毛世瑞,田野,王琳琳
MAO Shi-rui,TIAN Ye,WANG Lin-lin(School of Pharmacy

• 1:沈阳药科大学药学院

摘要(Abstract)：

目的对目前聚合物胶束作为药物纳米载体的国内外研究进展进行综述。方法参考近年来国内外文献50篇,从聚合物胶束的类别和构成,药物的包载方法,药物从聚合物胶束中的释放,聚合物胶束的稳定性,聚合物胶束的表征,聚合物胶束对药物的药动学和体内分布的影响以及聚合物胶束作为药物载体的应用等几个方面系统地介绍了其研究进展。结果聚合物胶束包括自聚集胶束,单分子胶束和交联的胶束,可采用化学结合法、物理包载和聚离子复合法包载药物;药物分子在聚合物胶束中的分布以及聚合物的降解行为决定了药物的释放速度;聚合物胶束的热力学和动力学稳定性与其结构组成密切相关;载药聚合物胶束可改变药物的药动学和体内分布;目前聚合物胶束已被用于作为肿瘤药物、难溶性药物的载体,也可作为药物药物经皮传递载体和药物的缓释载体,发展前景较好,但同时也面临挑战。结论聚合物胶束作为药物的纳米载体具有广泛的应用前景。
Objective To review the progress on polymeric micelles as drug nanocontainer.Methods In the present paper,the classification and composition of polymeric micelles,drug loading method,drug release from micelles,stability of micelles,characteristics of polymeric micelles,influence of polymeric micelles on the pharmacokinetics and in vivo distribution of therapeutic drugs,and application of polymeric micelles as drug nanocarriers were introduced.Results Polymeric micelles include self-assembled micelles,unimolecular micelles and cross-linked micelles.Drug substance can be loaded into the micelles by chemical conjunction,physical entrapment and polyionic complexation.The distribution of the drug substance in the micelle and the degradation behavior of the polymer have significant influence on drug release.The thermodynamic and dynamic stability of the polymeric micelles is composition dependent.The pharmacokinetics and drug distribution can be changed by using different polymer micelles as drug carriers.Polymeric micelles are now extensively studied as the carrier for the delivery of antitumor and poorly soluble drug substances,it can also be used as the carrier for transdermal and sustained drug delivery.However,it meets challenges in the meantime.Conclusions Polymeric micelles,as drug nanocontainer,have promising application for the delivery of a large number of diverse therapeutic compounds.

关键词(KeyWords)： 聚合物胶束;药物包载;药物释放;稳定性;纳米载体
polymeric micelle;drug loading;drug release;stability;nanocarrier

Abstract:

Keywords:

基金项目(Foundation): 国家重大基础研究计划项目(973计划,2009CB930300);; 国家科技部重大新药创制项目(2008ZX09401-004)

