两亲性核交联聚合物胶束的制备与载药应用研究
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摘要
两亲聚合物在选择性溶剂中发生自组装,其所形成的核-壳结构胶束可作为疏水性药物和核酸、蛋白等药物的载体,具有高效、长效、安全性和靶向性等特点,展现出很好的应用前景。但该类胶束受到溶液浓度的限制,当浓度低于胶束的临界胶束浓度(CMC)时,结构就会遭到破坏。两亲性核交联聚合物胶束具有一定的热力学稳定性,在稀释情况下也不会被破坏。因此,通过交联的方式使胶束的稳定性增强,药物扩散速度减慢具有重要意义。本论文合成了3种核交联聚合物。
以辛酸亚锡为催化剂,用溶液聚合法合成不同嵌段比例的聚乙二醇-b-聚己内酯两亲性二嵌段共聚物,再与丙烯酸在4-二甲氨基吡啶(DMAP)-N,N’-二异丙基碳二酰亚胺(DIPC)体系下催化酯化,将双键引入疏水嵌段。在制备胶束过程中,引发双键交联,得到核交联聚合物；
以聚乙二醇和油酸为原料,经DMAP-DIPC催化酯化合成两亲性油酸聚乙二醇酯,油酸中的双键在制备胶束过程中引发交联,得到核交联油酸聚乙二醇酯；
以L-天冬氨酸为原料,缩聚生成聚琥珀酰亚胺,以一定比例带有氨基的化合物(聚乙二醇、苄胺和半胱氨酸)对聚琥珀酰亚胺进行开环,形成两亲性接枝聚合物。并在制备胶束过程中,对巯基氧化,通过二硫键得到核交联聚合物。
通过透析法制备了上述各聚合物胶束及其核交联胶束,考察了胶束粒径大小及分布,发现胶束核交联后粒径明显减小；考察了胶束的抗稀释能力,核交联胶束具有良好的稳定性。
通过透析法制备了各聚合物纳米载药胶束,考察了其载药能力和体外释放行为。核交联胶束由于内核变小,载药量和载药率要低于未交联胶束。其中聚乙二醇-b-聚己内酯(5／8)载药能力最高。通过建立数学模型对释放动力学进行研究,证实药物的释放主要受药物扩散控制。
Amphiphilic polymers can occur self-assembly in selective solvents, form core-shell structure micelles that can be used as carriers for hydrophobic drugs, nucleic acids and proteins. Amphiphilic polymer micelles as drug carriers have good properties, for example, high efficiency, long effect, safety and targeting. But the micelles may be destroyed when the solution concentration below its critical micelle concentration (CMC). Core cross-linking is an effective way to avoid the micellar disintegration upon dilution. In this work, three core cross-linked polymers have been prepared.
Methoxy poly (ethylene glycol)-b-polycaprolactone (MePEG-b-PCL) diblock copolymer was polymerized in solution by using Sn(Oct)2 as catalyst, the double bonds of acrylic acid were joined on the hydrophobic block under the catalysis of DMAP-DIPC. The core cross-linked polymer was synthesized by cross-linking of the double bonds during the micelles formed.
Polyethylene glycol oleate was synthesized by esterification of polyethylene glycol and oil acid using DMAP-DIPC as a catalyst. Core cross-linked polyethylene glycol oleate was synthesized by cross-linking of the double bonds during the micelles formed.
Polysuccinimide (PSI) was synthesized by acid-catalyzed polycondenastion of L-aspartic acid. The grafted polyaspartic acid was synthesized by stepwise aminolytic ring-opening of PSI with Jeffamine, benzylamine and cysteine. The core cross-linked polymer was prepared by forming disulfide cross-linking.
Noncross-linked micelles and core cross-linked micelles were prepared by dialysis method. The core cross-linked micelles have smaller size, and are more stable upon dilution.
Drug-loading micelles were also prepared by dialysis method. The drug-loading capacity and drug release behavior from micelles in vitro was studied. The drug-loading content and drug-loading efficiency of cross-linked micelles are lower than those of noncross-linked micelles because cores were compacted by cross-linking. MePEG-b-PCL (5/8) has the best drug-loading capacity. Kinetic study manifested the release of drug from the micelles by drug diffusion.
以辛酸亚锡为催化剂,用溶液聚合法合成不同嵌段比例的聚乙二醇-b-聚己内酯两亲性二嵌段共聚物,再与丙烯酸在4-二甲氨基吡啶(DMAP)-N,N’-二异丙基碳二酰亚胺(DIPC)体系下催化酯化,将双键引入疏水嵌段。在制备胶束过程中,引发双键交联,得到核交联聚合物；
以聚乙二醇和油酸为原料,经DMAP-DIPC催化酯化合成两亲性油酸聚乙二醇酯,油酸中的双键在制备胶束过程中引发交联,得到核交联油酸聚乙二醇酯；
以L-天冬氨酸为原料,缩聚生成聚琥珀酰亚胺,以一定比例带有氨基的化合物(聚乙二醇、苄胺和半胱氨酸)对聚琥珀酰亚胺进行开环,形成两亲性接枝聚合物。并在制备胶束过程中,对巯基氧化,通过二硫键得到核交联聚合物。
通过透析法制备了上述各聚合物胶束及其核交联胶束,考察了胶束粒径大小及分布,发现胶束核交联后粒径明显减小；考察了胶束的抗稀释能力,核交联胶束具有良好的稳定性。
通过透析法制备了各聚合物纳米载药胶束,考察了其载药能力和体外释放行为。核交联胶束由于内核变小,载药量和载药率要低于未交联胶束。其中聚乙二醇-b-聚己内酯(5／8)载药能力最高。通过建立数学模型对释放动力学进行研究,证实药物的释放主要受药物扩散控制。
Amphiphilic polymers can occur self-assembly in selective solvents, form core-shell structure micelles that can be used as carriers for hydrophobic drugs, nucleic acids and proteins. Amphiphilic polymer micelles as drug carriers have good properties, for example, high efficiency, long effect, safety and targeting. But the micelles may be destroyed when the solution concentration below its critical micelle concentration (CMC). Core cross-linking is an effective way to avoid the micellar disintegration upon dilution. In this work, three core cross-linked polymers have been prepared.
