紫杉醇的PEG-壳聚糖聚合物胶束给药系统研究
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摘要
本文设计制备了聚乙二醇(PEG)-壳聚糖(Chitosan)聚合物胶束。该类聚合物在水中能自组装形成纳米胶束,可以作为药物增溶、缓释和控释的载体。为解决紫杉醇的水溶性问题,减少毒副作用,提高治疗效果,制备了紫杉醇的PEG-壳聚糖聚合物胶束给药系统。聚合物胶束的独特优点以及壳聚糖的生物活性使得对PEG-壳聚糖的研究具有重要的意义,主要进行了以下工作:
(1)以PEG-6000和壳聚糖为原料,摸索反应条件,确定合适的催化剂,通过两步反应合成目标产物。研究表明,第一步反应过程中,以丁二酸酐(SA)为连接臂,4-二甲氨基吡啶(DMAP)为催化剂合成中间产物PEG-SA效果最好;第二步反应以1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl)为偶联剂和脱水剂、N-羟基琥珀酰亚胺(NHS)为催化剂、pH值为3~4的HCl-Mes盐缓冲溶液作为反应介质,合成效果最佳。经红外光谱(IR)分析证实,所得产物即为目标产品PEG-壳聚糖。
(2)分别利用粘度法、荧光探针法测定了聚合物的分子量和临界胶束浓度(CMC),利用动态光散射技术(DLS)对PEG-壳聚糖在水中形成的胶束进行了粒径及粒径分布分析,利用透射电镜(TEM)观测了胶束的尺寸及形貌特征。结果显示,该聚合物的分子量约为2.14×105;CMC值为2.12×10-6 mol·dm-3;DLS分析显示,聚合物胶束的平均粒径为100 nm,分布较窄;TEM分析表明,聚合物胶束形貌呈球形,粒径大小比较均一。
(3)利用透析法制备了紫杉醇聚合物胶束给药系统,研究了载药后形成的胶束粒径及其分布、形貌特征、载药量及药物包封率等特性。DLS结果表明该胶束粒径约为200 nm,分布均匀,比载药前聚合物PEG-壳聚糖胶束的粒径大一倍;TEM结果表明胶束形貌由球状变成棒状,核内填充了大量疏水药物紫杉醇;高效液相色谱(HPLC)结果显示,随着投药量的增大,胶束的载药量逐渐增加,药物包封率先升高后降低,最高达到95 %。
Amphiphilic copolymer PEG?Chitosan was designed and synthesized. This kind of copolymer may increase the solubility of hydrophobic drugs and control their release in vivo due to the formation of self-assembled micelles. It may have potential application in drug delivery system. To solve the problem of low water-solubility, harmful side-effects and enhance the therapy efficacy of paclitaxel, Polymeric micelle formed with PEG-Chitosan was prepared. Due to the numerous advantages of polymeric micelle and the biologic consistent of Chitosan, the PEG-Chitosan polymeric micelle of paclitaxel is considered to be important theoretically and practically. The following work has been done in the thesis:
(1) PEG-Chitosan was synthesized through the reaction of PEG-6000 with Chitosan by two steps. Succinic anhydride was selected as the spacer to bind the two parts together in the first step. It was found that DMAP was better than pyridine. In the second step, 1-(3-dimethylaminopropyl) -3- ethyl carbodiimide (EDC·HCl) was used as dehydrating agent and N-hydroxysuccinimide (NHS) as the catalyst. HCl-Mes salt buffer solution with pH of 3-4 was proved to be the appropriate reaction medium. White powder product was finally obtained and attested to be the aim product of PEG-Chitosan by IR analysis.
(2) Molecular weight and the Critical Micelle Concentration (CMC) of PEG-Chitosan were determined by viscosity measuration and fluorescence spectroscopy analysis. The size and morphology of PEG-Chitosan micelle in water were characterized by Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM), respectively. The result showed that the molecular weight was 2.14×105 and the CMC value was 2.12×10-6 mol·dm-3. The average size of the micelles was found to be 100 nm by DLS and the shape was approximately spherical by TEM examination.
