Recent advances in polymeric micelles for anti-cancer drug delivery
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ReviewRecent advances in polymeric micelles for anti-cancer drug deliverySwati Biswas,Preeti Kumari,Prit Manish Lakhani,Balaram Ghosh ⁎Birla Institute of Technology and Science —Pilani,Hyderabad,Jawahar Nagar,Shameerpet,Hyderabad 500078,Telangana,Indiaa b s t r a c ta r t i c l e i n f o Article history:Received 11October 2015Received in revised form 8December 2015Accepted 27December 2015Available online 31December 2015Block co-polymeric micelles receive increased attention due to their ability to load therapeutics,deliver the cargo to the site of action,improve the pharmacokinetic of the loaded drug and reduce off-target cytotoxicity.While polymeric micelles can be developed with improved drug loading capabilities by modulating hydrophobicity and hydrophilicity of the micelle forming block co-polymers,they can also be successfully cancer targeted by sur-face modifying with tumor-homing ligands.However,maintenance of the integrity of the self-assembled system in the circulation and disassembly for drug release at the site of drug action remain a challenge.Therefore,stimuli-responsive polymeric micelles for on demand drug delivery with minimal off-target effect has been developed and extensively investigated to assess their sensitivity.This review focuses on discussing various poly-meric micelles currently utilized for the delivery of chemotherapeutic drugs.Designs of various stimuli-sensitive micelles that are able to control drug release in response to speci fic stimuli,either endogenous or exogenous have been delineated.©2015Elsevier B.V.All rights reserved.Keywords:Polymeric micelles Block polymer EPR effect AnticancerTargeted delivery Cancer therapyContents 1.Introduction ..............................................................1852.Polymeric micelles of therapeutic application in cancer treatment ......................................1852.1.Pluronics®...........................................................1852.2.PEG –PLA ............................................................1872.3.PEG –PCL ............................................................1882.4.PEG –lipid ............................................................1892.5.PEG –PLGA ...........................................................1902.6.PEG –poly(amino acids).....................................................1913.Stimuli-sensitive polymeric micelles ...................................................1923.1.Endogenous stimuli-sensitive polymeric micelles ..........................................1923.1.1.pH-sensitive polymeric micelles .............................................1923.1.2.Reduction-sensitive polymeric micelles ..........................................1933.1.3.Thermo-sensitive polymeric micelles ...........................................1953.2.Exogenous stimuli-sensitive polymeric micelles ...........................................1953.2.1.Light-sensitive polymeric micelle .............................................1953.2.2.Magnetic field sensitive polymeric micelles ........................................1963.2.3.Ultra-sound sensitive polymeric micelles .........................................1984.Margination of micro/nano-particles:requirement for optimum drug delivery (198)European Journal of Pharmaceutical Sciences 83(2016)184–202Abbreviations:ANAs,antinuclear antibodies;APRPG,Ala-Pro-Arg-Pro-Gly;CAP,capecitabine;CMC,critical micelles concentration;DOPE,dioleoyl(phosphatidylethanolamine);DOTMA,N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride;DOX,doxorubicin;DSPE,distearoyl(phosphatidylethanolamine);EPR,Enhanced Permeability and Retention;FN,fibronectin;HUVECs,human umbilical vein endothelial cells;LL,Lipofectin®lipids;LCST,lower critical solution temperature;MTX,methotrexate;PAA,poly(amino acids);pAsp,poly(L -aspartic acid);PCL,poly-ƹ-caprolactone;PDT,photodynamic therapy;PEG,poly(ethylene glycol);PEI,polyethylenimine;PEO,poly(ethylene oxide);pHis,poly(L -his-tidine);PLA,poly(L -lactide);PLGA,poly(lactide-co-glycolic acid);pNIPAAm,poly(N-isopropylacrylamide);PPO,poly(propylene oxide);PVP,poly(N-vinyl pyrrolidone);PEO –PS –PMMAZO,poly(ethylene oxide)-b-polystyrene-b-poly[6-(4-methoxy-4-oxy-azobenzene)hexyl methacrylate;ROS,reactive oxygen species;RSV,resveratrol;SPION,superparamagnetic iron oxide nanoparticles;TAPC,5,10,15,20-tetrakis (4-aminophenyl)-21H,23H-chlorin;TPGS,D -α-tocopheryl polyethylene glycol succinate;TPP,meso-tetraphenylporphine.