Methoxy poly (ethylene glycol)-b-polycaprolactone (MePEG-b-PCL) diblock copolymer was polymerized in solution by using Sn(Oct)2 as catalyst, the double bonds of acrylic acid were joined on the hydrophobic block under the catalysis of DMAP-DIPC. The core cross-linked polymer was synthesized by cross-linking of the double bonds during the micelles formed.
Polyethylene glycol oleate was synthesized by esterification of polyethylene glycol and oil acid using DMAP-DIPC as a catalyst. Core cross-linked polyethylene glycol oleate was synthesized by cross-linking of the double bonds during the micelles formed.
Polysuccinimide (PSI) was synthesized by acid-catalyzed polycondenastion of L-aspartic acid. The grafted polyaspartic acid was synthesized by stepwise aminolytic ring-opening of PSI with Jeffamine, benzylamine and cysteine. The core cross-linked polymer was prepared by forming disulfide cross-linking.
Noncross-linked micelles and core cross-linked micelles were prepared by dialysis method. The core cross-linked micelles have smaller size, and are more stable upon dilution.
Drug-loading micelles were also prepared by dialysis method. The drug-loading capacity and drug release behavior from micelles in vitro was studied. The drug-loading content and drug-loading efficiency of cross-linked micelles are lower than those of noncross-linked micelles because cores were compacted by cross-linking. MePEG-b-PCL (5/8) has the best drug-loading capacity. Kinetic study manifested the release of drug from the micelles by drug diffusion.
引文
[1]秦建民,李荫太.顺铂可降解淀粉微球兔胃动脉栓塞的实验研究[J].中华普通外科杂志,2000,15(2)：19-21.
[2]Leo E, Cameroni R, Forni F. Dynamic dialysis for the drug release evaluation from doxorubicin-gelatin nanoparticles conjugates [J]. International Journal of Pharmaceutics,1999,180(1):23-30.
[3]Weber C, Coester C, Kreuter J, et al. Desolvation process and surface characterization of protein nanoparticles[J]. International Journal of Pharmaceutics, 2000,194(1):91-102.
[4]元英进,刘名言,董岸杰.中药现代化生产关键技术[M].北京：化学工业出版社,2002：203-204.
[5]Uhrich K E, Cannizzaro S M, Langer R S, et al. Polymeric systems for controlled drug release[J]. Chemistry Review,1999,99:3181-3198.
[6]Yoo H S, Park T G. Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA-PEG block copolymer[J]. Journal of Controlled Release,2001, 70(1-2):63-70.
[7]Carino G P, Jacob J S, Mathiowitz E. Nanosphere based oral insulin delivery [J]. Journal of Controlled Release,2000,65(3):261-269.
[8]Hoste K, Schacht E, Seymour L. New derivatives of polyglutamic acid as drug carrier systems[J]. Journal of Controlled Release,2000,64(1-3):53-61.
[9]Yokoyama M, Fukushima S, Uehara R, et al. Characterization of physical entrapment and chemical conjugation of adriamycin in polymeric micelles and their design for in vivo delivery to a solid tumor[J]. Journal of Control Release,1998, 50(1-3):79-92.
[10]Allen C, Maysinger D, Eisenberg A. Nano-engineering block copolymer aggregates for drug delivery [J]. Colloids Surfaces B:Biointerfaces,1999,16(1-4):3-27.
[11]Miwa A, Ishibe A, Nakano M, et al. Development of novel chitosan derivatives as micelle carriers taxol[J]. Pharmaceutical Research,1998,15(2):1844-1850.
[12]Cheon Lee S, Kim C, Chan Kown I, et al. Polymeric micelles of poly(2-ethyl-2-oxazoline)-block-poly(varepsilon-caprolactone) copolymer as a carrier for paclitaxel[J]. Journal of Controlled Release,2003,89(3):437-446.
[13]Adams M L, Lavasanifar A, Kwon G S. Amphiphilic block copolymers for drug delivery[J]. Pharmaceutical Science,2003,92:1343-1355.
[14]Kataoka K, Harada A, Nagasaki Y. Block copolymermicelles for drug delivery: design, characterization and biological significance[J]. Advanced Drug Delivery Reviews,2001,47:113-131.
[15]Gaucher G, Dufresne M H, Sant V P, et al. Block copolymer micelles:preparation, characterization and application in drug delivery[J]. Journal of Controlled Release, 2005,109(1-3):169-188.
[16]Inoue T, Chen G, Nakamae K, et al. An AB block copolymer of oligo (methyl methacrylate) and poly (acrylic acid) for micellar delivery of hydrophobic drug[J]. Journal of Controlled Release,1998,51:221-229.
[17]Xiong X Y, Tam K C, Gan L H. Release kinetics of hydrophobicand hydrophilic model drugs from p luronic F127/poly (lactic acid) nanoparticles [J]. Journal of Controlled Release,2005,103:73-82.
[18]Kabanov A V, Batrakova E V. A new class of drug carriers:micelles of poly(oxyethylene)-poly(oxypropylene) block copolymers as microcontainers for drug targeting from bllod in brain[J]. Journal of Controlled Release,1992,22(2):141-158.
[19]Cammas S, Suzuki K, Sone C, et al. Thermmo-responsive polymer nanopartieles with a core-shell micell structure as sitespecific drug carriers[J]. Journal of Controlled Release,1997,48:157-164.
[20]Yu B G, Okano T, Kataoka K, et al. Polymeric micells for drug delivery: solubilization and hacmotytic activity of amphctericm[J]. Journal of Controlled Release,1998,53(1-3):131-136.
[21]Allen C, Hah J, Yu Y, et al. Polycaprolactone-b-poly (ethylene oxide) copolymer micelles as a delivery for dihydrotestosterone[J]. Journal of Controlled Release, 2000,63:275-286.