(3) The paclitaxel-loaded micelles were prepared by dialysis. The size and size distribution, the structure and the drug-loaded amount, the drug-fed amount were characterized by DLS, TEM and HPLC, respectively. The result showed that the average size of the paclitaxel-loaded micelles was 200 nm and was larger than that of PEG-Chitosan by DLS. The shape was changed from spherical into rod-like by TEM. It was found that as the amount of paclitaxel increased, the drug-loaded was increased step by step while the drug-fed was first increased to 95 % of the maximum and then decline by HPLC.
(1)以PEG-6000和壳聚糖为原料,摸索反应条件,确定合适的催化剂,通过两步反应合成目标产物。研究表明,第一步反应过程中,以丁二酸酐(SA)为连接臂,4-二甲氨基吡啶(DMAP)为催化剂合成中间产物PEG-SA效果最好;第二步反应以1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl)为偶联剂和脱水剂、N-羟基琥珀酰亚胺(NHS)为催化剂、pH值为3~4的HCl-Mes盐缓冲溶液作为反应介质,合成效果最佳。经红外光谱(IR)分析证实,所得产物即为目标产品PEG-壳聚糖。
(2)分别利用粘度法、荧光探针法测定了聚合物的分子量和临界胶束浓度(CMC),利用动态光散射技术(DLS)对PEG-壳聚糖在水中形成的胶束进行了粒径及粒径分布分析,利用透射电镜(TEM)观测了胶束的尺寸及形貌特征。结果显示,该聚合物的分子量约为2.14×105;CMC值为2.12×10-6 mol·dm-3;DLS分析显示,聚合物胶束的平均粒径为100 nm,分布较窄;TEM分析表明,聚合物胶束形貌呈球形,粒径大小比较均一。
(3)利用透析法制备了紫杉醇聚合物胶束给药系统,研究了载药后形成的胶束粒径及其分布、形貌特征、载药量及药物包封率等特性。DLS结果表明该胶束粒径约为200 nm,分布均匀,比载药前聚合物PEG-壳聚糖胶束的粒径大一倍;TEM结果表明胶束形貌由球状变成棒状,核内填充了大量疏水药物紫杉醇;高效液相色谱(HPLC)结果显示,随着投药量的增大,胶束的载药量逐渐增加,药物包封率先升高后降低,最高达到95 %。
Amphiphilic copolymer PEG?Chitosan was designed and synthesized. This kind of copolymer may increase the solubility of hydrophobic drugs and control their release in vivo due to the formation of self-assembled micelles. It may have potential application in drug delivery system. To solve the problem of low water-solubility, harmful side-effects and enhance the therapy efficacy of paclitaxel, Polymeric micelle formed with PEG-Chitosan was prepared. Due to the numerous advantages of polymeric micelle and the biologic consistent of Chitosan, the PEG-Chitosan polymeric micelle of paclitaxel is considered to be important theoretically and practically. The following work has been done in the thesis:
(1) PEG-Chitosan was synthesized through the reaction of PEG-6000 with Chitosan by two steps. Succinic anhydride was selected as the spacer to bind the two parts together in the first step. It was found that DMAP was better than pyridine. In the second step, 1-(3-dimethylaminopropyl) -3- ethyl carbodiimide (EDC·HCl) was used as dehydrating agent and N-hydroxysuccinimide (NHS) as the catalyst. HCl-Mes salt buffer solution with pH of 3-4 was proved to be the appropriate reaction medium. White powder product was finally obtained and attested to be the aim product of PEG-Chitosan by IR analysis.
(2) Molecular weight and the Critical Micelle Concentration (CMC) of PEG-Chitosan were determined by viscosity measuration and fluorescence spectroscopy analysis. The size and morphology of PEG-Chitosan micelle in water were characterized by Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM), respectively. The result showed that the molecular weight was 2.14×105 and the CMC value was 2.12×10-6 mol·dm-3. The average size of the micelles was found to be 100 nm by DLS and the shape was approximately spherical by TEM examination.