⁎Corresponding author at:Department of Pharmacy,Birla Institute of Technology and Science —Pilani,Hyderabad,Jawahar Nagar,Shameerpet,Hyderabad 500078,Telangana,India.E-mail address:balaram@hyderabad.bits-pilani.ac.in (B.Ghosh)./10.1016/j.ejps.2015.12.0310928-0987/©2015Elsevier B.V.All rightsreserved.Contents lists available at ScienceDirectEuropean Journal of Pharmaceutical Sciencesj o u r n a l h o m e pa ge :ww w.e l s e v i e r.c o m /l oc a t e /e j p s5.Conclusion (199)Acknowledgment (199)References (199)1.IntroductionAmphiphilic block co-polymers that form self-assembled micellar structure spontaneously have gained much attention in recent years for their application in drug delivery.Polymeric micelles composed of amphiphilic block-co-polymers are nano-sized,spherical,supramolecu-lar colloidal particles with a hydrophobic core and a hydrophilic corona (Aliabadi and Lavasanifar,2006;Torchilin,2007).The amphiphilic block co-polymers,the structural units of polymeric micelles are macromole-cules with distinct hydrophobic and hydrophilic block domains.On aqueous exposure,the block co-polymers aggregate to form entropical-ly favored,supra-molecular assembly at or above certain polymer concentration,referred to as critical micelle concentration(CMC). CMC depends on the hydrophilic/hydrophobic balance of the block co-polymers,chemical characteristics,and molecular weight of the blocks.While hydrophobic segment of the polymer forms the core of the micelles that solubilize the hydrophobic drug molecules,hydrophilic segment forms the corona that provides compatibility of the micelles in the aqueous environment.The hydrophobic core accommodates va-riety of hydrophobic molecules,such as therapeutics and imaging agents,thus,improving the solubility and stability in the biological system.The hydrophilic corona shields the core,and protects the loaded drugs from interactions with the blood components.The biocompatible polymeric corona causes reduced recognition of the micelles by reticulo-endothelial systems,thus providing long circulation of the loaded component in the blood stream.The nano-ranged size(between 10and100nm)along with the long circulatory property allows poly-meric micelles to eventually accumulate in any compromised tissue-vasculature sites,e.g.tumor via a passive targeting phenomenon commonly referred to as Enhanced Permeability and Retention (EPR)effect.Unlike small molecules which go in and out from the in-terstitial space by diffusion,macromolecules,nanocarriers,including micelles once extravasated cannot diffuse out from the interstitial space(Fig.1).Maeda and co-worker were thefirst to establish the concept of EPR and coined the term in1986(Matsumura and Maeda,1986).The concept of EPR is the characteristics of tumor which has recently been exploited for anti-tumor drug delivery (Maeda et al.,2000).The aberrant fenestration on the blood vessels surrounding tumor tissues causes enhanced permeability of macro-molecules of certain size to the tumor microenvironment,and poor lymphatic drainage in the tumor area allows retention of the extrav-asated nanocarriers(Maeda et al.,2000,2006;Torchilin,2011;Fang et al.,2011;Iyer et al.,2006).In addition to demonstrating EPR effect for eventual passive targeting of polymeric micelles to the tumor sites,polymeric mi-celles could actively be targeted to tumor by their easy surface functionalization(Jhaveri and Torchilin,2014).Amphiphilic block co-polymers having ligand/antibodies at the distal end of the hydrophilic block possessing strong affinity for cancer homing re-ceptors/antigens could be inserted into the micellar assembly with-out disrupting micellar thermodynamic stability.The newly developed surface modified polymeric micelles are actively targeted nanocarrier system that would deliver loaded cargo more efficiently to the tumor compared to passive targeted micellar system relying only on EPR effect or passive targeting for accumulation in tumor area(Yang et al.,2013; Sawant et al.,2014;Chung et al.,2014;Liao et