[22]Sakuma S, Suzuki N, Kikuchi H, et al. Absorption enhancement of orally administered salmon calcitonin by polystyrene nanoparticles having poly (N-isopropylacrylamide) branches on their surfaces[J]. International Journal of Pharmaceutics,1997,158:69-78.
[23]Yokoyama M, Kataoka K, Inoue S, et al. Polymeric micelles as novel drug carrier: adriamycin-conjugated poly(ethylene glycol)-poly(aspar-tic acid) block copolymer[J]. Journal of Controlled Release,1990,11(123):269-278.
[24]Kataoka K, Matsumoto T, Yokoyama M, et al. Doxorubucin-loaded poly(ethylene glycol)-poly(P-benzyl-L-aspartate) copolymer micelles:their pharmaceutical characteristics and biological significance[J]. Journal of Controlled Release,2000,64(1-3):143-151.
[25]董岸杰,邓联东,孙多先,等.紫杉醇两亲嵌段共聚物纳米囊的研究[J].药学学报,2004,39(2)：149-152.
[26]彭瑾.PLA-PEG-PLA载药缓释微球的研究[D].成都：四川大学,2005.
[27]Kim S Y, Shin IL G, Lee Y M, et al. Methoxy poly(ethylene glycol) and s-caprolactone amphiphilic block copolymeric micelle containing indomethacin.Ⅱ.Micelle formation and drug release behaviours[J]. Journal of Controlled Release,1998,51:13-22.
[28]邓联东,孙多先,霍建中,等.聚乙二醇／聚己内酯两亲性三嵌段共聚物纳米胶束[J].高分子材料科学与工程,2004,20(2)：217-219.
[29]何天白,胡汉杰.海外高分子科学的新进展[M].北京：化学工业出版社,1997：9.
[30]George M W, Jhon P M. Molecular self-assembly and nanochemistry:a chemical strategy for the synthesis of nanostructures[J]. Macromolecules,1992,254: 1312-1318.
[31]Halperin A. Bilayer Morphologies of Self-Assembled Crew-Cut Aggregates of Amphiphilic PS-b-PEO Diblock Copolymers in Solution[J]. Advances in Polymer Science,1992,100:311.
[32]Yuan J, Li Y, Cheng S, et al. The "crew-cut" aggregates of polystyrene-b-poly(ethylene oxide)-b-polystyrene triblock copolymers in aqueous media[J]. European Polymer Journal,2003,39(4):767-776.
[33]Yu Y, Zhang L, Eisenberg A. Multiple Morphologies of Crew-Cut Aggregates of Polybutadiene-b-poly(acrylic acid) Diblocks with Low T Cores[J]. Langmuir,1997, 13(9):2578-2581.
[34]Yu K, Bartels C, Eisenberg A. Bilayer Morphologies of Self-Assembled Crew-Cut Aggregates of Amphiphilic PS-b-PEO Diblock Copolymers in Solution[J]. Macromolecules,1998,31:3509-3518.
[35]Johnson D L, Polikandritou-Lambros M, Martonen T B. Drug Encapsulation and Aerodynamic Behavior of a Lipid Microtubule Aerosol [J]. Drug Delivery,1996, 3(1):9-15.
[36]Zhang L, Eisenberg A. Thermodynamic vs Kinetic Aspects in the Formation and Morphological Transitions of Crew-Cut Aggregates Produced by Self-Assembly of Polystyrene-b-poly(acrylic acid) Block Copolymers in Dilute Solution[J]. Macromolecules,1999,32(7):2239-2249.
[37]Minatti E, Viville P, Borsali R, et al. Micellar Morphological Changes Promoted by Cyclization of PS-b-PI Copolymer:DLS and AFM Experiments [J]. Macromolecule, 2003,36(11):4125-4133.
[38]Butun V, Armes S, Billingham N C, et al. The Remarkable "Flip-Flop" Self-Assembly of a Diblock Copolymer in Aqueous Solution[J]. Macromolecules, 2001,34(5):1503-1511.
[39]Lei L, Gohy J, Willet N, et al. Tuning of the Morphology of Core-Shell-Corona Micelles in Water. I. Transition from Sphere to Cylinder[J]. Macromolecules,2004, 37(3):1089-1094.
[40]Fu J, Luan B, Yu X, et al. Self-Assembly of Crystalline-Coil Diblock Copolymer in Solvents with Varying Selectivity:From Spinodal-like Aggregates to Spheres, Cylinders, and Lamellae[J]. Macromolecules,2004,37(3):976-986.
[41]Lodge T P, Bang J, Hanley K J, et al. Origins of Anomalous Micellization in Diblock Copolymer Solutions[J]. Langmuir,2003,19(6):2103-2109.
[42]Lodge T P, Pudil B, Hanley K J. The Full Phase Behavior for Block Copolymers in Solvents of Varying Selectivity [J]. Macromolecules,2002,35(12):4707-4717.
[43]Weaver J, Armes S, Liu S. A "Holy Trinity" of Micellar Aggregates in Aqueous Solution at Ambient Temperature:Unprecedented Self-Assembly Behavior from a Binary Mixture of a Neutral-Cationic Diblock Copolymer and an Anionic Polyelectrolyte[J]. Macromolecules,2003,36(26):9994-9998.
[44]Lee A, Butun V, Vamvakaki M, et al. Structure of pH-Dependent Block Copolymer Micelles:Charge and Ionic Strength Dependence [J]. Macromolecules,2002,35(22): 8540-8551.
[45]Schillen K, Bryskhe K, Menikova Y. Vesicles Formed from a Poly(ethyleneoxide)-Poly (propylene oxide)-Poly(ethylene oxide) Triblock Copolymer in Dilute Aqueous Solution[J]. Macromolecules,1999,32(20):6885-6888.
[46]Torchilin V P. Structure and design of polymeric surfactantbased drug delivery systems[J]. Journal of Controlled Release,2001,73(2-3):137-172.
[47]张明.紫杉醇聚合物胶束的研究[D].南京：中国药科大学,2004：29-31.