(3) The paclitaxel-loaded micelles were prepared by dialysis. The size and size distribution, the structure and the drug-loaded amount, the drug-fed amount were characterized by DLS, TEM and HPLC, respectively. The result showed that the average size of the paclitaxel-loaded micelles was 200 nm and was larger than that of PEG-Chitosan by DLS. The shape was changed from spherical into rod-like by TEM. It was found that as the amount of paclitaxel increased, the drug-loaded was increased step by step while the drug-fed was first increased to 95 % of the maximum and then decline by HPLC.
引文
[1] Holton RA, Carmen Somoza, Hyeong Baik Kim, et al. First total synthesis of taxol. 1. Functionation of the B ring. J. Am. Chem. Soc. , 1994 , 116 (4) : 1597-1598
[2]方瑾,王芸庆,宋今丹,大肠癌免疫脂质体导向紫杉醇的实验研究,中国免疫学杂志, 1998, 14 (3) : 198-199
[3] Chelvi TP, Sharma D, Kaur J, Ralhan R. Short communication: Thermosensitive liposomal taxol formulation: heatimediated targeted drug delivery in murine melanoma. Melanoma Research, 1998, 8 (3) : 240-244
[4]阎家麒,王悦,王九一,紫杉醇隐形脂质体的制备及在小鼠体内的组织分布,药学学报, 2000, 35 (9) : 706-709
[5]方华丰,周宜开,任恕,生物素化壳聚糖微球的体外抗癌活性,药学学报, 2000, 35 (5) : 385-388
[6] Straubinger RM, Sharma A. Noval taxol formulations, preparation and characterization of taxol-containing liposomes. Pharm. Res. , 1994, 11 (6) : 889-896
[7] Ulbrich K, ?ubr. V. Polymeric anticancer drugs with pH-controlled activation. Adv. Drug. Deliv. Rev. , 2004, 56 (7) : 1023-1050
[8] Still JG. Development of oral insulin: progress and current status. Diabetes/Metabolism Research and Reviews, 2002, 18 (suppl 1) :S29-S37
[9] Godard G, Boutorine AS. Antisense effects of Cholesterol-Oligodeoxynucleotide conjugates associated with poly (alkylcyanoacrylate) nanoparticles. European Journal of Biochemistry, 1995, 232 (2) : 404-410
[10] Kataoka K, Matsumoto T, Yokoyama M, et al. Doxorubicin-loaded poly (ethylene glycol)-poly (β-benzyl-L-aspartate) copolymer micelles: their pharmaceutical characteristics and biological significance. Journal of Controlled Realease, 2000, 64: 143-153
[11] Hiemenz JW, Walsh TJ. Lipid formulations of amphotericin B recent progress future dirctions. Clin Infect Dis, 1996, 22: 133
[12] Lukyanov AN, Torchilin VP. Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs. Advanced Drug Delivery Reviews, 2004, 56: 1273-1289
[13] Engin K, Leeper DB, Cater JR. Extracellular pH distribution in human tumors. International Journal of Hyperthermia, 1995, 11 (2) : 211-216
[14] Yoo HS, Park TG. Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA-PEG block copolymer. Journal of Controlled Realease, 2001, 70 (1) : 63-70
[15] Kwon GS, Kataoka K. Block copolymer micelles as long-circulating drug vehicles. Advanced Drug Delivery Reviews, 1995, 16 (2-3) : 295-309
[16] Torchilin VP. Structure and design of polymeric surfactant-based drug delivery systems. Journal of Controlled Realease, 2001, 73: 137-172
[17] Tsukada Y, Sela M, et al. Effect of a conjugate of daunomycin and antibodies to ratα-fetoprotein on the growth ofα-fetoprotein- producing tumor cells. Proceedings of the National Academy of Sciences, 1982, 79 (2) : 621-625
[18] Lukyanov AN, Gao Z, Torchilin VP. Micelles from polyethylene glycol/phosphatidylethanolamine conjugates for tumor drug delivery. Journal of Controlled Realease, 2003, 91: 97-102
