核交联聚（N-异丙基丙烯酰胺-co-N，N-二甲基丙烯酰胺）-b-聚已内酯胶束及紫杉醇控制释放研究
|
摘要
高分子胶束粒径较小,一般不超过100nm,具有纳米材料的特性,是近几年正在发展的一类新型的药物载体,其载药范围广、结构稳定、具有优良的组织渗透性,体内滞留时间长,能使药物有效地到达靶点。而如何使其带有智能靶向性以及怎样减弱其初期爆发释放行为成为了最近研究的热点。本研究中,制备出了具有温度响应性的纳米胶束,并得到了具有不同核交联度的载药胶束,并对其药物释放行为进行了研究。主要工作如下：
1、本研究利用两步聚合法合成了含有带端羟基的聚(N-异丙基丙烯酰胺-cO-N,N-二甲基丙烯酰胺)亲水段和聚己内酯疏水段的两亲性嵌段共聚物P(NIPAAm-co-DMAAm)-b-PCL。以巯基乙醇为链转移剂,通过调节巯基乙醇和单体的比例,以及NIPAAm和]DMAAm的比例,可以做到对P(NIPAAm-co-VMAAm)的分子量和低临界溶液温度(LCST)的调控。在异辛酸亚锡的催化下,再利用其端羟基引发己内酯开环聚合。进一步用丙烯酰氯和该嵌段共聚物的端羟基反应,得到PCL链末端带有丙烯酰基官能团的嵌段共聚物。
2、将端羟基和端丙烯酰基的P(NIPAAm-co-DMAAm)-b-PCL按不同比例混合得到的胶束,经光引发交联后得到具有不同核交联密度的胶束。将疏水性药物紫杉醇载入上述胶束中,在37℃或43℃进行药物释放试验。结果表明,P(NIPAAm-co-DMAAm)-b-PCL嵌段共聚物胶束对紫杉醇的释放有一定的温度敏感性；PCL核交联程度对紫杉醇释放的影响更为明显,随着核交联程度的提高,紫杉醇的释放速度减慢,而且,对初期的爆发释放行为有了明显的减弱。
生物可降解的两亲性嵌段共聚物P(NIPAAm-co-DMAAm)-b-PCL形成的核交联的温敏性高分子胶束低临界溶液温度约为42℃,具有较好的药物包覆及释放性能,有可能结合实体肿瘤的局部过热治疗,用于对肿瘤的靶向给药治疗。
The sizes of polymeric micelles are generally less than 100nm. With the characteristics of nano-materials they are being researched as drug carriers in recent years. Polymeric micelles have the features of structural, stability, excellent tissue permeability, long residence time in vivo, and they also can effectively reach the target drugs. To develop new kind of polymeric micelles for target drug delivery and to decrease the initial burst release are the major two issues in this area. In this study, we produced thermo-sensitive nanoscale micelles with different core-crosslinkings, and their drug release behaviors were studied. Main tasks are listed as follows:
1, In this study we used the two-step polymerization to produce the poly(N-isopropylacrylanide-co-N,N-dimethylacrylanide)-b-poly(-capr olactone) block copolymers (P (NIPAAm-co-DMAAm)-b-PCL). At first with mercaptoethanol as chain transfer agent, and by adjusting the monomer ratio of NIPAAm and DMAAm, the molecular weight and lower critical solution temperature (LCST) of P (NIPAAm-co-DMAAm) can be controlled. Then, caprolactones were ring-polymerized by the hydroxyl endgroup of P (NIPAAm-co-DMAAm) by using stannous octotate as catalyst to obtain hydroxyl-terminated P (NIPAAm-co-DMAAm)-b-PCL. By reacting with acryloyl chloride, the hydroxyl endgroups were changed into acryloyl endgroups.