al.,2011).Therefore, advantages of polymeric micelles as drug delivery carriers in cancer therapy include their potential to solubilize the pharmaceutical compo-nents of poor aqueous solubility into the hydrophobic core,improve the pharmacokinetic properties and biodistribution,and specifically target their payload to the tumor tissues by tuning their size for passive targeting via EPR effect,or by anchoring tumor targeted ligands on the micellar surface by using various amenable surface functionalization techniques.Moreover,polymeric micelles offer tunable payload release when constituted by using stimuli-sensitive block co-polymers,which disassemble under certain physiologic condition triggering disassembly of the system leading to drug release(Na et al.,2006;Torchilin,2009).Various amphiphilic co-polymers,including di-block(A–B),triblock (A–B–A),and graft co-polymers have been utilized to form micelles. The most common hydrophilic block in the co-polymeric structure is poly(ethylene oxide)(PEO),also referred to as poly(ethylene glycol) (PEG).PEG is hydrophilic,electrically neutral,non-toxic,andflexible polymer that has commonly been used to coat nanoparticles.PEG-coating decreases the interaction of the nanocarrier-surface with serum components,thus prolonging their circulation.Other hydrophilic block forming polymers include chitosan,poly(N-vinyl pyrrolidone) (PVP),and poly(N-isopropylacrylamide)(pNIPAAm).There are various polymer blocks utilized to form micellar core,including the class of polyethers such as poly(propylene oxide)(PPO),various polyesters such as poly(L-lactide)(PLA),poly-ƹ-caprolactone(PCL),poly(lactide-co-glycolic acid)(PLGA),poly(β-aminoesters),polyamino acids such as poly(L-histidine)(pHis),poly(L-aspartic acid)(pAsp) and lipids such as dioleoyl(phosphatidylethanolamine)(DOPE), distearoyl(phosphatidylethanolamine)(DSPE).The assembly of block co-polymers,in which PPO attached to PEG as A–B–A triblock co-polymers(PEO–PPO–PEO)is known as Pluronics.The block co-polymers included in the poly(ester)class are prone to hydrolysis in the biological system and gets degraded to non-toxic monomers (Anseth et al.,2002;Wu and Wang,2001).Unlike polyethers and es-ters,aliphatic chains in the lipid core do not disintegrate easily to form monomers.Unlike other classes of core-forming polymers, block co-polymers of poly(aminoacids)could carry drugs by chemi-cal modifications due to the presence of functionalizable groups in the co-polymer.Micelles containing poly(ethers)and poly(ester)-core encapsulate poorly-water soluble pharmaceutical agents by physical encapsulation.An important class of micellar system could also be constituted comprising of polymers with stimuli-sensitive behavior(Jhaveri and Torchilin,2014;Yang et al.,2013;Na et al., 2006;Torchilin,2009).In this paper,structural features as well as current trend in using various polymeric micelles comprised of extensively studied micelles-forming block-co-polymers,including Pluronics,PEGylated PLA,PCL,lipid,PLGA,poly(amino acids) for the delivery of chemotherapeutic drugs in cancer has been discussed.Structural features of few currently utilized stimuli-sensitive polymeric micelles and their use in anticancer drug deliv-ery have been represented.2.Polymeric micelles of therapeutic application in cancer treatment 2.1.Pluronics®Pluronics®,also known as poloxamers are amphiphilic,nonionic block copolymer of A–B–A structure,which is composed of hydrophobic propylene oxide(PO)fragments,and hydrophilic ethylene oxide(EO) branches.Poloxamers consist of a central poly(propylene oxide)(PPO) block forming hydrophobic core that isflanked on both sides by two hydrophilic chains of poly(ethylene oxides)(PEO)forming hydrophilic corona,yielding a structure of(PEO)a–(PPO)b–(PEO)a type as shown in185S.Biswas et al./European Journal of Pharmaceutical Sciences83(2016)184–202Fig.2(Rowe et al.,2006).Applicability of poloxamers is based on their self-assembly to from micelles.They have also been used as an emulsi-fier,or a protective coating for nanocarriers,where central PPO block is anchored on to the surface of the nanoparticles via hydrophobic interac-tions (Torcello-Gomez et al.,2014).Pluronic class of polymers is approved by FDA as inactive excipients (Rowe et al.,2006;Mansour et al.,2010;Dumortier