[19] Kwon GS, Okano T. Polymeric micelles as new drug carriers. Advanced Drug Delivery Reviews, 1996, 21: 107-116
[20] Allen C, Maysinger D, Eisenberg A. Nano-engineering block copolymer aggregates for drug delivery. Colloids and Surfaces B: Biointerfaces, 1999, 16: 3-27
[21]张宏娟,张灿,平其能,聚合物胶束作为药用载体的研究与应用,药学进展, 2002, 26 (6) :326-329
[22] Torchilin VP. Structure and design of polymeric surfactant-based drug delivery systems. Journal of Controlled Realease, 2001, 73 (2) : 137-172
[23] Kim SY, Shin IG, Lee YM, et al. Methoxy poly(ethylene glycol) andε-caprolactone amphiphilic block copolymeric micelle containing indomethacin. Journal of Controlled Realease, 1996, 51 (1) : 13-22
[24] Sanford PA, Skjak BT, Anthonsen PA, et al. Chitin and chitosan-ources, chemistry, biochemistry, physical properties and application. London: Elsevier, 1989, 51
[25] Okamoto Y, Yano R, Miyatake K, et al. Effects of chitin and chitosan on blood coagulation. Carbohydrate Polymers, 2003, 53 (3) : 337-342
[26] Ravi Kumer MNV, Muzzarelli RAA, Muzzarelli C, et al. Chitosan chemistry and pharmaceutical perspectives. Chemical Reviews. 2004, 104 (12) : 6017-6084
[27] Lim SH, Hudson SM. Synthesis and antimicrobial activity of a water-soluble chitosan derivative with a fiber-reactive group. Carbohydrate Research, 2004, 339 (2) :313-319
[28] Santos KSCR, Coelho JFJ, Ferreira P, et al. Synthesis and characterization of membranes obtained by graft copolymerization of 2-hydroxyethyl methacrylate and acrylic acid onto chitosan. International Journal of Pharmaceutics, 2006, 310 (1-2) :37-45
[29] Qian F, Cui FY, Ding JY. Chitosan graft copolymer nanoparticles for oral Protein drug delivery: preparation and characterization. Biomacromoleeules, 2006, 7 (10) : 2722-2727
[30] Sherbiny MEL, Abdel-Bary EM, Harding DRK. Swelling characteristics and in vitro drug release atudr with pH- and thermally sensitive hydrogels based on modified chitosan. Journal of Applied Polymer Science, 2006, 102 (2) : 977-985
[31] Bhattarai N, Hassna R, Jonathan G, et al. PEG-grafted-chitosan as an injectable thermosensitive hydrogel for sustained protein release. Journal of Controlled Realease, 2005, 103 (5) : 609-624
[32] Weijun Liu, Yongming Huang, Honglai Liu, et al. Composite structure of temperature sensitive chitosan microgel and anomalous behavior in alcohol solutions. Journal of Colloid and Interface Science, 2007, 313 (1) : 117-121
[33]郭保林,袁金芳,高青雨,温度和pH敏感性壳聚糖接枝物对辅酶A的控制释放,精细化工, 2006, 23 (10) : 988-991
[34]童身毅,万敏,张良均,两亲性高聚物及其应用,材料导报, 1995, 13 (5) : 46-48
[35] Lee JH, Lee HB, Andrade JosD. Blood compatibility of polyethylene oxide surfaces. Progress in Polymer Science, 1995, 20 (6) : 1043-1079
[36] Shen WC, Ryser H. Cis-aconityl spacer between daunomycin and macromolecular carriers: A model of pH-sensitive linkage releasing drug from a lysosomotropic conjugate. Biochemical and Biophysical Research Communications, 1981, 102 (3) : 1048-1054
[37] 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. Journal of Controlled Realease, 1998, 50: 79-92
[38] Adams ML, Lavasanifar A, Kwon GS. Amphiphilic block copolymer for drug delivery. Journal of Pharmaceutical Sciences, 2003, 92 (7) : 1343-1355