[48]Creutz S, Stam J V, Schryver F C D,et al. Dynamics of Poly((dimethylamino) alkyl methacrylate-block-sodium methacrylate) Micelles. Influence of Hydrophobicity and Molecular Architecture on the Exchange Rate of Copolymer Molecules[J]. Macromolecules,1998,31(3):681-689.
[49]Wang Y, Diermeier R C, Rajagopalan R. Exchange kinetics in spherical geometry[J]. Langmuir,1997,13(8):2348-2353.
[50]Torchilin V P. PEG-based micelles as carriers of contrast agents for different imaging modalities[J]. Advanced Drug Delivery Reviews,2002,54(2):235-52.
[51]Kwon G S, Kataoka K. Block copolymer micelles as long-circulating drug vehicles [J]. Advanced Drug Delivery Reviews,1995,16:295-309.
[52]Kwon G S, Okano T. Polymeric micelles as new drug carriers[J]. Advanced Drug Delivery Reviews,1996,21:107-116.
[53]Thurmond K B, Kowalewski T, Wooley K L. Water-soluble Knedel-like structures: the preparation of shell-cross-linked small particles[J]. Journal of the American Chemical Society,1996,118(30):7239-7240.
[54]Sanji T, Nakatsuka Y, Ohnishi S, et al. Preparation of nanometer-sized hollow particles by photochemical degradation of polysilane shell cross-linked micelles and reversible encapsulation of guest molecules[J]. Macromolecules,2000,33(23): 8524-8526.
[55]Ding J F, Liu G J. Polystyrene-block-poly(2-cinnamoylethyl methacrylate) nanospheres with cross-linked shells[J]. Macromolecules,1998,31:6554-6558.
[56]Huang H Y, Kowalewski T, Wooley K L. Nanodrop lets of polyisoprene fluid contained within poly(acrylic acid-co-acrylamide) shells[J]. Journal of Polymer Science Part A:Polymer Chemistry,2003,41(11):1659-1668.
[57]Iijima M, Nagasaki Y, Kataoka K, et al. Core-Polymerized Reactive Micelles from Heterotelechelic Amphiphilic Block Copolymers[J]. Macromolecules,1999,32(4): 1140-1146.
[58]Liu G, Zhao L, Yan X. Synthesis and characterization of polystyrene-block-polyisoprene nanofibers with different crosslinking densities[J]. Polymer,2003, 44(25):7721-7727.
[59]Jaturanpinyo M, Harada A, Yuan X, et al. Preparation of bionanoreactor based on core-shell structured polyion complex micelles entrapping trypsin in the core cross-linked with glutaraldehyde[J]. Bioconjug Chem,2004,15(2):344-348.
[60]Shuai X, Merdan T, Schaper A K, et al. Core-Cross-Linked Polymeric Micelles as Paclitaxel Carriers [J]. Bioconjugate Chemistry,2004,15:441-448.
[61]Harada A, Kataoka K. Formation of polyin complex micelles in an aqueous milien form a pair of oppositely-charged block copolymers with poly(ethylene-glycol) segments[J]. Macromolecules,1995,28(15):5294-5299.
[62]Kabanov A V, Bronich T K, Kabanov V A, et al. Soluble stoichiometric complexes from poly(N-ethyl-4-vinyl pyridinium) cations and poly(ethylene oxide)-block-polymethacrylate anions[J]. Macromolecule,1996,29(21): 6797-6802.
[63]Otsuka H, Nagasaki Y, Kataoka K. PEGylated nanoparticles for biological and pharmaceutical applications[J]. Advanced Drug Delivery Reviews,2003,55(3): 403-419.
[64]Seo M H, Yi Y W, Yu J W. Stable polymeric micelle-type drug compositon and method for the preparation thereof[P]. US:20030143184.2003-07-31.
[65]Kalyanasundaram K, Thomas J K. Enviromental effects on vibronic band intensities in pyrene monomer fluorescence and their application in studies of micellar system [J]. Journal of the American Chemical Society,1977,99:2039-2044.
[66]Yokoyama M, Okano T, Sakurai Y, et al. Introdution of cisplatin into polymeric micelle[J]. Journal of Controlled Release,1996,39:351-356.
[67]Nishiyama N, Kataoka K. Preparation and characterization of size-controlled polymeric micelle containing cis-dichlorodiammineplatinum(II) in the core[J]. Journal of Controlled Release,2001,74(1-3):83-94.
[68]Karasulu E, Karasulu H Y, Ertan G. Extended release lipophilic indomethacin microspheres:formulation factors and mathematical equations fitted drug release rates[J]. European Journal of Pharmacology,2003,19:99-104.
[69]Higuchi T. Rate of release of medicaments from ointment bases containing drugs in suspensions [J]. Journal of Pharmaceutical Science,1961,50:874-875.
[70]王彩霞.紫杉醇聚合物胶束给药系统的研究[D].天津：天津大学,2006.
[71]Gregg Caldwell, Maria G Meirim, David D N'Da, et al. Carrier-Bound Methotrexate. II. Water-Soluble Polyaspartamide Methotrexate Conjugates with Amide Links in Polymer-Drug Spacer[J]. Journal of Applied Polymer Science,2006, 100:3415-3424.
[72]Katja Riebeseel, Elfi Biedermann, Roland Loser, et al. Polyethylene Glycol Conjugates of Methotrexate Varying in Their Molecular Weight from MW 750 to MW 40000:Synthesis, Characterization, and Structure-Activity Relationships in Vitro and in Vivo[J]. Bioconjugate Chemistry,2002,13:773-785.
[73]王银松,韩月莲,李英霞,等.甲氨喋呤-乳糖酰基壳聚糖的制备及其体外实验[J].高等学校化学学报,2007,28：1092-1097.
[74]De Groot J H, Zijlstra F M, Kuijpers H W, et al. Meniscal tissue regeneration in porous 50/50 copoly (L-lactide/s-capralactone) implants[J]. Biomaterials,1997,18: 613-622.