et al.,2006).Poloxamer has been recognized as polymer for effective delivery of anti-cancer drugs.Pluronics have disadvantage of instability and aggregate formation (Sezgin et al.,2006).However,Pluronics have an important therapeutic property of multiple drug resistance,which is extensively exploited in anticancer therapy (Zhang et al.,2011;Wang et al.,2012).Poloxamers have been extensively exploited as polymericmicelles or formulation aid for the delivery of chemotherapeutic agents in cancer.Zhao et al.had demonstrated loading of curcumin in mixed micelles composed of Pluronic P123and F68(Zhao et al.,2012).They observed high drug entrapment and loading,86.93andFig.2.Chemical structure ofpoloxamers.Fig.1.Schematic representation of the mode of nanocarrier targeting to tumor.a.Passive targeting of the nanocarriers.(1)Nanocarriers reach tumors through the leaky vasculature surrounding the tumors.(2)Schematic illustration of the in fluence of the size for retention in the tumor tissue.Low molecular weight drugs diffuse easily in and out of the tumor blood vessels due to their small size and thus their effective concentrations in the tumor decrease paratively,drug-loaded nanocarriers cannot diffuse back into the blood stream because of their large size,leading to progressive accumulation:the EPR effect.b.Schematic of active targeting strategy.Ligands grafted at the surface of the nanocarriers bind to receptors overexpressed by (1)cancer cells or (2)angiogenic endothelial cells.186S.Biswas et al./European Journal of Pharmaceutical Sciences 83(2016)184–2026.99%respectively.In vitro cytotoxic assay demonstrated marked re-duction in IC50value for curcumin on MCF-7cells.In another study, Park et al.formulated singlet-oxygen producible polymeric micelles of Pluronic F127conjugated to chlorin e6.Doxorubicin was loaded into micelles,which further enhanced the anti-cancer activity of chlorin e6(Park et al.,2014).Resistance to doxorubicin was reduced without any adverse effect,thereby enhancing the efficiency of the therapy.Sahu et al.demonstrated curcumin delivery by using Pluronic F127and F68as micelle-forming polymers(Sahu et al., 2011).Both micelles demonstrated long-term stability.Moreover, Pluronic F127exhibited higher entrapment efficiency compared to F68due to better hydrophobic interaction.It also showed prolonged drug release.In a recent study,a micelle-like structure of poloxamer–methotrex-ate(MTX)conjugate as nanocarrier for methotrexate delivery have been developed(Ren et al.,2015).MTX was physically entrapped,and chemically conjugated to the same drug delivery system.Poloxamer–MTX(p-MTX)conjugate was synthesized,where MTX was conjugated to poloxamer via ester bond.Due to the hydrophobicity,MTX formed the inner core of the p-MTX micelles,which could also physically encap-sulate free MTX.The pharmacokinetic study revealed that the formula-tion delayed the MTX elimination from the blood stream and prolonged in vivo residence time compared to free MTX.Poloxamer427was com-bined with vitamin E TPGS(D-α-tocopheryl polyethylene glycol succi-nate)to form mixed micelles to be utilized as drug delivery carrier. The mixed micelles entrapped doxorubicin in the core.The surface of the micelles was decorated with folic acid by incorporating folic acid-conjugated P407into the micelles.The purpose of introducing TPGS in cancer therapy is that it reduces multiple drug resistance,induces apoptosis,and exhibits anticancer activity.Based on the fact that poloxamers have also been shown to reverse multiple drug resistance, a recent study utilized PLGA-TPGS/Poloxamer235nanoparticles to overcome multiple drug resistance in docetaxel-resistant human breast cancer cell line(Tang et al.,2015).The poloxamer-coating on the PLGA-TPGS nanoparticles improved cellular uptake of the nanoparticles in docetaxel-resistant MCF-7human breast cancer cell line compared to PLGA-TPGS.The poloxamer-coated nanoparticles produced significant-ly higher cytotoxicity of loaded docetaxel,both in vitro and in vivo compared to both,docetaxel-loaded PLGA-TPGS and clinically used docetaxel formulation,Taxotere®.2.2.PEG–PLAPoly(lactic)acid(PLA),a FDA approved,synthetic biodegradable polymer has recently gained much attention among researchers.It is used up in citric acid cycle