NPs. It seems that copolymers NP can protect protein
drugs more efciently compared with PLGA NP. BSA-loaded PLGA
NP showed a initial burst release followed by a slow and non-
release prole which may be attributed to the non-covalent
protein aggregation happened due to the acidic microenviron-
ment from the degradation of PLGA. PLA-TPGS copolymer NPs
showed a biphasic BSA release prole and the release rate depen-
dedon theTPGScompositionsin thecopolymers. After initial burst
release, 80%, 55%and 43%of entrapped BSA released from PLA-
TPGS 88:12, 94:6 and 97:3 copolymers nanoparticles after 30
days incubation in PBS at 37
C, respectively. The release was also

affected by the BSA loading. The higher BSA loading, the faster
invitroreleasehappenedfromthesimilar PLA-TPGSNPs. Tofurther
study the advantages of PLA-TPGS copolymers, the BSA integrity
was studied by SDS-PAGE for released BSA fromNPs. The primary
structure of BSA can be retained more than 5 weeks for PLA-TPGS
94:6 NPs. However, the protein aggregation happened after rst
day release from the presence of higher molecular weight band.
There were not signicant alterations in the CD spectra of BSA
released from copolymers NPs but decrease in the alfa-helix
content presented from PLGA NP. The copolymer nanoparticles
have great potential to protein drug delivery.
7.3.6. Supraparamagnetic iron oxides
Superparamagnetic iron oxide nanocrystals are developed for
assessing and treating diseases in humans. Prashant Cet al devel-
oped PLA-TPGSNP for SPIOs encapsulation for medical imagingby
magnetic resonance imaging (MRI) [11,73]. IO nanoparticles were
well dispersed within PLA-TPGSNP as visualized fromTEM images
andthenanoparticleswerepreparedbysingleemulsion methodor
nanoprecipitation method with optimization. Thebiocompatibility
and cellular uptake of IOs-PLA-TPGS NP were studied on MCF-7
breast cancer cells and NIH-3T3 mouse broblast cells with
comparison to commercial formulation, Resovist
. The copolymer
NP can achieve 256 nmwith 64%encapsulation efciency for 1.2%
Feloadedin nanoparticleswithmonodispersenature. Nanocrystals
was distributed uniformly in the matrix with enhanced biocom-
patibility of the nanocrystals as cell toxicity study [73]. Compared
with commercial particles, PLA-TPGSNP was w10 fold less toxic to
NIH-3T3 mouse broblast cell line. PLA-TPGS NP formulated IOs
were good contrast agent for T2 weighted imaging using MRI and
canbeclearedin liver within24hcomparedwithseveral weeksfor
Resovist
[73]. Nanoparticles formulation demonstrated the