[75]Bezwada R S, Jamiolkowski D D, Shalaby S W. Segmented copolymers of ε-capralactone and glycolide[P]. USP 5133739,1992.
[76]Spenlehauer G, Vert M, Benoit J P, et al. Biodegradable cisplatine microspheres prepared by the solvent evaporation method:Morphology and release characteristics[J]. Journal of Controlled Release,1988,7:217-229.
[77]陈红丽,贝建中,王身国.生物降解高分子——聚己内酯／聚氧乙烯／聚丙交酯三元共聚物水解行为的研究[J].高分子学报,2000,5：626-630.
[78]Ahmat, Cheng T Y, Chen Z W. A Study on physical and chemical of polycaprolacton(PCL) as a new biodegradable implant material[J]. Shanghai Journol of Biomedical Engineering,1999,20(4):6-11.
[79]Song C X, Wang P Y, Sun H F, et al. The in vivo degradation, dsorption and excretion of Poly(ε-caprolactone)[J]. Journal of Biomedical Engineering,2000, 17(1):25-31.
[80]Hurter P N, Hatton T A. Solubilization of polycyclic aromatic hydrocarbons by poly(ethylene oxide-propylene oxide) block copolymer micelles:effects of polymer structure[J]. Langmuir,1992,8:1291-1299.
[81]Otsuka H, Nagasaki Y, Kataoka K. Self-assembly of poly(ethylene glycol)-based block copolymers for biomedical applications[J]. Current Opinion in Colloid & Interface Science,2001,6:3-10.
[82]Sawhney A S, Pathak C P, Hubbell J A. Bioerodible hydrogels based on photopolymerized poly(ethylene glycol)-co-poly(ahydroxy acid) diacrylate Macromers[J]. Macromolecules,1993,26:581-587.
[83]Sedlak M, Buchta V, Kubicova L, et al. Synthesis and characterization of a new amphotericin b-methoxypoly(ethylene glycol) conjugate[J]. Bioorganic & Medicinal Chemistry Letters,2001,11(21):2833-2835.
[84]Zhu Z, Xiong C, Zhang L, et al. Sythesis and characterization of poly(ε-capralactone)-poly(ethylene glycol) block copolymer[J]. Journal of Polymer Science Part A:Polymer Chemistry,1997,35(4):709-714.
[85]Choi C, Chae S Y, Kim T H, et al. Synthesis and Physicochemical Characterization of Amphiphilic Block Copolymer Self-Aggregates Formed by Poly(ethylene glycol)-block-Poly(ε-caprolactone)[J]. Journal of Applied Polymer Science,2006, 99:3520-3527.
[86]邓联东.两亲性嵌段共聚物及其自组装载药胶束的研究[D].天津：天津大学,2002.
[87]Kowalski A, Duda A, Penczek S. Mechanism of Cyclic Ester Polymerization Initiated with Tin(II) Octoate.2. Macromolecules Fitted with Tin(II) Alkoxide Species Observed Directly in MALDI-TOF Spectra[J]. Macromolecules,2000,33(3): 689-695.
[88]Kricheldorf H R, Kreiser-Saunders I, Stricker A. Polylactones 48:Sn(Oct)2 initiated polymerizations of lactide:A mechanistic study[J]. Macromolecules,2000,33: 702-709.
[89]Wilhelm M, Zhao C L, Wang Y, et al. Poly(styrene-ethylene oxide) block copolymer micelle formation in water:a fluorescence probe study[J]. Macromolecules,1991, 24:1033-1040.
[90]Kwon G S, Yokoyama M, Okano T, et al. Biodistribution of Micelle-Forming Polymer-Drug Conjugates[J]. Pharmaceutical Research,1993,10:970-974.
[91]Shin lL G, Kim S Y, Lee Y M, et al. Methoxy poly(ethylene glycol)/ε-caprolactone amphiphilic block copolymeric micelle containing indomethacin. Ⅰ. Preparation and characterization[J]. Journal of Controlled Release,1998,51:1-11.
[2]Leo E, Cameroni R, Forni F. Dynamic dialysis for the drug release evaluation from doxorubicin-gelatin nanoparticles conjugates [J]. International Journal of Pharmaceutics,1999,180(1):23-30.
[3]Weber C, Coester C, Kreuter J, et al. Desolvation process and surface characterization of protein nanoparticles[J]. International Journal of Pharmaceutics, 2000,194(1):91-102.
[4]元英进,刘名言,董岸杰.中药现代化生产关键技术[M].北京：化学工业出版社,2002：203-204.
[5]Uhrich K E, Cannizzaro S M, Langer R S, et al. Polymeric systems for controlled drug release[J]. Chemistry Review,1999,99:3181-3198.
[6]Yoo H S, Park T G. Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA-PEG block copolymer[J]. Journal of Controlled Release,2001, 70(1-2):63-70.
[7]Carino G P, Jacob J S, Mathiowitz E. Nanosphere based oral insulin delivery [J]. Journal of Controlled Release,2000,65(3):261-269.
[8]Hoste K, Schacht E, Seymour L. New derivatives of polyglutamic acid as drug carrier systems[J]. Journal of Controlled Release,2000,64(1-3):53-61.
[9]Yokoyama M, Fukushima S, Uehara R, et al. Characterization of physical entrapment and chemical conjugation of adriamycin in polymeric micelles and their design for in vivo delivery to a solid tumor[J]. Journal of Control Release,1998, 50(1-3):79-92.
[10]Allen C, Maysinger D, Eisenberg A. Nano-engineering block copolymer aggregates for drug delivery [J]. Colloids Surfaces B:Biointerfaces,1999,16(1-4):3-27.
[11]Miwa A, Ishibe A, Nakano M, et al. Development of novel chitosan derivatives as micelle carriers taxol[J]. Pharmaceutical Research,1998,15(2):1844-1850.
[12]Cheon Lee S, Kim C, Chan Kown I, et al. Polymeric micelles of poly(2-ethyl-2-oxazoline)-block-poly(varepsilon-caprolactone) copolymer as a carrier for paclitaxel[J]. Journal of Controlled Release,2003,89(3):437-446.