[39] Lukyanov AN, Gao Z, Mazzola L, et al. Polyethylene Glycol-Diacyllipid micelles demonstrate increased acculumation in subcutaneous tumors in micelles. Pharmaceutical Research, 2003, 19 (10) : 1424-1429
[40] Lukyanov AN, Gao Z, Torchilin VP. Micelles from polyethylene glycol / phosphatidylethanolamine conjugates for tumor drug delivery. Journal of Controlled Realease, 2003, 91: 97-102
[41] Lukyanov AN, Torchilin VP. Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs. Advanced Drug Delivery Reviews, 2004, 56: 1273-1289
[42] BASF Corp. Pluronic and technical brochure tetronic surfactants. BASF Corp., Parsipanny, N.J., 1989
[43] Laverty PH, Leskovar A, Breur GJ, et al. A preliminary study of intravenous surfactants in parap legic dogs. Polymer Therapy in Canine Clinical Science, 2004, 21 (12) : 1767-1777
[44] Jewell RC, Khor SP, Kisor DF, et al. Pharmacokinetics of RheothRx injection in healthy male volunteers. Pharmaceutical Sciences, 1997, 86 (7) : 808-812
[45] Moghimi SM, Hunter AC, Dadswell CM, et al. Causative factors behind poloxamer 188-induced complement activation in human sera. A protective role against poloxamer-mediated complement activation by elevated serum lipop rotein levels. Biochin. Biophys. Acta. , 2004, 1689 (2) : 103-112
[46] KY Cho, TW Chun, BC Kim, et al. Release of ciprofloxacin from poloxamer-graft-hyaluronic acid hydrogels in vitro. International Journal of Pharmaceutics, 2003, 260: 83-91
[47] Kyung Min Park, Jin Woo Bae, Yoon Ki Joung, et al. Nanoaggregate of thermosensitive chitosan-Pluronic for sustained release of hydrophobic drug. Colloids and Surfaces B, 2008, 63: 1-6
[48] Kim IS, Kim SH. Evaluation of polymeric nanoparticles composed of cholic acid and methoxy poly (ethylene glycol). International Journal of Pharmaceutics, 2001, 226: 23-29
[49]查刘生,高海峰,杨武利等,聚合物纳米粒子用于给药载体,高分子通报) , 2002, 3: 24-31
[50]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,药学学报, 2004, 39 (2) : 149-152
[2]方瑾,王芸庆,宋今丹,大肠癌免疫脂质体导向紫杉醇的实验研究,中国免疫学杂志, 1998, 14 (3) : 198-199
[3] Chelvi TP, Sharma D, Kaur J, Ralhan R. Short communication: Thermosensitive liposomal taxol formulation: heatimediated targeted drug delivery in murine melanoma. Melanoma Research, 1998, 8 (3) : 240-244
[4]阎家麒,王悦,王九一,紫杉醇隐形脂质体的制备及在小鼠体内的组织分布,药学学报, 2000, 35 (9) : 706-709
[5]方华丰,周宜开,任恕,生物素化壳聚糖微球的体外抗癌活性,药学学报, 2000, 35 (5) : 385-388
[6] Straubinger RM, Sharma A. Noval taxol formulations, preparation and characterization of taxol-containing liposomes. Pharm. Res. , 1994, 11 (6) : 889-896
[7] Ulbrich K, ?ubr. V. Polymeric anticancer drugs with pH-controlled activation. Adv. Drug. Deliv. Rev. , 2004, 56 (7) : 1023-1050
[8] Still JG. Development of oral insulin: progress and current status. Diabetes/Metabolism Research and Reviews, 2002, 18 (suppl 1) :S29-S37
[9] Godard G, Boutorine AS. Antisense effects of Cholesterol-Oligodeoxynucleotide conjugates associated with poly (alkylcyanoacrylate) nanoparticles. European Journal of Biochemistry, 1995, 232 (2) : 404-410
[10] Kataoka K, Matsumoto T, Yokoyama M, et al. Doxorubicin-loaded poly (ethylene glycol)-poly (β-benzyl-L-aspartate) copolymer micelles: their pharmaceutical characteristics and biological significance. Journal of Controlled Realease, 2000, 64: 143-153