enhanced permeation and retention (EPR) effect of the tumor
vasculature compared with commercial Resovist
from xenograft
tumor model MRI study [11].
7.3.7. Quantumdots
QDs have been widely studied as luminescence probes in
medical images in recent years which may be due to its broad
excitation spectra, high quantum yield of uorscence, strong
brightness, excellent photostability and high resistance to photo-
bleaching. To reduce its toxicity, recent strategy was used to load
QDs in polymeric NP which could greatly improve its biocompati-
bility, stability and realize a controlled and sustained release. To
further reduce the toxicity and increase the efciency in medical
imaging. QDs-loaded PLA-TPGS NP was fabricated by modied
solvent extraction evaporation method with PVA as surfactant.
0.15 ml 1 mM organic QDs was mixed with PLA-TPGSDCM solution
and poured into water phase with 0.5%PVA. After sonicated for
3 min at 20W output, the NP was collected as normal single
emulsion method. MAA-coated QDs was also fabricated as
comparison on side effects and imaging effect with NP. PLA-TPGS
88:12 (weight ratio, Mw 23,072) was used in NP fabrication.
The particles size was around 200 nmwith no QDs located in the
surfaceof NPfromXPSanalysis. QDswereconrmedintheNPfrom
TEM images and XPSanalysis and NP was covered by TPGSon the
surfacewhich can realized advantages of TPGSin NP. PLA-TPGSNP
achieved better photostability by protecting QDs emission inten-
sities after irradiation. For freeQDs, the relative emission intensity
were almost decreased to zero at 12 h, whereas, NP can still keep
the intensity even after 30 days irradiation process. NP entrapped
QDsexhibitedhigher cell viabilitycomparedwith MAA-coatedQDs
on MCF-7 cells. In summary, PLA-TPGS copolymer can entrap QDs
in theNP with relativesmall size, realized protection effect on QDs
from long term irradiation, reduced its side effects and improved
thebiocompatibilitycomparedwithfreeQDs. It haspotential touse
NP entrap QDsascell imagingwhich maypromoteQDsapplication
in medical imaging without serious side effects [104]. Foliate-
decorated QDs-loaded PLA-TPGS NP was further formulated with
targeting cancer diagnosis [103].
7.3.8. Multimodal imaging system
Co-delivery of IOs and QDs in PLA-TPGS NP was fabricated by
modied nanoprecipitation method for concurrent imaging of the
magnetic resonance imaging (MRI) and the uorescence imaging.
These multimodal imaging will combine their advantages, over-
come their disadvantages, promote a sustained and controlled
imaging with passive targeting effects to the diseased cells. The
transmission electron microscopy (TEM) images exhibited direct
evidence that QDs and IOs well dispersed and distributed within
the PLA-TPGS NPs (as seen in Fig. 8). These multimodal imaging
exhibited great advantages of both contrast agents making the
resultant probe highly sensitive with good depth penetration (as
seenin Figs. 9e11). Thecopolymer PLA-TPGScanrealizethePLAfor
the needed mechanical strength and biodegradability, and TPGS
component for enhancing the biocompatibility and providing
stealth from RES as well as inhibits the multiple drug resistance
(MDR) [114e116].
8. Targeting strategies
Although TPGSitself cannot realizetargetingeffect but it can be
used as the linking agent for realizing different targeting effect in
nanoparticles fabrication. Foliate was widely studied on targeting
drug delivery because most of tumor cells overexpressed foliate
receptor on the tumor cell surface compared with normal cells.
Foliate has small molecular weight and is not easy to apply as
matrix of nanoparticles or without effect after directly added to
drugsolution. Therearetwo ways for targetingdelivery fromTPGS
in NP until now developed, oneway was to useTPGS-COOH as the
blend matrix with polymer to fabricate polymer NP and then tar-
geting agent was post-conjugated to the surface with TPGS-COOH
decorated NP. Another way was to synthesis TPGS-Folate or other
targeting agent and then as blend matrix to fabricate NP with
folate-decorated NP. Until now there was not report on the
comparison with these two kinds of targeting strategies.
8.1. TPGS-FOL conjugate
Zhang ZP et al. synthesized TPGS-Folate polymer and applied
this polymer for targeting delivery of copolymer NP. TPGS-FOL
synthesis was shown as Scheme 4. TPGS-NHS was synthesized by
reacting TPGS, glutaric acid and DCCat molar ratio 1:1:1 in DMSO
under nitrogen at room temperature for 24 h the product was
ltered, dialyzed against DMSOfor 24h, dialyzed against water for
24 h and then freeze-dried. The product was further reacted with
NHS/DCC for 6 h at 50