作者(Author): 毛世瑞,田野,王琳琳
MAO Shi-rui,TIAN Ye,WANG Lin-lin(School of Pharmacy

DOI: 10.14066/j.cnki.cn21-1349/r.2010.12.008

参考文献(References)：

• [1]K IM S,SH I Y,K IM J Y,et al.Overcom ing the barriersin m icellar drug delivery:load ing effic iency,in vivosta-b ility and m icelle-cell interaction[J].Expert Op inD rug Deliv,2010,7(1):49-62.
• [2]KABANOV AV,NAZAROVA IR,ASTAFIEVA IV,etal.M icelle form ation and solub ilization of fluorescentprobes in poly(oxyethylene-b-oxypropylene-b-oxyethyl-ene)solutions[J].M acromolecu les,1995,28(7):2303-2314.
• [3]ALLEN C,MAYSINGER D,E ISENBERG A.Nano-engineering b lock copolym er aggregates for drug de-livery[J].Coll Surf B:B iointerf,1999,16(25):3-27.
• [4]KATAOKA K,HARADA A and NAGASAK I Y.B lockcopolym erm icelles for drug delivery:design,character-ization and b iological sign ificance[J].Adv D rug DelRev,2001,47(1):113-131.
• [5]B IAN F,JIA L,YU W,et al.Se lf-assemb led m ice llesofN-phthaloylch itosan-g-polyvinylpyrrolidone for drugde livery[J].Carbohy Polym,2009,76(3):454-459.
• [6]DUNCAN R,KOPECEK J.Solub le synthetic polym ersas potential drug carriers[J].Adv Polym Sc i,1984,57:51-101.
• [7]ADAMS M L,LAVASANIFAR A,KWON G S.Am-ph iph ilic b lock copolym ers for drug delivery[J].JPharm Sc i,2003,92(7):1343-1355.
• [8]MOGH IM I S M,HUNTER A C,MURRAY J C.Long-c ircu lating and target-spec ific nanopartic les:Theory topractice[J].Pharm acol R ev,2001,53(2):283-318.
• [9]HU F,ZHAO M,YUAN H,et al.A novel ch itosan oli-gosaccharide-stearic ac id m icelles for gene delivery:Properties and in vitro transfection stud ies[J].Int JPharm,2006,315(1-2):158-166.
• [10]LUKYANOV A N,TORCH ILIN V P.M icelles from lip-id derivatives ofwater-solub le polym ers as delivery sys-tem s for poorly solub le drugs[J].Adv D rug Deliv Rev,2004,56(9):1273-1289.
• [11]徐建平,陈伟东,计剑,沈家骢.新型仿生聚合物胶束用于纳米药物载体的研究[J].高等学校化学学报,2007,28(2):394-396.
• [12]KABANOV A V,ALAKHOV V Y.P luron ic b lock co-polym ers in drug delivery:from m icellar nanocontainersto b iological response mod ifiers[J].CritRev Ther D rugCarr Syst,2002,19(1):1-72.
• [13]ZHANG L,YU K,EISENBERY A.Ion-induced mor-phological changes in“crew-cut”aggregates of am-ph iph ilic b lock copolym ers[J].Sc ience,1996,272(5269):1777-1779.
• [14]K IM K H,GUO H C,LIM H J,et al.Synthesis and m i-cellization of star-shaped poly(ethylene glycol)-b lock-poly(e-caprolactone)[J].M acromolec Chem Phys,2004,205(12):1684-1692.
• [15]G ITSOV I,LAMBRYCH K R,REMNANT V A,et al.M icelles w ith h ighly branched nanoporous interior:So-lution properties and b ind ing capab ilities of amph iph iliccopolym ers w ith linear dendritic arch itecture[J].JPolym Sc i PartA:Polym Chem,2000,38(15):2711-2727.
• [16]WANG F,BRONICH T K,KABANOV A V,et al.Syn-thesis and evaluation of a star amph iph ilic b lock copol-ym er from poly(epsilon-caprolactone)and poly(ethyl-ene glycol)as a potential drug delivery carrier[J].B io-con jug Chem,2005,16(2):397-405.
• [17]IIJIMA M,NAGASAK I Y,OKADA T,et al.Core-poly-m erized reactive m icelles from heterotelechelic am-ph iph ilic b lock copolym ers[J].M acromolecu les,1999,32(4):1140-1146.
• [18]ZHANG Q,REMSEN E E,WOOLEY K L.Shell cross-lined nanopartic les contain ing hydrolytically degrad-ab le,crystalline core dom ains[J].J Am Chem Soc,2000,122(15):3642-3651.
• [19]K IM J H,EMOTO K,IIJIMA M,et al.Core-stab ilizedpolym eric m icelle as potential drug carrier:increasedsolub ilization of taxol[J].Polym Adv Technol,1999,10(11):647-654.
• [20]BADER H,R INGSDORF H and SCHM IDT B.W ater-solub le polym ers in m ed ic ine[J].Angew M akromolChem,1984,123/124(1):457-485.
• [21]BULMUS V,WOODWARD M,LIN L,et al.A new pH-responsive and glutath ione-reactive,endosom al m em-brane-d isruptive polym eric carrier for intracellu lar de-livery of b iomolecu lar drugs[J].J Controlled Release,2003,93(2):105-120.
• [22]BAE Y,N ISH IYAMA N,FUKUSH IMA S,et al.Prep-aration and b iological characterization of polym eric m i-ce lle drug carriers w ith intrace llu lar pH-triggered drugre lease property:Tum or perm eab ility,controlled sub-ce llu lar drug d istribution,and enhanced in vivo antitu-m or efficacy[J].B iocon jug Chem,2005,16(1):122-130.
• [23]YAKOYAMA M,FUKUSH IMA S,UEHARA R,et al.Characterization of physical entrapm ent and chem icalcon jugation of adriamyc in in polym eric m icelles andthe ir design for in vivo delivery to a solid tumor[J].JControlled Release,1998,50(1-3):79-92.
• [24]SAVIC R,LUO L,EISENBERG A,et al.M icellarnanocontainers d istribute to defined cytop lasm ic organ-elles[J].Sc ience,2003,300(5619):615-618.