[11] Hiemenz JW, Walsh TJ. Lipid formulations of amphotericin B recent progress future dirctions. Clin Infect Dis, 1996, 22: 133
[12] Lukyanov AN, Torchilin VP. Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs. Advanced Drug Delivery Reviews, 2004, 56: 1273-1289
[13] Engin K, Leeper DB, Cater JR. Extracellular pH distribution in human tumors. International Journal of Hyperthermia, 1995, 11 (2) : 211-216
[14] Yoo HS, Park TG. Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA-PEG block copolymer. Journal of Controlled Realease, 2001, 70 (1) : 63-70
[15] Kwon GS, Kataoka K. Block copolymer micelles as long-circulating drug vehicles. Advanced Drug Delivery Reviews, 1995, 16 (2-3) : 295-309
[16] Torchilin VP. Structure and design of polymeric surfactant-based drug delivery systems. Journal of Controlled Realease, 2001, 73: 137-172
[17] Tsukada Y, Sela M, et al. Effect of a conjugate of daunomycin and antibodies to ratα-fetoprotein on the growth ofα-fetoprotein- producing tumor cells. Proceedings of the National Academy of Sciences, 1982, 79 (2) : 621-625
[18] Lukyanov AN, Gao Z, Torchilin VP. Micelles from polyethylene glycol/phosphatidylethanolamine conjugates for tumor drug delivery. Journal of Controlled Realease, 2003, 91: 97-102
[19] Kwon GS, Okano T. Polymeric micelles as new drug carriers. Advanced Drug Delivery Reviews, 1996, 21: 107-116
[20] Allen C, Maysinger D, Eisenberg A. Nano-engineering block copolymer aggregates for drug delivery. Colloids and Surfaces B: Biointerfaces, 1999, 16: 3-27
[21]张宏娟,张灿,平其能,聚合物胶束作为药用载体的研究与应用,药学进展, 2002, 26 (6) :326-329
[22] Torchilin VP. Structure and design of polymeric surfactant-based drug delivery systems. Journal of Controlled Realease, 2001, 73 (2) : 137-172
[23] Kim SY, Shin IG, Lee YM, et al. Methoxy poly(ethylene glycol) andε-caprolactone amphiphilic block copolymeric micelle containing indomethacin. Journal of Controlled Realease, 1996, 51 (1) : 13-22
[24] Sanford PA, Skjak BT, Anthonsen PA, et al. Chitin and chitosan-ources, chemistry, biochemistry, physical properties and application. London: Elsevier, 1989, 51
[25] Okamoto Y, Yano R, Miyatake K, et al. Effects of chitin and chitosan on blood coagulation. Carbohydrate Polymers, 2003, 53 (3) : 337-342
[26] Ravi Kumer MNV, Muzzarelli RAA, Muzzarelli C, et al. Chitosan chemistry and pharmaceutical perspectives. Chemical Reviews. 2004, 104 (12) : 6017-6084
[27] Lim SH, Hudson SM. Synthesis and antimicrobial activity of a water-soluble chitosan derivative with a fiber-reactive group. Carbohydrate Research, 2004, 339 (2) :313-319
[28] Santos KSCR, Coelho JFJ, Ferreira P, et al. Synthesis and characterization of membranes obtained by graft copolymerization of 2-hydroxyethyl methacrylate and acrylic acid onto chitosan. International Journal of Pharmaceutics, 2006, 310 (1-2) :37-45
[29] Qian F, Cui FY, Ding JY. Chitosan graft copolymer nanoparticles for oral Protein drug delivery: preparation and characterization. Biomacromoleeules, 2006, 7 (10) : 2722-2727
[30] Sherbiny MEL, Abdel-Bary EM, Harding DRK. Swelling characteristics and in vitro drug release atudr with pH- and thermally sensitive hydrogels based on modified chitosan. Journal of Applied Polymer Science, 2006, 102 (2) : 977-985