C at molar ratio 1:2:2. FOL-NH
2
was
produced byreactingfolatewith DCC/NHSin DMSOfor 6h at 50
C
and then reacted with excess ethylene diamine in the presence of
pyridineas catalyst. TPGS-NHSand FOL-NH2 was reacted in DMSO
at molar ratio1:2for 2daysat roomtemperatureandthen dialyzed
and freeze-dried to get yellowish product TPGS-FOL [93]. Different
TPGS-FOL blend component with PLGA-TPGS was utilized to
fabricate targeting NP for folate-receptor rich tumors. XPS images
exhibited folate decorated on the surface of NP. NP realized tar-
geting effect fromin vitro cellular uptake and cell viability results.
Compared with no TPGS-FOL NP, 50%TPGS-FOL NP increased cell
uptakeefciency up to 1.5-fold and 1.6-fold for MCF-7 and C6 cells
after incubated with cells for 1.5 h, respectively. IC
50
valueof MCF7
cellswasdecreasedfrom>100uM for 0%TPGS-FOLNPto39.8, 28.5,
19.4mM for 20%, 33%and50%TPGS-FOLNP, respectivelywhich was
also lower than 43.7 mM for free drug. For C6 cells, the value was
decreased from 95.9 mM for 0%TPGS-FOL NP to 12.6, 7.47, and
3.25 mM for TPGS decorated NP. Confocal images results also
demonstrated the targeting effect from TPGS-FOL decorated NP
and folate-receptor mediateendocytosis was exhibited [93]. TPGS-
FOL was also added in fabricating PTX-loaded PLA-MPEG
Fig. 8. TEM Images of A: theIOs-loaded PLA-TPGSNPs, B: theQDs-loaded PLA-TPGSNPs and C: theQDs and IOs-loaded PLA-TPGSNPs (scalebar 200nm) (Reproduced from[114]
with permission).
nanoparticles with 50%TPGS-FOL, which increased cellular uptake
for tumor HeLa and glioma C6 cells but no difference on NIH3T3
cells [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 of
DOX by 15.2%compared with freedrugand further increased 6.3%
for TPGS-DOX-FOL for 0.5h cell culture. Also theIC
50
valuefor 24h
cell culture with MCF-7 cells exhibited 1.19 and 45.0-fold more
effective than the free drug for the prodrug and TPGS-DOX-FOL,
respectively. The prodrug and the targeted formulation of pro-
drugshowed 3.79- and 3.9-fold higher half lifeand 19.2- and 14.5-
fold of AUCthan DOX, respectively. The targeting formulation also
further reduced the cardiotoxicity and gastrointestinal side effect
by changing the in vivo biodistribution of the drug to heart and
gastrointestinal 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 can
be reacted with TPGS-COOH group in the nanoparticles by EDC/
NHSmethod (as seen in Scheme5) [103,118]. Theresearchers used
post-conjugation method to induce targeting agent foliate and
considered targeted NP effect on MCF-7 cells which overexpress
foliate receptors and NIH313 cells with few foliate receptors.
Compared with non-targeted NP, foliate conjugated NP exhibits
much higher cellular uptaken on MCF-7 cells which not shown in
NIH313 cells. Foliate-conjugated TPGS-COOH co-matrix PLGA
nanoparticles achieved 11.22-fold decrease in IC
50
value of
entrapped DOC which is much higher than 7.58-fold decrease in
IC
50
for non-targetednanoparticlesafter 48hincubationwithMCF-
7 breast cancer cells. Foliate post-conjugated TPGS-COOH/PLGA
nanoparticleswasalsoshowedbetter imagingeffects.16.7%foliate-
decorated NPs achieved 1.03-, 1.12-, 1.12-, and 1.25-fold higher
cellular uptakeefciency than non-targeted TPGS-COOH/PLGA NPs
after 0.5,1.0, 2.0and4.0hincubationwithMCF-7cells, respectively.
It seems that introducing TPGS-COOH in the fabrication of nano-
particles can realize post-conjugatingof targetingagents and even
precise 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 method
fabricatedquantumdots-loadedPLA-TPGSNP. FromXPSimageswe
can see, theweight percentagesof nitrogen on theparticlessurface
were 3.62%and 4.33%for NP with 11.1%and 16.7%TPGS-COOH in
the blend of matrix while fabricating NP, respectively [103]. Tar-
geting delivery of PTX was realized by using TPGS-COOH blended
with PLA-TPGS in matrix fabricating NP. NP contained 9.1%, 16.7%
and 33.3%TPGS-COOH in the fabricating mixture was studied to
analyze foliate amount effect on cellular uptake and cytotoxicity.
16%FD NP (containing 16.7%TPGS-COOH in fabricating NP and
foliate conjugated, FC NP means non foliate conjugated) demon-
strated 1.5 and 1.6-fold higher cellular uptake than FCNP after 4 h
incubation with MCF-7 cells and the glioma C6 cells, respectively.
Cell viability on MCF cells was decreased from53.0%for Taxol
, to
48.4%for 0%FC NP, 36.6%16.7%FD NP and 33.4%for 33.3%FD NP
after incubated 24 h with 25 mg/ml drug concentration. As the
similar way, FDNP also enhanced cell cytotoxicity on C6cells. After
24 h incubating with the formulations, the cell viability was
decreased from 43.8%for Taxol
to 38.6%for 0%FC NP, 29.2%and