to produce water and carbon dioxide.PLA is weakly hydrophilic,however,co-polymerization greatly improved hydrophilicity,rate of degradation,crystallization and stealth(Hu and Liu,1993,1994;Bazile et al.,1995).PEG–PLA diblock copolymer self-assembles in water to form micelles.The size of micelle formed is re-ported to be in the range of10–100nm(Letchford and Burt,2007). The clinically approved micellar preparation of paclitaxel,Genexol-PM has mPEG–PLA as micelle-forming polymer.In a recent pre-clinical study,a mixed micelle-formulation of mPEG–PLA and Vitamin E-TPGS for the delivery of paclitaxel have been developed to increase the effica-cy of Genexol-PM against MDR tumors(Z.Fan et al.,2015).As stated earlier,Vitamin E-TPGS is an inhibitor of the efflux transporter, P-glycoprotein,which is up-regulated in multi-drug resistant tumors. Incorporation of Vitamin E-TPGS in the formulation improved the drug loadability of Genexol-PM.PEG–PLA has also been conjugated to various ligands for active targeting of the polymeric micelles to the tumor site.In a study,a pep-tide,APRPG(Ala-Pro-Arg-Pro-Gly)that specifically targetsαvβ3 integrin over-expressed during angiogenesis was conjugated to the dis-tal end of the PEG-chain in Maleimide–PEG–PLA co-polymer(Wang et al.,2014a).The peptide-conjugated PEG–PLA micelles encapsulated an angiogenesis inhibitor,TNP-470efficiently.The drug-loaded nano-particles demonstrated effective inhibition of proliferation,migration, and tube formation in human umbilical vein endothelial cells(HUVECs). The actively tumor targeted PEG–PLA micelles efficiently delivered angiogenic inhibitor resulting in retardation of tumor growth,apoptosis among endothelial cells and blockade of endothelial cell proliferation. Another over-expressed extracellular matrix component of tumor micro-environment,fibronectin(FN)was targeted by using FN-targeting CLT-1peptide,which was conjugated to the PEG–PLA nano-particles(Zhang et al.,2014).The FN-targeted PEG–PLA micelles loaded with paclitaxel was utilized for the treatment of glioma that has demon-strated over-expression of FN in its extracellular matrix.The targeted nano-formulation penetrated glioma cells more efficiently compared to non-targeted formulations,and prolonged the median survival time of glioma-bearing mice.For glioma therapy,in another study,PEG–PLA was conjugated to transferrin(Tf)ligand that recognized over-expressed transferrin receptors(Guo et al.,2013).The Tf-modified PEG–PLA nanoparticles were conjugated to resveratrol(RSV)and the therapeutic efficacy was tested in vitro and in vivo.The result demon-strated that the targeted nano-formulation effectively decreased cell viability of C6and U87glioma cells.In vivo study performed on C6-glioma-bearing rats indicated that targeted formulation accumulated in brain tumor and decreased the tumor volumes more efficiently com-pared to free RSV,and RSV-conjugated micellar system.In another study,highly over-expressed neuropilin(NRP)on the surface of the glioma cells have been targeted by using NRP targeting ligand,tLyp-1 peptide,a kind of tumor homing and penetrating peptide,which was functionalized on the surface of the PEG–PLA micelles(Hu et al., 2013a).The paclitaxel-loaded targeted mPEG–PLA system significantly improved the efficacy of glioma therapy.Another over-expressed mark-er on glioma cells and endothelial cells of glioma angiogenic blood ves-sels,nucleolin have been targeted by using nucleolin-targeted F3 peptide,which was anchored on the surface of the mPEG–PLA micelles for targeted paclitaxel delivery to glioblastoma(Hu et al.,2013b).Folic acid(FA)conjugated PEG–PLA has been synthesized to decorate mi-celles to recognize over-expressed folate receptor in tumor for active targeting(X.Li et al.,2015).In another study,dodecanol(Dol)and FA conjugated PEG–PLA system,Dol–PLA–PEG–FA was prepared where Dol and FA were attached to the distal end of the PLA and PEG,respec-tively.The CMC of the micelles was much lower compared to plain mi-celles.The folate anchoring imparted much higher selecting capability to breast cancer cells compared to normalfibroblast cells.PEG–PLA micelles have been attempted to deliver into the brain as a carrier for potent chemotherapeutic agents.Brain delivery of PEG–PLA micelles was achieved