[31] Bhattarai N, Hassna R, Jonathan G, et al. PEG-grafted-chitosan as an injectable thermosensitive hydrogel for sustained protein release. Journal of Controlled Realease, 2005, 103 (5) : 609-624
[32] Weijun Liu, Yongming Huang, Honglai Liu, et al. Composite structure of temperature sensitive chitosan microgel and anomalous behavior in alcohol solutions. Journal of Colloid and Interface Science, 2007, 313 (1) : 117-121
[33]郭保林,袁金芳,高青雨,温度和pH敏感性壳聚糖接枝物对辅酶A的控制释放,精细化工, 2006, 23 (10) : 988-991
[34]童身毅,万敏,张良均,两亲性高聚物及其应用,材料导报, 1995, 13 (5) : 46-48
[35] Lee JH, Lee HB, Andrade JosD. Blood compatibility of polyethylene oxide surfaces. Progress in Polymer Science, 1995, 20 (6) : 1043-1079
[36] Shen WC, Ryser H. Cis-aconityl spacer between daunomycin and macromolecular carriers: A model of pH-sensitive linkage releasing drug from a lysosomotropic conjugate. Biochemical and Biophysical Research Communications, 1981, 102 (3) : 1048-1054
[37] 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. Journal of Controlled Realease, 1998, 50: 79-92
[38] Adams ML, Lavasanifar A, Kwon GS. Amphiphilic block copolymer for drug delivery. Journal of Pharmaceutical Sciences, 2003, 92 (7) : 1343-1355
[39] Lukyanov AN, Gao Z, Mazzola L, et al. Polyethylene Glycol-Diacyllipid micelles demonstrate increased acculumation in subcutaneous tumors in micelles. Pharmaceutical Research, 2003, 19 (10) : 1424-1429
[40] Lukyanov AN, Gao Z, Torchilin VP. Micelles from polyethylene glycol / phosphatidylethanolamine conjugates for tumor drug delivery. Journal of Controlled Realease, 2003, 91: 97-102
[41] Lukyanov AN, Torchilin VP. Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs. Advanced Drug Delivery Reviews, 2004, 56: 1273-1289
[42] BASF Corp. Pluronic and technical brochure tetronic surfactants. BASF Corp., Parsipanny, N.J., 1989
[43] Laverty PH, Leskovar A, Breur GJ, et al. A preliminary study of intravenous surfactants in parap legic dogs. Polymer Therapy in Canine Clinical Science, 2004, 21 (12) : 1767-1777
[44] Jewell RC, Khor SP, Kisor DF, et al. Pharmacokinetics of RheothRx injection in healthy male volunteers. Pharmaceutical Sciences, 1997, 86 (7) : 808-812
[45] Moghimi SM, Hunter AC, Dadswell CM, et al. Causative factors behind poloxamer 188-induced complement activation in human sera. A protective role against poloxamer-mediated complement activation by elevated serum lipop rotein levels. Biochin. Biophys. Acta. , 2004, 1689 (2) : 103-112
[46] KY Cho, TW Chun, BC Kim, et al. Release of ciprofloxacin from poloxamer-graft-hyaluronic acid hydrogels in vitro. International Journal of Pharmaceutics, 2003, 260: 83-91
[47] Kyung Min Park, Jin Woo Bae, Yoon Ki Joung, et al. Nanoaggregate of thermosensitive chitosan-Pluronic for sustained release of hydrophobic drug. Colloids and Surfaces B, 2008, 63: 1-6
[48] Kim IS, Kim SH. Evaluation of polymeric nanoparticles composed of cholic acid and methoxy poly (ethylene glycol). International Journal of Pharmaceutics, 2001, 226: 23-29
[49]查刘生,高海峰,杨武利等,聚合物纳米粒子用于给药载体,高分子通报) , 2002, 3: 24-31
[50]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,药学学报, 2004, 39 (2) : 149-152
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