[13]Adams M L, Lavasanifar A, Kwon G S. Amphiphilic block copolymers for drug delivery[J]. Pharmaceutical Science,2003,92:1343-1355.
[14]Kataoka K, Harada A, Nagasaki Y. Block copolymermicelles for drug delivery: design, characterization and biological significance[J]. Advanced Drug Delivery Reviews,2001,47:113-131.
[15]Gaucher G, Dufresne M H, Sant V P, et al. Block copolymer micelles:preparation, characterization and application in drug delivery[J]. Journal of Controlled Release, 2005,109(1-3):169-188.
[16]Inoue T, Chen G, Nakamae K, et al. An AB block copolymer of oligo (methyl methacrylate) and poly (acrylic acid) for micellar delivery of hydrophobic drug[J]. Journal of Controlled Release,1998,51:221-229.
[17]Xiong X Y, Tam K C, Gan L H. Release kinetics of hydrophobicand hydrophilic model drugs from p luronic F127/poly (lactic acid) nanoparticles [J]. Journal of Controlled Release,2005,103:73-82.
[18]Kabanov A V, Batrakova E V. A new class of drug carriers:micelles of poly(oxyethylene)-poly(oxypropylene) block copolymers as microcontainers for drug targeting from bllod in brain[J]. Journal of Controlled Release,1992,22(2):141-158.
[19]Cammas S, Suzuki K, Sone C, et al. Thermmo-responsive polymer nanopartieles with a core-shell micell structure as sitespecific drug carriers[J]. Journal of Controlled Release,1997,48:157-164.
[20]Yu B G, Okano T, Kataoka K, et al. Polymeric micells for drug delivery: solubilization and hacmotytic activity of amphctericm[J]. Journal of Controlled Release,1998,53(1-3):131-136.
[21]Allen C, Hah J, Yu Y, et al. Polycaprolactone-b-poly (ethylene oxide) copolymer micelles as a delivery for dihydrotestosterone[J]. Journal of Controlled Release, 2000,63:275-286.
[22]Sakuma S, Suzuki N, Kikuchi H, et al. Absorption enhancement of orally administered salmon calcitonin by polystyrene nanoparticles having poly (N-isopropylacrylamide) branches on their surfaces[J]. International Journal of Pharmaceutics,1997,158:69-78.
[23]Yokoyama M, Kataoka K, Inoue S, et al. Polymeric micelles as novel drug carrier: adriamycin-conjugated poly(ethylene glycol)-poly(aspar-tic acid) block copolymer[J]. Journal of Controlled Release,1990,11(123):269-278.
[24]Kataoka K, Matsumoto T, Yokoyama M, et al. Doxorubucin-loaded poly(ethylene glycol)-poly(P-benzyl-L-aspartate) copolymer micelles:their pharmaceutical characteristics and biological significance[J]. Journal of Controlled Release,2000,64(1-3):143-151.
[25]董岸杰,邓联东,孙多先,等.紫杉醇两亲嵌段共聚物纳米囊的研究[J].药学学报,2004,39(2)：149-152.
[26]彭瑾.PLA-PEG-PLA载药缓释微球的研究[D].成都：四川大学,2005.
[27]Kim S Y, Shin IL G, Lee Y M, et al. Methoxy poly(ethylene glycol) and s-caprolactone amphiphilic block copolymeric micelle containing indomethacin.Ⅱ.Micelle formation and drug release behaviours[J]. Journal of Controlled Release,1998,51:13-22.
[28]邓联东,孙多先,霍建中,等.聚乙二醇／聚己内酯两亲性三嵌段共聚物纳米胶束[J].高分子材料科学与工程,2004,20(2)：217-219.
[29]何天白,胡汉杰.海外高分子科学的新进展[M].北京：化学工业出版社,1997：9.
[30]George M W, Jhon P M. Molecular self-assembly and nanochemistry:a chemical strategy for the synthesis of nanostructures[J]. Macromolecules,1992,254: 1312-1318.
[31]Halperin A. Bilayer Morphologies of Self-Assembled Crew-Cut Aggregates of Amphiphilic PS-b-PEO Diblock Copolymers in Solution[J]. Advances in Polymer Science,1992,100:311.
[32]Yuan J, Li Y, Cheng S, et al. The "crew-cut" aggregates of polystyrene-b-poly(ethylene oxide)-b-polystyrene triblock copolymers in aqueous media[J]. European Polymer Journal,2003,39(4):767-776.
[33]Yu Y, Zhang L, Eisenberg A. Multiple Morphologies of Crew-Cut Aggregates of Polybutadiene-b-poly(acrylic acid) Diblocks with Low T Cores[J]. Langmuir,1997, 13(9):2578-2581.
[34]Yu K, Bartels C, Eisenberg A. Bilayer Morphologies of Self-Assembled Crew-Cut Aggregates of Amphiphilic PS-b-PEO Diblock Copolymers in Solution[J]. Macromolecules,1998,31:3509-3518.
[35]Johnson D L, Polikandritou-Lambros M, Martonen T B. Drug Encapsulation and Aerodynamic Behavior of a Lipid Microtubule Aerosol [J]. Drug Delivery,1996, 3(1):9-15.
[36]Zhang L, Eisenberg A. Thermodynamic vs Kinetic Aspects in the Formation and Morphological Transitions of Crew-Cut Aggregates Produced by Self-Assembly of Polystyrene-b-poly(acrylic acid) Block Copolymers in Dilute Solution[J]. Macromolecules,1999,32(7):2239-2249.
[37]Minatti E, Viville P, Borsali R, et al. Micellar Morphological Changes Promoted by Cyclization of PS-b-PI Copolymer:DLS and AFM Experiments [J]. Macromolecule, 2003,36(11):4125-4133.
[38]Butun V, Armes S, Billingham N C, et al. The Remarkable "Flip-Flop" Self-Assembly of a Diblock Copolymer in Aqueous Solution[J]. Macromolecules, 2001,34(5):1503-1511.