2, Hydroxyl-terminated and acryloyl-terminated of P(NIPAAm-co-DMAAm)-b-PCL were mixed to get polymeric micelles with the different degrees of core crosslinking. The hydrophobic drug was paclitaxel loaded in the micelles, and the temperatures of the drug release tests were setting at 37℃or 43℃. The results showed that the drug release from the micelles exhibifed a certain themosentivity. The cross-linking degrees had a more remarkable effect paclitaxel release. With the cross-linking degree of increase, the release of paclitaxel slowed down, and the initial burst release was reduced. The results of the present study show that the micelles based on thermosentive P(NIPAAm-co-DMAAm)-b-PCL with a LCST around-40℃maybe able to realize a thermo-responsive release behavior at temperatures above and below LCST. Furthermore, the core-crosslinking method can be used to increase the stability of micelles and adjust the drug release rates. With further deep investigation, this kind of thermosensitive micelles can have potential use as carriers for hydrophobic anticancer agents targeted for solid tumor therapy with local hyperthermia therapy.
1、本研究利用两步聚合法合成了含有带端羟基的聚(N-异丙基丙烯酰胺-cO-N,N-二甲基丙烯酰胺)亲水段和聚己内酯疏水段的两亲性嵌段共聚物P(NIPAAm-co-DMAAm)-b-PCL。以巯基乙醇为链转移剂,通过调节巯基乙醇和单体的比例,以及NIPAAm和]DMAAm的比例,可以做到对P(NIPAAm-co-VMAAm)的分子量和低临界溶液温度(LCST)的调控。在异辛酸亚锡的催化下,再利用其端羟基引发己内酯开环聚合。进一步用丙烯酰氯和该嵌段共聚物的端羟基反应,得到PCL链末端带有丙烯酰基官能团的嵌段共聚物。
2、将端羟基和端丙烯酰基的P(NIPAAm-co-DMAAm)-b-PCL按不同比例混合得到的胶束,经光引发交联后得到具有不同核交联密度的胶束。将疏水性药物紫杉醇载入上述胶束中,在37℃或43℃进行药物释放试验。结果表明,P(NIPAAm-co-DMAAm)-b-PCL嵌段共聚物胶束对紫杉醇的释放有一定的温度敏感性；PCL核交联程度对紫杉醇释放的影响更为明显,随着核交联程度的提高,紫杉醇的释放速度减慢,而且,对初期的爆发释放行为有了明显的减弱。
生物可降解的两亲性嵌段共聚物P(NIPAAm-co-DMAAm)-b-PCL形成的核交联的温敏性高分子胶束低临界溶液温度约为42℃,具有较好的药物包覆及释放性能,有可能结合实体肿瘤的局部过热治疗,用于对肿瘤的靶向给药治疗。
The sizes of polymeric micelles are generally less than 100nm. With the characteristics of nano-materials they are being researched as drug carriers in recent years. Polymeric micelles have the features of structural, stability, excellent tissue permeability, long residence time in vivo, and they also can effectively reach the target drugs. To develop new kind of polymeric micelles for target drug delivery and to decrease the initial burst release are the major two issues in this area. In this study, we produced thermo-sensitive nanoscale micelles with different core-crosslinkings, and their drug release behaviors were studied. Main tasks are listed as follows:
1, In this study we used the two-step polymerization to produce the poly(N-isopropylacrylanide-co-N,N-dimethylacrylanide)-b-poly(-capr olactone) block copolymers (P (NIPAAm-co-DMAAm)-b-PCL). At first with mercaptoethanol as chain transfer agent, and by adjusting the monomer ratio of NIPAAm and DMAAm, the molecular weight and lower critical solution temperature (LCST) of P (NIPAAm-co-DMAAm) can be controlled. Then, caprolactones were ring-polymerized by the hydroxyl endgroup of P (NIPAAm-co-DMAAm) by using stannous octotate as catalyst to obtain hydroxyl-terminated P (NIPAAm-co-DMAAm)-b-PCL. By reacting with acryloyl chloride, the hydroxyl endgroups were changed into acryloyl endgroups.