by applying microbubble-enhanced unfocused ultrasound(Yao et al.,2014).PEG–PLA signal was distributed deeply into the parenchyma after the ultrasound treatment.Another potent chemotherapeutic drug Gemcitabine,thefirst line treatment option for pancreatic cancer has been delivered to the Gemcitabine-resistant cells by synthesizing a hydrophobic pro-drug and loading it in the PEG–PLA micelles.Gemcitabine was modified with a stearyl group to form a lipophilic pro-drug,GemC18,which was loaded into PEG–PLA polymeric micelles(Daman et al.,2014). GemC18-loaded micelles could effectively reduce the cell viability of Gemcitabine-resistant AsPC-1cells.Another hydrophobic,potent chemotherapeutic agent curcumin have been loaded inside the PEG–PLA polymers by conjugation via pH labile hydrazone bond(Z.Wang et al.,2015).The curcumin-conjugated PEG–PLA could self-assemble, doubled the loading dose,and enhanced the release rate compared to PEG–PLA micelles.As PEGylated polyester nanoparticles,including PEG–PLA micelles can be prepared of wide size range by using PEG–PLA polymers of varying molecular weights,it is questionable which PEG and PLA combination could cause maximum transcellular trans-port.In this regard,one study characterized the cellular transport path-way of PEG–PLA nanoparticles and determined the effect of polymer architecture including length of PEG chain and core material on its187S.Biswas et al./European Journal of Pharmaceutical Sciences83(2016)184–202cellular interaction and transcellular transport in Caco-2cell line.The result indicated that for PEG5000–PLA40,000nanoparticles higher drug loading capacity and slower drug release were observed(Song et al.,2013).PEG–PLA has also been utilized for co-delivery of two potent chemo-therapeutic agents to achieve synergistic anticancer activity.In a study, Crizotinib,an antitumoral drug approved for the treatment of non-small cell lung cancer in humans,and Sildenafil(Viagra®)were loaded in PEG–PLA micelles and their synergistic drug action was evaluated in breast cancer cells.High drug loading was achievable by using PEG–PLA micelles.The result demonstrated that delivery of both the drugs led to2.7fold increase in the anti-tumoral effect even after administer-ing half the concentration of the free drugs producing the effect (Marques et al.,2014).2.3.PEG–PCLPEGylated poly(caprolactone)(PEG–PCL),another class of amphi-philic polyester polymers is widely used copolymers for the encapsula-tion of anti-cancer drugs.The amphiphilic property and ease to synthesis make it an ideal candidate for injectable drug delivery sys-tems.It exhibits good biocompatibility,biodegradability and low toxic-ity profile(Gou et al.,2008;Ge et al.,2002).In recent years,PEG–PCL has been extensively used for co-delivery of chemotherapeutic and photodynamic therapy agent listed in Table1.Cheng-Liang Peng and co-workers synthesized 4-armed star-shaped chlorin-core diblock copolymers based on methoxy poly(ethyleneglycol)(mPEG)and poly(3-caprolactone) (PCL)encapsulating anti-cancer drug paclitaxel.The nano-structure aims to deliver,both the chemotherapeutic drug and the photo sensitiz-ing agent(Peng et al.,2008).Photodynamic therapy(PDT)uses photo-sensitizers(PSs)for the treatment of various cancers(Dolmans et al., 2003).Reactive oxygen species(ROS)is generated when photosensi-tizers are activated and the generated ROS leads to death of cancer cells(Seshadri et al.,2005).Synergistic effect was observed when pho-todynamic therapy was given with chemotherapy with increased efficiency of killing cancer cells.Another photosensitizer,5,10,15,20-tetrakis(4-aminophenyl)-21H,23H-chlorin(TAPC)was conjugated to PCL by the reaction between the acid-chloride of PCL(PCL-COCl)and the amine group of TAPC to form chlorin-core star mPEG-b-PCL copoly-mer(CSBC)(Peng et al.,2008).CSBC52(5000-mPEG:2000-PCL)and CSBC58(5000-mPEG:8000-PCL),PEG–PCL co-polymers with varied hy-drophobicity was prepared and their drug loading efficiency was stud-ied.CSBC58displayed low CMC value(0.008wt.%)compared to CSBC52(0.032wt.