[39]Lei L, Gohy J, Willet N, et al. Tuning of the Morphology of Core-Shell-Corona Micelles in Water. I. Transition from Sphere to Cylinder[J]. Macromolecules,2004, 37(3):1089-1094.
[40]Fu J, Luan B, Yu X, et al. Self-Assembly of Crystalline-Coil Diblock Copolymer in Solvents with Varying Selectivity:From Spinodal-like Aggregates to Spheres, Cylinders, and Lamellae[J]. Macromolecules,2004,37(3):976-986.
[41]Lodge T P, Bang J, Hanley K J, et al. Origins of Anomalous Micellization in Diblock Copolymer Solutions[J]. Langmuir,2003,19(6):2103-2109.
[42]Lodge T P, Pudil B, Hanley K J. The Full Phase Behavior for Block Copolymers in Solvents of Varying Selectivity [J]. Macromolecules,2002,35(12):4707-4717.
[43]Weaver J, Armes S, Liu S. A "Holy Trinity" of Micellar Aggregates in Aqueous Solution at Ambient Temperature:Unprecedented Self-Assembly Behavior from a Binary Mixture of a Neutral-Cationic Diblock Copolymer and an Anionic Polyelectrolyte[J]. Macromolecules,2003,36(26):9994-9998.
[44]Lee A, Butun V, Vamvakaki M, et al. Structure of pH-Dependent Block Copolymer Micelles:Charge and Ionic Strength Dependence [J]. Macromolecules,2002,35(22): 8540-8551.
[45]Schillen K, Bryskhe K, Menikova Y. Vesicles Formed from a Poly(ethyleneoxide)-Poly (propylene oxide)-Poly(ethylene oxide) Triblock Copolymer in Dilute Aqueous Solution[J]. Macromolecules,1999,32(20):6885-6888.
[46]Torchilin V P. Structure and design of polymeric surfactantbased drug delivery systems[J]. Journal of Controlled Release,2001,73(2-3):137-172.
[47]张明.紫杉醇聚合物胶束的研究[D].南京：中国药科大学,2004：29-31.
[48]Creutz S, Stam J V, Schryver F C D,et al. Dynamics of Poly((dimethylamino) alkyl methacrylate-block-sodium methacrylate) Micelles. Influence of Hydrophobicity and Molecular Architecture on the Exchange Rate of Copolymer Molecules[J]. Macromolecules,1998,31(3):681-689.
[49]Wang Y, Diermeier R C, Rajagopalan R. Exchange kinetics in spherical geometry[J]. Langmuir,1997,13(8):2348-2353.
[50]Torchilin V P. PEG-based micelles as carriers of contrast agents for different imaging modalities[J]. Advanced Drug Delivery Reviews,2002,54(2):235-52.
[51]Kwon G S, Kataoka K. Block copolymer micelles as long-circulating drug vehicles [J]. Advanced Drug Delivery Reviews,1995,16:295-309.
[52]Kwon G S, Okano T. Polymeric micelles as new drug carriers[J]. Advanced Drug Delivery Reviews,1996,21:107-116.
[53]Thurmond K B, Kowalewski T, Wooley K L. Water-soluble Knedel-like structures: the preparation of shell-cross-linked small particles[J]. Journal of the American Chemical Society,1996,118(30):7239-7240.
[54]Sanji T, Nakatsuka Y, Ohnishi S, et al. Preparation of nanometer-sized hollow particles by photochemical degradation of polysilane shell cross-linked micelles and reversible encapsulation of guest molecules[J]. Macromolecules,2000,33(23): 8524-8526.
[55]Ding J F, Liu G J. Polystyrene-block-poly(2-cinnamoylethyl methacrylate) nanospheres with cross-linked shells[J]. Macromolecules,1998,31:6554-6558.
[56]Huang H Y, Kowalewski T, Wooley K L. Nanodrop lets of polyisoprene fluid contained within poly(acrylic acid-co-acrylamide) shells[J]. Journal of Polymer Science Part A:Polymer Chemistry,2003,41(11):1659-1668.
[57]Iijima M, Nagasaki Y, Kataoka K, et al. Core-Polymerized Reactive Micelles from Heterotelechelic Amphiphilic Block Copolymers[J]. Macromolecules,1999,32(4): 1140-1146.
[58]Liu G, Zhao L, Yan X. Synthesis and characterization of polystyrene-block-polyisoprene nanofibers with different crosslinking densities[J]. Polymer,2003, 44(25):7721-7727.
[59]Jaturanpinyo M, Harada A, Yuan X, et al. Preparation of bionanoreactor based on core-shell structured polyion complex micelles entrapping trypsin in the core cross-linked with glutaraldehyde[J]. Bioconjug Chem,2004,15(2):344-348.
[60]Shuai X, Merdan T, Schaper A K, et al. Core-Cross-Linked Polymeric Micelles as Paclitaxel Carriers [J]. Bioconjugate Chemistry,2004,15:441-448.
[61]Harada A, Kataoka K. Formation of polyin complex micelles in an aqueous milien form a pair of oppositely-charged block copolymers with poly(ethylene-glycol) segments[J]. Macromolecules,1995,28(15):5294-5299.
[62]Kabanov A V, Bronich T K, Kabanov V A, et al. Soluble stoichiometric complexes from poly(N-ethyl-4-vinyl pyridinium) cations and poly(ethylene oxide)-block-polymethacrylate anions[J]. Macromolecule,1996,29(21): 6797-6802.
[63]Otsuka H, Nagasaki Y, Kataoka K. PEGylated nanoparticles for biological and pharmaceutical applications[J]. Advanced Drug Delivery Reviews,2003,55(3): 403-419.
[64]Seo M H, Yi Y W, Yu J W. Stable polymeric micelle-type drug compositon and method for the preparation thereof[P]. US:20030143184.2003-07-31.
[65]Kalyanasundaram K, Thomas J K. Enviromental effects on vibronic band intensities in pyrene monomer fluorescence and their application in studies of micellar system [J]. Journal of the American Chemical Society,1977,99:2039-2044.