27.9%for 16.7%and 33.3%FD NP, respectively [119].
Trastuzumab, a humanized monoclonal antibody directed
against the human epidermal growth factor receptor-2 (HER2), is
Fig. 9. Axial MRI imagesections of theMCF-7graftedtumor bearingmice. ImagesA and Bshow thepart of thetumor (shown by thearrow) beforeand after 6h of administration of
theQDs and IOs-loaded PLA-TPGSNPs into themice. Images Cand Dshow thekidney (K) and liver (L) part of themicebeforeand 6 h after theadministration of thePLA-TPGSNPs
formulation of QDSand IOs(dosage: 1.5mgof Cd/kgof body weight or equivalent of 6.0mgof Fe/kgbody weight). Thedecreasein intensity in theregionsof thetumor and liver can
be noticed in comparison with the color scale aside (reproduction from [114] with permission).
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 with
trastuzumabfunctionalized[108,120]. NPswerefabricatedbyusing
TPGS-COOH and PLA-TPGS as matrix and emulsied with TPGS.
Trastuzumab can be conjugated to the surface of NP by EDC/NHS
method. The in vitro targeting effect was studied by SK-BR-3
(higher HER2 overexpression) and MCF-7 cells (moderate HER2
overexpression) after incubated with 125 mg/ml coumarin-loaded
targeted nanoparticles or non-targeting conjugated nanoparticles
at 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-,
1.15-, 1.17-fold higher for MCF-7 cells after incubated for 0.5, 1, 2,
and4h, respectivelycomparedwithnon-conjugatednanoparticles.
The cell mortality also demonstrated the advantages of
trastuzumab-conjugated nanoparticles. Targeting nanoparticles
showed 1.22-fold and 1.70-fold more effective for MCF-7 and SK-
BR-3 cells, respectively. It also shows evidence that targeting
effect of nanoparticles depend on theHER2 receptor expression on
thecells. It seems that TPGS-COOH can beacted as targetingagent
linker and co-matrix for fabricating nanoparticles. There is
combinational effect from anticancer drug DOC and antibody
therapy, trastuzumab [108,121]. Zhao J et al further realized
preciselycontrol thetargetingeffects byadjustingPLA-TPGS:TPGS-
Fig. 10. Confocal laser scanningmicroscopy sections of themousetumor sections. Images A, Band Cshow thetumor sections of thecontrol with notreatment (scalebar 30mm). 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 tumor
sectionsof themousetreated with theQDs andIOs-loaded PLA-TPGSNPs(scalebar 20mm). D: Bluecoded DAPI stained nuclei. E: Red coded QDfromNPsin cytoplasm. F: Complete
overlapped image (reproduction from[114] with permission). (For interpretation of the references to colour in this gure legend, the reader is referred to the web version of this
article.)
Fig. 11. Field emission transmission electron microscope (FETEM) image of immunogold labeled PLAS-TPGS nanoparticles (reproduction from [121] 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 ne control [121].
8.3. Antibody coated on the surface of nanoparticles
Transferrin (Tf), a single polypeptide glycoprotein with about
679aminoacids, isaco-factor in DNAreplication, irontransport for
cellular growth or differentiation. Tf conjugated PLA-TPGS NP
(simply PLA-TPGS/Tf-NP) loaded DOC exhibited great advantages
over PLA-TPGSNP or Taxotere
formulation. Theparticles sizewas

around 160 nm with 79%encapsulation efciency to DOC. Tf was
adsorbedon thesurfaceof NPsfromNatomsignal fromXPSresults
on theN bindingenergy scan region. Therewas not any N signal in
PLA-TPGS NP or PLGA NP XPS results but the obvious N signal
demonstrated in Tf conjugated PLA-TPGSNP XPSimage. Thesignal
attributed to the N-glycosidic chains of the Tf, which allows that
the Tf on the surface of nanoparticles can interact with Tf receptor
on the cell surface and achieve targeting effect. In vitro cellular
uptakeand confocal images after coumarin 6-loaded nanoparticles
were incubated with glioma C6 cells also exhibited the targeting
effect. Tf conjugated targeting nanoparticles exhibited stronger
intensity compared with PLA-TPGS NP or PLGA NP or extra Tf
conjugated NP with extraTf reagent in culturemediumto compete
with NP. Tf conjugated NP demonstrated higher cellular uptake
was attributed toTf conjugated on thesurfaceof nanoparticles and
the activity would be blocked after including extra Tf. IC
50
data
after formulations were incubated with C6 cells 24 h also showed
that theadvantages of Tf-conjugated PLA-TPGSNPs formulation of
DOC. The IC
50
of Tf conjugated NPs was lower as 5.10 mg/ml
compared with 6.53 mg/ml, 5.96 mg/ml and 16.77 mg/ml for PLGA
NP, PLA-TPGS NP and clinical formulation, respectively. The parti-
cles formulation exhibited 23.4%, 16.9%and 229%more efcient
than the PLGA NPs, the PLA-TPGSNPs formulations and Taxotere
after 24 h treatment, respectively. Coumarin-loaded Tf conjugated