2, Hydroxyl-terminated and acryloyl-terminated of P(NIPAAm-co-DMAAm)-b-PCL were mixed to get polymeric micelles with the different degrees of core crosslinking. The hydrophobic drug was paclitaxel loaded in the micelles, and the temperatures of the drug release tests were setting at 37℃or 43℃. The results showed that the drug release from the micelles exhibifed a certain themosentivity. The cross-linking degrees had a more remarkable effect paclitaxel release. With the cross-linking degree of increase, the release of paclitaxel slowed down, and the initial burst release was reduced. The results of the present study show that the micelles based on thermosentive P(NIPAAm-co-DMAAm)-b-PCL with a LCST around-40℃maybe able to realize a thermo-responsive release behavior at temperatures above and below LCST. Furthermore, the core-crosslinking method can be used to increase the stability of micelles and adjust the drug release rates. With further deep investigation, this kind of thermosensitive micelles can have potential use as carriers for hydrophobic anticancer agents targeted for solid tumor therapy with local hyperthermia therapy.
引文
[1]Lehn J M. Comprehensive Supramolecular Chemistry[M]. New York: Pergamon Press,1996
[2]Lehn J M. Supramolecular Chemistry[M]. VCH:Weinheim,1995
[3]Bard A J Integrated Chemical Systems[M]. NewYork:wiley,1995
[4]Torchilin V.P. Structure and Design of Polymeric Surfactant-based drug delivery systerms[J]. Control Release.,2001,73:137-172
[5]Duncan R. The Dawning Era of Polymer Therapeutics[J]. Nature Rev. Drug Discovery.,2003,2:347-360
[6]Torchilin V.P. Micellar nanocarriers:Pharmaceutical Perspectives[J]. Pharmaceutical Research.,2007,24:1-16
[7]吉静,黄明智.开发智能性明胶[J].明胶科学与技术,2001,21(1)：12-22
[8]袁金颖,魏高原,王延梅等.ABA型两亲嵌段共聚物的合成及表征[J].高分子学报,2001,5：625-628
[9]Price C, Woods D. A method for studying micellar aggregates in block and graft copolymers[J]. European Polymer Journal.,1973,9:827
[10]Halperin A. Polymeric micelles:a star moder[J]. Macromolecules.,1987,20: 2943
[11]Halperin A, Tirrel M, Lodge T P. Tethered chains in polymer microstructures[J]. Adv. Polym. Sci.,1992,100:31
[12]杨子刚,袁建军,程时远.两亲嵌段共聚物溶液自组装新进展[J].功能高分子学报,2003,16：287
[13]Shen H, Zhang L, Eisenberg A. Multiple pH-Induced Morphological Changes in Aggregates of Polystyrene-block-poly(4-vinylpyridine) in DMF/H2O Mixtures[J]. Am. Chem. Soc.,1999,121:2728
[14]Yu G, Eisenberg A. Multiple Morphologies Formed from an Amphiphilic ABC Triblock Copolymer in Solution[J]. Macromolecules.,1998,31:5546
[15]Yu K, Bartels C, Eisenberg A. Vesicles with Hollow Rods in the Walls:A Trapped Intermediate Morphology in the Transition of Vesicles to Inverted Hexagonally Packed Rods in Dilute Solutions of PS-b-PEO[J]. Macromolecules.,1998,31:9399
[16]Yu Y, Zhang L, Eisenberg A. Morphogenic Effect of Solvent on Crew-Cut Aggregates of Amphiphilic Diblock Copolymers[J]. Macromolecules.,1998, 31:1144
[17]Yu K, Eisenberg A. Bilayer Morphologies of Self-Assembled Crew-Cut Aggregates of Amphiphilic PS-b-PEO Diblock Copolymers in Solution[J]. Macromolecules.,1998,31:3509
[18]Cameron N S, Corbierre M K, Eisenberg A. Assemmetric amphilic block copolymers in solution:a morphologies wonderland[J]. Can. J. Chem.,1999, 77:1311.