[66]Yokoyama M, Okano T, Sakurai Y, et al. Introdution of cisplatin into polymeric micelle[J]. Journal of Controlled Release,1996,39:351-356.
[67]Nishiyama N, Kataoka K. Preparation and characterization of size-controlled polymeric micelle containing cis-dichlorodiammineplatinum(II) in the core[J]. Journal of Controlled Release,2001,74(1-3):83-94.
[68]Karasulu E, Karasulu H Y, Ertan G. Extended release lipophilic indomethacin microspheres:formulation factors and mathematical equations fitted drug release rates[J]. European Journal of Pharmacology,2003,19:99-104.
[69]Higuchi T. Rate of release of medicaments from ointment bases containing drugs in suspensions [J]. Journal of Pharmaceutical Science,1961,50:874-875.
[70]王彩霞.紫杉醇聚合物胶束给药系统的研究[D].天津：天津大学,2006.
[71]Gregg Caldwell, Maria G Meirim, David D N'Da, et al. Carrier-Bound Methotrexate. II. Water-Soluble Polyaspartamide Methotrexate Conjugates with Amide Links in Polymer-Drug Spacer[J]. Journal of Applied Polymer Science,2006, 100:3415-3424.
[72]Katja Riebeseel, Elfi Biedermann, Roland Loser, et al. Polyethylene Glycol Conjugates of Methotrexate Varying in Their Molecular Weight from MW 750 to MW 40000:Synthesis, Characterization, and Structure-Activity Relationships in Vitro and in Vivo[J]. Bioconjugate Chemistry,2002,13:773-785.
[73]王银松,韩月莲,李英霞,等.甲氨喋呤-乳糖酰基壳聚糖的制备及其体外实验[J].高等学校化学学报,2007,28：1092-1097.
[74]De Groot J H, Zijlstra F M, Kuijpers H W, et al. Meniscal tissue regeneration in porous 50/50 copoly (L-lactide/s-capralactone) implants[J]. Biomaterials,1997,18: 613-622.
[75]Bezwada R S, Jamiolkowski D D, Shalaby S W. Segmented copolymers of ε-capralactone and glycolide[P]. USP 5133739,1992.
[76]Spenlehauer G, Vert M, Benoit J P, et al. Biodegradable cisplatine microspheres prepared by the solvent evaporation method:Morphology and release characteristics[J]. Journal of Controlled Release,1988,7:217-229.
[77]陈红丽,贝建中,王身国.生物降解高分子——聚己内酯／聚氧乙烯／聚丙交酯三元共聚物水解行为的研究[J].高分子学报,2000,5：626-630.
[78]Ahmat, Cheng T Y, Chen Z W. A Study on physical and chemical of polycaprolacton(PCL) as a new biodegradable implant material[J]. Shanghai Journol of Biomedical Engineering,1999,20(4):6-11.
[79]Song C X, Wang P Y, Sun H F, et al. The in vivo degradation, dsorption and excretion of Poly(ε-caprolactone)[J]. Journal of Biomedical Engineering,2000, 17(1):25-31.
[80]Hurter P N, Hatton T A. Solubilization of polycyclic aromatic hydrocarbons by poly(ethylene oxide-propylene oxide) block copolymer micelles:effects of polymer structure[J]. Langmuir,1992,8:1291-1299.
[81]Otsuka H, Nagasaki Y, Kataoka K. Self-assembly of poly(ethylene glycol)-based block copolymers for biomedical applications[J]. Current Opinion in Colloid & Interface Science,2001,6:3-10.
[82]Sawhney A S, Pathak C P, Hubbell J A. Bioerodible hydrogels based on photopolymerized poly(ethylene glycol)-co-poly(ahydroxy acid) diacrylate Macromers[J]. Macromolecules,1993,26:581-587.
[83]Sedlak M, Buchta V, Kubicova L, et al. Synthesis and characterization of a new amphotericin b-methoxypoly(ethylene glycol) conjugate[J]. Bioorganic & Medicinal Chemistry Letters,2001,11(21):2833-2835.
[84]Zhu Z, Xiong C, Zhang L, et al. Sythesis and characterization of poly(ε-capralactone)-poly(ethylene glycol) block copolymer[J]. Journal of Polymer Science Part A:Polymer Chemistry,1997,35(4):709-714.
[85]Choi C, Chae S Y, Kim T H, et al. Synthesis and Physicochemical Characterization of Amphiphilic Block Copolymer Self-Aggregates Formed by Poly(ethylene glycol)-block-Poly(ε-caprolactone)[J]. Journal of Applied Polymer Science,2006, 99:3520-3527.
[86]邓联东.两亲性嵌段共聚物及其自组装载药胶束的研究[D].天津：天津大学,2002.
[87]Kowalski A, Duda A, Penczek S. Mechanism of Cyclic Ester Polymerization Initiated with Tin(II) Octoate.2. Macromolecules Fitted with Tin(II) Alkoxide Species Observed Directly in MALDI-TOF Spectra[J]. Macromolecules,2000,33(3): 689-695.
[88]Kricheldorf H R, Kreiser-Saunders I, Stricker A. Polylactones 48:Sn(Oct)2 initiated polymerizations of lactide:A mechanistic study[J]. Macromolecules,2000,33: 702-709.
[89]Wilhelm M, Zhao C L, Wang Y, et al. Poly(styrene-ethylene oxide) block copolymer micelle formation in water:a fluorescence probe study[J]. Macromolecules,1991, 24:1033-1040.
[90]Kwon G S, Yokoyama M, Okano T, et al. Biodistribution of Micelle-Forming Polymer-Drug Conjugates[J]. Pharmaceutical Research,1993,10:970-974.
[91]Shin lL G, Kim S Y, Lee Y M, et al. Methoxy poly(ethylene glycol)/ε-caprolactone amphiphilic block copolymeric micelle containing indomethacin. Ⅰ. Preparation and characterization[J]. Journal of Controlled Release,1998,51:1-11.