PLA-TPGS NP also demonstrated signicant higher ex vivo distri-
bution in brain and benet to be developed to deliver imaging/
therapeutic agents across the blood brain barrier for further
development [99].
9. Advantages of the PLA-TPGS series copolymer
PLA-TPGS has been shows as potential candidate for drug
delivery carrier as exhibited above. It can be developed to deliver
anticancer reagent such as pacltiaxel, DOC, DOX, protein BSA, and
imagingreagent QDs and iron nanoparticles and so on with higher
encapsulation efciencycompared with commonly used PLGA. The
amphiphilic structure of the polymer can promote nanoparticles
Scheme 4. Synthetic scheme of TPGS-FOL conjugate (reproduction from [93] with permission).
increasedthecellular uptakeof NPsandcell cytotoxicityof payload,
extended much longer circulation timeinvivo, across somebarrier
such as blood brain barrier. Li et al found the PLA-TPGS NP can
inhibit P-gp activity without changing P-gp expression [98]. PLA-
TPGS NP may inhibit the efux pump and increase the entry of
DOX into the nucleus in drug-resistant MCF7/ADR cells. It seems
that the copolymer NP may have great potential for i.v. or oral and
cross blood brain barrier drug delivery of protein or anticancer
drugs. Theoral bioavailability of DOCwas increased from3.59%for
Taxotere
(10 mg/kgdrugdose) to 16%, 21%, 91%and 78%for PLGA

NP, 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 imagingagent can bedeveloped as imaging
nanoparticles in further development. The recent development
may bedueto theamphiphilic structurefromthepolymer and the
polymer NP can realizeTPGSbound tothesurfaceof nanoparticles,
which is much stronger and stable than TPGS-emulsied PLA or
PLGA nanoparticles. Until now we need more data to support the
copolymer application. There was not data exhibited the compar-
ison between PLA-MPEG and PLA-TPGS polymers. Still there is
more space for in vivo experiment need to be developed on this
kind of polymers.
Acknowledgments
The work was nancially supported jointly by National Basic
Research Programof China (973 Program, 2012CB932500) and the
Singapore-China Collaborative Grant, A*STAR, Singapore (R-398-
000-077-305, PI: SSFeng) andNUSFRCR-397-000-136-731(Co-PI:
SSFeng).
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Review

Vitamin E TPGS as a molecular biomaterial for drug delivery

of only 22 h effective chemo-

) has to usean adjuvant called Cremophor EL, which causes

for thermotherapy and

, TPGS2k micelles and FA TPGS2k micelles after

formulation from in vitro C6 cell mortality experi-

at doseshigher than 20mg/kgshowedapathyand

at a same dose of 10 mg/kg. The half life of Taxol

and 18.0%and 48.6%for TPGS-emulsied nano-

formulation after 24, 48, 72, 96 h treatment,

after incubation NP with

(8510 ng-h/ml vs. 872 ng-h/ml for Taxol

and PTX formulated in TPGS-emulsied PLGA nano-

at thesamedoseof 10mg/kg(asseen inFig. 5and

. Moreover, there is drug

after 24, 48,

and the TPGS-emulsied PLA-TPGS NPs formulation using

and TPGS-emulsied DOC-loaded PLA-TPGS nano-

,16%for normal PLGANPand21%for PLGA/MMTNP. PLA-

[94e96]. DOC-loaded TPGS-

at the same dose on

and(B) PLA-TPGSNPsafter i.v. administration at thesameDOCdoseof 10mg/kgtoSDrats. (C) DOCcontent in thebrain at

[12,102]. Paclitaxel-loaded various

for morethan 10 mg/kgbody

was distributed above the toxic drug level

, 2.8 h and 2.6 h, respectively. AUC

and mayhavepotential to usefor delivering

formulation. After 35days, only onethird of

, compared with the i.v.

and oral DOCformulated in theTaxotere

, PLGA NPs, PLGA/MMT, PLAeTPGSNPsand PLAeTPGS/MMTat the

C, respectively. The release was also

[73]. Nanoparticles formulation demonstrated the

to 38.6%for 0%FC NP, 29.2%and

formulation. Theparticles sizewas

after 24 h treatment, respectively. Coumarin-loaded Tf conjugated

(10 mg/kgdrugdose) to 16%, 21%, 91%and 78%for PLGA

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