[19]Chung J E, Yokoyama M, Aoyagi T, et al. Effect of molecular architecture of hydrophobically modified poly(N-isopropylacrylamide) on the formation of themoresponsive core-shell micellar drug carriers[J]. Control. Rel.,1998,53: 119
[20]Bader H, Ringsdorf H, Schmidt B, et al. Watersoluble polymers in medicine[J]. Macromolecular Materials and Engineering.,1984,123:457
[21]查刘生,高海峰,杨武利等.聚合物纳米粒子用于给药载体[J].高分子通报,2002,3：24
[22]陈建海.药用高分子材料与现代药剂[M].北京：科学出版社,2003.19-21
[23]陆彬.胶束给药系统及其进展(上)[J].中国药师(继续药学教育),2006,9：428
[24]林宏英,吴建梅,赵李宏.难溶性抗肿瘤药物载体-嵌段共聚物胶束[J].中草药,2006,4(37)：48
[25]李珺婵.嵌段共聚物胶束作为抗肿瘤药物载体的研究进展[J].国外医学药学分册,2004,31(1)：48
[26]Narayan Bhattarai, Shanta Raj Bhattarai, Myung Seob Khil, et al. Aqueous solution properties of amphiphilic triblock copolymer poly(p-dioxanone-co-L-lactide)-block-poly(ethylene glycol)[J]. Eur Polym.,2003,20:2021-2027
[27]Byeongmoon Jeong, You Han Bae, Sung Wan Kim. Biodegradable thermosensitive micelles of PEG-PLGA-PEG triblock copolymers[J]. Control. Rel.,2000,63:155-163
[28]In-Sook Kim, Sung-Ho Kim. Development of a polymeric nanoparticulate drug delivery system in vitro characterization of nanoparticles based on sugarcontaining conjugates[J]. International Journal of Pharmaceutics.,2002, 245:67-73
[29]Schillen K, Bryskhe K, Melnikova Y S. Vesicles foxed from a triblock copolymer in dilute aqueous solution[J]. Macromolecules.,1999,32:6885
[30]Corenelissen J L M, Fischer M, Semmerdijk A J M, et al. Helical Superstructures from Charged Poly(styrene)-Poly(isocyanodipeptide) Block Copolymers[J]. Science.,1998,280:1427
[31]Discher B M, Won Y Y, Ege D S, et al. Polymersome:Tough Vesicles Made from Diblock Copolymers[J]. Science.,1999,284:1143
[32]尹常晴,隋卫平,汪源浩.两亲性高分子聚集体在药物载体中的应用[J].化学通报,2006,69：1
[33]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]. Control. Rel.,1998,50: 79
[34]Allen C, Maysinger D, Eisenberg A. Nano-engineering block copolymer aggregates for drug delivery[J]. Colloids and Surfaces B:Biointerfaces.,1999, 16:3
[35]Capek I. Fate of excited probes in micellar systems[J]. Adv. Colloid Interface Sci.,2002,97:91
[36]曾灿,陈伟,胡建等.聚乙二醇／聚天冬氨酸(阿霉素)的制备与毒性[J].复 旦学报(自然科学版),2006,45：708
[37]Kim S Y, Shin I G, Lee Y M, et al. Micelle formation and drug release behaviours[J]. Control. Rel.,1998,51:13
[38]施斌,方超,裴元英.两亲嵌段共聚物胶束的研究进展[J].中国医药工业杂志,2005,36：239
[39]李超英,蒋学华,侯世祥.淋巴靶向给药系统研究与应用[J].中国新药杂志,2001,10(12)：903
[40]Chung J E, Yokoyama M, Okano T. Inner core segment design for delivery control of thermo-responsive polymeric micelles[J]. Control. Rel.,2000,65: 93
[41]Yu B G, Okano T, Kataoka K, et al. Polymeric micelles for drug delivery: solubilization and haemolytic activity of amphotericin B[J]. Control. Rel., 1998,53:131
[42]HuaWei, Si Xue Cheng, Xian Zheng Zhang, et al. Thermo-sensitive polymeric micelles based on poly(N-isopropylacrylamide) as drug carriers[J]. Progress in Polymer Science.,2009,34:893-910