%)due to their longer hydrophobic segment (Letchford et al.,2004).Generally CMC decrease with an increase in the length of the PCL core block is in linear diblock copolymers (Letchford et al.,2004;Zeng et al.,2005).However,it was not observed in star-shaped copolymers which can be explained through steric or en-tropic effects in micellization(Huh et al.,2004).PEG–PCL micellar nanoparticles were actively targeted to tumor by surface anchorage of cancer targeting ligands.Nguyen-Van Cuong and co-workers synthesized star-shape Folate–PEG–PCL copolymer in which doxorubicin is encapsulated for targeted delivery in breast can-cer.The distal end of the PEG chain was modified by conjugating a folic acid.Folate receptors are over-expressed in tumors of breast and ovarian cancer.Therefore,targeted delivery of the drug would be possi-ble by conjugation of folic acid to the micellar carrier,PEG–PLA(Cabral and Kataoka,2010).Folic acid is taken into the cancer cells by receptor mediated endocytosis(Yoo and Park,2004;Prabaharan et al.,2009). In this study,a novel step is involved in the synthesis of star-shaped poly(3-caprolactone)block copolymer.Pentaerythritol ethoxylate was used as an initiator with Sn(Oct)2as a catalyst in the ring opening poly-merization of3-caprolactone(Cuong et al.,2012).The formation of star-shaped micelles was facilitated by the initiator.Star-shaped micelles were selected because amphiphilic branched polymers have globular architecture,low conformational freedom,good stability and increased diffusion near the tumor site(Chen et al.,2008;Kono et al.,2008;Wang et al.,2008).As drug loading content and loading efficiency depend upon the in-teractions of the drug with hydrophobic part of the copolymer,different feed ratio of copolymer:drug had been tried ranging from1:0.075to 1:0.2(Shuai et al.,2004a).The drug loading content and drug loading ef-ficiency increased when the copolymer/drug feed ratios increased from 1:0.075to1:0.15and decreased when the ratio exceeded1:0.15.Hence the optimal copolymer/drug feed ratio was found to be1:0.15.Drug loading amount and the drug loading efficiency at1:0.15were found to be13%and90%,respectively.The average particle size of the DOX-loaded micelle,determined by dynamic light scattering was148.2nm. The polydispersity index of the particle size distribution was0.45.The zeta-potential was(−8.4to−1.2mV),making it more negative than micelle without folic acid conjugation(−2.5to−0.8mV).Few studies were reported dealing with the release kinetics of the drug loaded in PEG–PCL micelles.The release profile of doxorubicin from the star-shaped block copolymer was found to be initial burst re-lease followed by a sustained release which may be attributed to the fast degradation of the micelles(Gaucher et al.,2005).The total releases of DOX in a period of156h with pH5.4and7.4were78%and42%of total DOX concentration,respectively.The fast release rate of DOX at pH5.4and slow release of doxorubicin at pH7.4may be due to weak and strong hydrophobic interactions,respectively between drug and hydrophobic part of copolymer(PCL)from the star-shaped micelles (Shuai et al.,2004a;Cuong et al.,2010).Li and co-workers prepared series of amphiphilic cationic graft poly-mers(PEC)coupling poly(e-caprolactone)(PCL)of differing molecular weights(MW)to low MW,branched polyethylenimine(PEI)via an amide group.Novelty was introduced by giving chemical and gene ther-apy together in order to decrease multidrug resistance while treating cancer.The negative charge of PEI promoted condensation of nucleic acids.Branched PEI is used as vector for non-viral gene delivery because of its excellent transfection efficiency(Green et al.,2008;Mao et al.,Table1Various PEG-poly(caprolactone)-based polymeric micelles reported in pre-clinical studies.Name of the polymer Name of the drug Comments ReferencesChlorin-core star-shaped PCL–mPEG Paclitaxel In vitro Peng et al.(2008) Star-shaped PCL-b-PEG Honokiol In vitro Dong et al.(2010) Folate PCL-b-PEG Doxorubicin In vitro Cuong et al.(2012) PCL–PEG–PCL Honokiol In vitro Gou et al.(2009b) Polyethylenimine-grafted-PCL Doxorubicin In vitro Qiu and Bae(2007) Polycaprolactone-b-methoxy-PEG Cisplatin In vitro Xu et al.(2006)Paclitaxel In vitro Shuai et al.(2004b) Poly(caprolactone/trimethylene carbonate)–PEG Ellipticin In vitro Liu et al.(2005) PEG–PCL Rapamycin Yáñez et al.(2008)Cucurbitacin-I and B Molavi et al.(2008)Paclitaxel Forrest et al.(2008) 188S.Biswas et al./European Journal of Pharmaceutical Sciences83(2016)184–202。