• [25]LETCHFORD K,BURT H.A review of the form ationand c lassification of amph iph ilic b lock copolym er nano-particu late structures:m icelles,nanospheres,nanocap-su les and polym ersom es[J].Eur J Pharm B iopharm,2007,65(3):259-269.
• [26]ZHANG J X,LI X J,QIU L Y,et al.Indom ethac in-loaded polym eric nanocarriers based on amph iph ilicpolyphosphazenes w ith poly(N-isopropylacrylam ide)and ethyl tryptophan as side groups:Preparation,invitro and in vivo evaluation[J].J Controlled Release,2006,116(3):322-329.
• [27]GADELLE F,KOROSW J,SCHECHTER R S.Solub i-lization of arom atic solutes in b lock copolym ers[J].M acromolecu les,1995,28(14):4883-4892.
• [28]LAVASANIFAR A,SAMUEL J,KWON G S.Poly(eth-ylene oxide)-b lock-poly(L-am ino ac id)m icelles fordrug delivery[J].Adv D rug Deliv Rev,2002,54(2):169-190.
• [29]LIU J,X IAO Y,ALLEN C.Polym er-drug compatib ili-ty:a gu ide to the developm ent of delivery system s forthe anticancer agent,elliptic ine[J].J Pharm Sc i,2004,93(1):132-143.
• [30]HARADA A,KTATOKA K.Form ation of polyion com-p lex m icelles in an aqueous m ilieu from a pair of oppo-sitely-charged b lock copolym ers w ith poly(ethylene gly-col)segm ents[J].M acromolecu les,1995,28(15):5294-5299.
• [31]KABANOV V A,KABANOV A V.Interpolyelectrolyteand b lock ionom er comp lexes for gene delivery:physi-co-chem ical aspects[J].Adv D rug Deliv Rev,1998,30(1-3):49-60.
• [32]KAK IZAWA Y and KATAOKA K.B lock copolym erm icelles for delivery of gene and related compounds[J].Adv D rug Del Rev,2002,54(2):203-222.
• [33]TENG Y,MORR ISON M E,MUNK P,et al.Releasek inetics stud ies of arom atic molecu les into water fromb lock polym er m icelles[J].M acromolecu les,1998,31(11):3578-3587.
• [34]CHOUCAIR A,EISENBERG A.Interfac ial solub iliza-tion ofmodel amph iph ilic molecu les in b lock copolym erm icelles[J].J Am Chem Soc,2003,125(39):11993-12000.
• [35]K IM S Y,SH IN I G,LEE Y M,et al.M ethoxy poly(ethylene glycol)and epsilon-caprolactone amph iph ilicb lock copolym eric m icelle contain ing indom ethac in.II.M icelle form ation and drug release behaviours[J].JControlled Release,1998,51(1):13-22.
• [36]KWON G S,OKANO T.Solub le self-assemb led b lockcopolym ers for drug delivery.Pharm Res,1999,16(5):597-600.
• [37]NAKASH IMA K,BAHADUR P.Aggregation of water-solub le b lock copolym ers in aqueous solutions:Recenttrends.Adv Colloid Interface Sc i,2006,123-126:75-96.
• [38]KOZLOV M Y,MELIK-NUBAROV N S,BATRAKO-VA E V,et al.R e lationsh ip between p luron ic b lock co-polym er structure,critical m ice llization concentrationand partition ing coeffic ients of low m olecu larm ass sol-utes[J].M acrom olecu les,2000,33(9):3305-3313.
• [39]X ING L,MATTICE W L.Strong solub ilization of sm allmolecu les by trib lock copolym er m icelles in selectivesolvents[J].M acromolecu les,1997,30(6):1711-1717.
• [40]HURTER P N,SCHEUTJENS J and HATTON T A.Molecu lar modeling ofm icelle form ation and solub iliza-tion in b lock copolym er m icelles.2.Lattice theory formonom ers w ith internal degrees of freedom[J].M acro-molecu les,1993,26(21):5030-5040.
• [41]NISH IYAMA N,OKAZAK I S,CABRAL H,et al.Novelc isp latin-incorporated polym eric m icelles can erad icatesolid tumors in m ice[J].Cancer Res,2003,63(24):8977-8983.
• [42]GREICH K,SAWA T,FANG J,et al.SMA-doxorub i-c in,a new polym eric m icellar drug for effective targe-ting to solid tumours[J].J Controlled Release,2004,97(2):219-230.
• [43]LEE E S,NA K and BAE Y H.Doxorub ic in loadedpH-sensitive polym eric m icelles for reversal of resistantMCF-7 tumor[J].J Controlled Release,2005,103(2):405-418.
• [44]MAEDA H,BHARATE G Y,DARUWALLA J.Poly-m eric drugs for effic ient tumor-targeted drug deliverybased on EPR-effect[J].Eur J Pharm B iopharm,2009,71(3):409-419.
• [45]RAPOPORT N.Physical stimu li-responsive polym ericm icelles for anti-cancer drug delivery[J].Prog PolymSc i,2007,32(8-9):962-990.
• [46]BROMBERG L.Polym eric m icelles in oral chemothera-py[J].J Controlled Release,2008,128(2):99-112.
• [47]Y I Y,YOON H J,K IM B O,et al.A m ixed polym ericm icellar formu lation of itraconazole:Characteristics,tox-ic ity and pharm acok inetics[J].J Controlled Release,2007,117(1):59-67.
• [48]SANTA V P,SM ITHB D,LEROUX J.Enhancem ent oforal b ioavailab ility of poorly water-solub le drugs by poly(ethylene glycol)-b lock-poly(alkyl acrylate-co-m etha-crylic ac id)self-assemb lies[J].J Controlled Release,2005,104(2):289-300.
• [49]董岸杰,邓联东.可生物降解聚合物纳米胶囊型药物载体及组合胶囊的药物控制释放[J].中国医学工程,2005,13(2):128-131.
• [50]XU X,LI L,ZHOU J,et al.Preparation and character-ization ofN-succ inyl-N-octyl ch itosan m icelles as doxo-rub ic in carriers for effective anti-tumor activity[J].Colloids and Surfaces B:B iointerfaces,2007,55(2):222-228.