[43]魏彦,周建平,霍美蓉.难溶药物载体：聚合物胶束的研究进展[J].江苏药学与临床研究,2006,14(4)：228
[44]Kohori F, Sakai K, Aoyagi T, et al. Preparation and characterization of thermally responsive block copolymer micelles comprising poly (N-isopropylacrylamide-b-D, L-lactide) [J]. Control. Rel.,1998,55:87
[45]Kohori F, Sakai K, Aoyagi T, et al. Control of adriamycin cytotoxic activity using thermally responsive polymeric micelles composed of poly(N-isopropylacrylamide-co-N, N-dimethylacrylamide)-b-poly(D,L-lactid) [J]. Colloids and Surfaces B:Biointerfaces.,1999,16:195
[46]Wei H, Zhang X Z, Zhou Y, et al. Self-assembled thermoresponsive micelles of poly(N-isopropylacrylamide-b-methyl methacrylate)[J]. Biomaterials., 2006,27:2028
[47]任现文,江明.交联度对原位聚合法制备聚合物胶束性质的影响及相应的空心球制备[J].高等学校化学学报,2006,27(11)：2204
[48]Topp M D C, Dijkstra P J, Talsma H, et al. Thermosensitive micelle-forming block copolymers of poly(ethylene glyc01)and poly(N-isopropylacrylamide) [J]. Macromolecules.,1997,30:8518
[49]Kwon I K, Matsuda T. Photo-iniferter-based thermoresponsive block copolymers composed of poly(ethylene glycol) band poly(N-isopropylacrylamide) and chondrocyte immobilization[J]. Biomaterials.,2006,27:986
[50]Kim K H, Kim J, Jo W H. Preparation of hydrogel nanoparticles by atom transfer radical polymerization of N-isopropylacrylamide in aqueous media using PEG macro-initiator[J]. Polymer.,2005,46:2836
[51]Stolnik S, Ilium L, Davis S S. Long circulating microparticulate drug carriers[J]. Adv. Drug Delivery Rev.,1995,16:195
[52]Neradovic D, Van Nostrum C F, Hennink W E. Thermoresponsive Polymeric Micelles with Controlled Instability Based on Hydrolytically Sensitive
[68]Wilson D J, Riess G. Photochemical stabilization of block copolymer micelles[J]. Eur Polym.,1988,24(7):617-621
[69]Wang GM, Liu WB, Cai Q, et al. Preparation and Its Stability of Thermo-Sensitive Block Copolymer Nano-Micelles[J]. Func Polym (Chinese).,2008,21:242-248
[2]Lehn J M. Supramolecular Chemistry[M]. VCH:Weinheim,1995
[3]Bard A J Integrated Chemical Systems[M]. NewYork:wiley,1995
[4]Torchilin V.P. Structure and Design of Polymeric Surfactant-based drug delivery systerms[J]. Control Release.,2001,73:137-172
[5]Duncan R. The Dawning Era of Polymer Therapeutics[J]. Nature Rev. Drug Discovery.,2003,2:347-360
[6]Torchilin V.P. Micellar nanocarriers:Pharmaceutical Perspectives[J]. Pharmaceutical Research.,2007,24:1-16
[7]吉静,黄明智.开发智能性明胶[J].明胶科学与技术,2001,21(1)：12-22
[8]袁金颖,魏高原,王延梅等.ABA型两亲嵌段共聚物的合成及表征[J].高分子学报,2001,5：625-628
[9]Price C, Woods D. A method for studying micellar aggregates in block and graft copolymers[J]. European Polymer Journal.,1973,9:827
[10]Halperin A. Polymeric micelles:a star moder[J]. Macromolecules.,1987,20: 2943
[11]Halperin A, Tirrel M, Lodge T P. Tethered chains in polymer microstructures[J]. Adv. Polym. Sci.,1992,100:31
[12]杨子刚,袁建军,程时远.两亲嵌段共聚物溶液自组装新进展[J].功能高分子学报,2003,16：287
[13]Shen H, Zhang L, Eisenberg A. Multiple pH-Induced Morphological Changes in Aggregates of Polystyrene-block-poly(4-vinylpyridine) in DMF/H2O Mixtures[J]. Am. Chem. Soc.,1999,121:2728
[14]Yu G, Eisenberg A. Multiple Morphologies Formed from an Amphiphilic ABC Triblock Copolymer in Solution[J]. Macromolecules.,1998,31:5546
[15]Yu K, Bartels C, Eisenberg A. Vesicles with Hollow Rods in the Walls:A Trapped Intermediate Morphology in the Transition of Vesicles to Inverted Hexagonally Packed Rods in Dilute Solutions of PS-b-PEO[J]. Macromolecules.,1998,31:9399
[16]Yu Y, Zhang L, Eisenberg A. Morphogenic Effect of Solvent on Crew-Cut Aggregates of Amphiphilic Diblock Copolymers[J]. Macromolecules.,1998, 31:1144
[17]Yu K, Eisenberg A. Bilayer Morphologies of Self-Assembled Crew-Cut Aggregates of Amphiphilic PS-b-PEO Diblock Copolymers in Solution[J]. Macromolecules.,1998,31:3509
[18]Cameron N S, Corbierre M K, Eisenberg A. Assemmetric amphilic block copolymers in solution:a morphologies wonderland[J]. Can. J. Chem.,1999, 77:1311.
[19]Chung J E, Yokoyama M, Aoyagi T, et al. Effect of molecular architecture of hydrophobically modified poly(N-isopropylacrylamide) on the formation of themoresponsive core-shell micellar drug carriers[J]. Control. Rel.,1998,53: 119
[20]Bader H, Ringsdorf H, Schmidt B, et al. Watersoluble polymers in medicine[J]. Macromolecular Materials and Engineering.,1984,123:457
[21]查刘生,高海峰,杨武利等.聚合物纳米粒子用于给药载体[J].高分子通报,2002,3：24
[22]陈建海.药用高分子材料与现代药剂[M].北京：科学出版社,2003.19-21
[23]陆彬.胶束给药系统及其进展(上)[J].中国药师(继续药学教育),2006,9：428
[24]林宏英,吴建梅,赵李宏.难溶性抗肿瘤药物载体-嵌段共聚物胶束[J].中草药,2006,4(37)：48
[25]李珺婵.嵌段共聚物胶束作为抗肿瘤药物载体的研究进展[J].国外医学药学分册,2004,31(1)：48
[26]Narayan Bhattarai, Shanta Raj Bhattarai, Myung Seob Khil, et al. Aqueous solution properties of amphiphilic triblock copolymer poly(p-dioxanone-co-L-lactide)-block-poly(ethylene glycol)[J]. Eur Polym.,2003,20:2021-2027
[27]Byeongmoon Jeong, You Han Bae, Sung Wan Kim. Biodegradable thermosensitive micelles of PEG-PLGA-PEG triblock copolymers[J]. Control. Rel.,2000,63:155-163
[28]In-Sook Kim, Sung-Ho Kim. Development of a polymeric nanoparticulate drug delivery system in vitro characterization of nanoparticles based on sugarcontaining conjugates[J]. International Journal of Pharmaceutics.,2002, 245:67-73
[29]Schillen K, Bryskhe K, Melnikova Y S. Vesicles foxed from a triblock copolymer in dilute aqueous solution[J]. Macromolecules.,1999,32:6885
[30]Corenelissen J L M, Fischer M, Semmerdijk A J M, et al. Helical Superstructures from Charged Poly(styrene)-Poly(isocyanodipeptide) Block Copolymers[J]. Science.,1998,280:1427
[31]Discher B M, Won Y Y, Ege D S, et al. Polymersome:Tough Vesicles Made from Diblock Copolymers[J]. Science.,1999,284:1143
[32]尹常晴,隋卫平,汪源浩.两亲性高分子聚集体在药物载体中的应用[J].化学通报,2006,69：1
[33]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]. Control. Rel.,1998,50: 79
[34]Allen C, Maysinger D, Eisenberg A. Nano-engineering block copolymer aggregates for drug delivery[J]. Colloids and Surfaces B:Biointerfaces.,1999, 16:3
[35]Capek I. Fate of excited probes in micellar systems[J]. Adv. Colloid Interface Sci.,2002,97:91
[36]曾灿,陈伟,胡建等.聚乙二醇／聚天冬氨酸(阿霉素)的制备与毒性[J].复 旦学报(自然科学版),2006,45：708
[37]Kim S Y, Shin I G, Lee Y M, et al. Micelle formation and drug release behaviours[J]. Control. Rel.,1998,51:13
[38]施斌,方超,裴元英.两亲嵌段共聚物胶束的研究进展[J].中国医药工业杂志,2005,36：239
[39]李超英,蒋学华,侯世祥.淋巴靶向给药系统研究与应用[J].中国新药杂志,2001,10(12)：903
[40]Chung J E, Yokoyama M, Okano T. Inner core segment design for delivery control of thermo-responsive polymeric micelles[J]. Control. Rel.,2000,65: 93
[41]Yu B G, Okano T, Kataoka K, et al. Polymeric micelles for drug delivery: solubilization and haemolytic activity of amphotericin B[J]. Control. Rel., 1998,53:131
[42]HuaWei, Si Xue Cheng, Xian Zheng Zhang, et al. Thermo-sensitive polymeric micelles based on poly(N-isopropylacrylamide) as drug carriers[J]. Progress in Polymer Science.,2009,34:893-910
[43]魏彦,周建平,霍美蓉.难溶药物载体：聚合物胶束的研究进展[J].江苏药学与临床研究,2006,14(4)：228
[44]Kohori F, Sakai K, Aoyagi T, et al. Preparation and characterization of thermally responsive block copolymer micelles comprising poly (N-isopropylacrylamide-b-D, L-lactide) [J]. Control. Rel.,1998,55:87
[45]Kohori F, Sakai K, Aoyagi T, et al. Control of adriamycin cytotoxic activity using thermally responsive polymeric micelles composed of poly(N-isopropylacrylamide-co-N, N-dimethylacrylamide)-b-poly(D,L-lactid) [J]. Colloids and Surfaces B:Biointerfaces.,1999,16:195
[46]Wei H, Zhang X Z, Zhou Y, et al. Self-assembled thermoresponsive micelles of poly(N-isopropylacrylamide-b-methyl methacrylate)[J]. Biomaterials., 2006,27:2028
[47]任现文,江明.交联度对原位聚合法制备聚合物胶束性质的影响及相应的空心球制备[J].高等学校化学学报,2006,27(11)：2204
[48]Topp M D C, Dijkstra P J, Talsma H, et al. Thermosensitive micelle-forming block copolymers of poly(ethylene glyc01)and poly(N-isopropylacrylamide) [J]. Macromolecules.,1997,30:8518
[49]Kwon I K, Matsuda T. Photo-iniferter-based thermoresponsive block copolymers composed of poly(ethylene glycol) band poly(N-isopropylacrylamide) and chondrocyte immobilization[J]. Biomaterials.,2006,27:986
[50]Kim K H, Kim J, Jo W H. Preparation of hydrogel nanoparticles by atom transfer radical polymerization of N-isopropylacrylamide in aqueous media using PEG macro-initiator[J]. Polymer.,2005,46:2836
[51]Stolnik S, Ilium L, Davis S S. Long circulating microparticulate drug carriers[J]. Adv. Drug Delivery Rev.,1995,16:195
[52]Neradovic D, Van Nostrum C F, Hennink W E. Thermoresponsive Polymeric Micelles with Controlled Instability Based on Hydrolytically Sensitive
[68]Wilson D J, Riess G. Photochemical stabilization of block copolymer micelles[J]. Eur Polym.,1988,24(7):617-621
[69]Wang GM, Liu WB, Cai Q, et al. Preparation and Its Stability of Thermo-Sensitive Block Copolymer Nano-Micelles[J]. Func Polym (Chinese).,2008,21:242-248