MMA-PEG-PLA两亲性嵌段共聚物的合成及其在制备胶束和药物释放中的应用
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摘要
本论文制备了基于聚乳酸—聚乙二醇两亲性嵌段共聚物的胶束体系,并提出了能有效提高胶束稳定性的方法。首先以甲基丙烯酸和氯化亚砜为原料,合成了甲基丙烯酰氯(MAC)。通过MAC与聚乙二醇(PEG)的反应,得到了聚乙二醇单甲基丙烯酸酯(PEG-MMA)。在辛酸亚锡的引发作用下,将PEG-MMA和丙交酯进行聚合反应,合成出了聚乳酸—聚乙二醇单甲基丙烯酸酯(MMA-PEG-PLA)两嵌段共聚物。通过IR、1H-NMR、GPC和LC-MS等检测手段对其结构进行了表征。
通过两亲性嵌段共聚物制备了MMA-PEG-PLA胶束水溶液。然后再在由过硫酸铵(APS)和四甲基乙二胺(TEMED)组成的氧化还原引发剂的作用下,向胶束水溶液中加入交联剂N-乙烯基吡咯烷酮(NVP),得到了交联反应后的PVP-PEG-PLA胶束。本实验对交联反应前后胶束的性质,如粒径大小、粒径分布、临界聚集浓度(CAC)和微观形貌等进行了分析和对比,并对所得胶束的稳定性进行了初步的探讨。最后以粉防己碱(TED)为模型药物,探讨了载药胶束在PBS缓冲液中的释放行为。
This paper presented a new approach to improve the physical and chemical stability of biodegradable poly(ethylene glycol)-block-poly(lactic acid) (PEG-PLA) micelles. First of all, methacryloyl chloride (MAC) was synthesized by reacting methacrylic acid with thionyl chloride. Then, PEG monomethacrylate (PEG-MMA) was obtained through mono-terminated-group capping PEG with MAC. Initiating by stannous octoate, monomethacrylate-terminated PEG-PLA (MMA-PEG-PLA) was subsequently synthesized by polymerization reaction between PEG-MMA and lactide, which was prepared by catalyzing lactic acid with tin powder. Techniques like IR, 1H-NMR, GPC and LC-MS were utilized for characterization and measurement.
MMA-PEG-PLA micelle was obtained based on amphiphilic diblock copolymer. Then, PVP-PEG-PLA micelle was prepared through adding crosslinking agent N-vinyl-2-pyrrolidone (NVP), which was catalyzed by a redox free-radical initiator composed of ammonium persulfate (APS) and tetramethylethylenediamine (TEMED). For the purpose of studying stability, characteristics such as particle diameter, polydispersity, critical association concentration (CAC) and morphology of micelles were monitored and compared before and after crosslinked reaction. Tetrandrine (TED) loaded micelles were as well prepared and their drug releasing behaviors were taken into consideration.
通过两亲性嵌段共聚物制备了MMA-PEG-PLA胶束水溶液。然后再在由过硫酸铵(APS)和四甲基乙二胺(TEMED)组成的氧化还原引发剂的作用下,向胶束水溶液中加入交联剂N-乙烯基吡咯烷酮(NVP),得到了交联反应后的PVP-PEG-PLA胶束。本实验对交联反应前后胶束的性质,如粒径大小、粒径分布、临界聚集浓度(CAC)和微观形貌等进行了分析和对比,并对所得胶束的稳定性进行了初步的探讨。最后以粉防己碱(TED)为模型药物,探讨了载药胶束在PBS缓冲液中的释放行为。
This paper presented a new approach to improve the physical and chemical stability of biodegradable poly(ethylene glycol)-block-poly(lactic acid) (PEG-PLA) micelles. First of all, methacryloyl chloride (MAC) was synthesized by reacting methacrylic acid with thionyl chloride. Then, PEG monomethacrylate (PEG-MMA) was obtained through mono-terminated-group capping PEG with MAC. Initiating by stannous octoate, monomethacrylate-terminated PEG-PLA (MMA-PEG-PLA) was subsequently synthesized by polymerization reaction between PEG-MMA and lactide, which was prepared by catalyzing lactic acid with tin powder. Techniques like IR, 1H-NMR, GPC and LC-MS were utilized for characterization and measurement.
MMA-PEG-PLA micelle was obtained based on amphiphilic diblock copolymer. Then, PVP-PEG-PLA micelle was prepared through adding crosslinking agent N-vinyl-2-pyrrolidone (NVP), which was catalyzed by a redox free-radical initiator composed of ammonium persulfate (APS) and tetramethylethylenediamine (TEMED). For the purpose of studying stability, characteristics such as particle diameter, polydispersity, critical association concentration (CAC) and morphology of micelles were monitored and compared before and after crosslinked reaction. Tetrandrine (TED) loaded micelles were as well prepared and their drug releasing behaviors were taken into consideration.
引文
[1]刘盛辉,郎美东,新一代生物医用材料,高分子通报,2005,6:113~128
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[2] Hench L L. Biomaterials. Science, 1980, 208(4446): 826~831
[3]奚廷斐,生物医用材料现状和发展趋势,中国医疗器械信息,2006,12(5):1~4
[4] Polak J, Hench L. Gene therapy progress and prospects: In tissue engineering. Gene Therapy, 2005, 12(24): 1725~1733
[5] Hench LL. Bioactive materials: the potential for tissue regeneration. Journal of Biomedical Materials Research, 1998, 41(4): 511~518
[6] Jacoby M. Biomaterials– Tough bones. Chemical Engineering News, 2001, 79(51): 13
[7] Hench LL, Polak JM. Third-generation biomedical materials, Science, 2002, 295(5557): 1014~1017
[8] Griffith LG, Naughton G. Tissue engineering-current challenges and expanding opportunities. Science, 2002, 295(5557): 1009~1014
[9] Peter B Maurus, Christopher C Kaeding. Bioabsorbable implant material review. Operative Techniques in Sports Medicine, 2004, 12(3): 158
[10] Ruan Gang, Feng Sishen. Preparation and characterization of poly(lactic acid)-poly(ethylene glycol)-poly(lactic acid) (PLA-PEG-PLA) microspheres for controlled release of paclitaxel. Biomaterials, 2003, 24(27): 5037
[11] Erolu H, Kay HS, Oner L, et al. The in-vitro and in-vivo characterization of PLGA: L-PLA microspheres containing dexamethasone sodium phosphate. Journal of Microencapsulation, 2001, 18(5): 603
[12] Zhou Shaobing, Liao Xueyan, Li Xiaohong, et al. Poly-D, L-lactide-co-poly(ethylene glycol) microspheres as potential vaccine delivery systems. Journal of Controlled Release, 2003, 86(17): 195
[13] Slager J, Domb AJ. Stereocomplexes based on poly(lactic acid) and insulin: formulation and release studies. Biomaterials, 2002, 23(22):4389
[14] Valerie Langlois, Karine Vallee-Rehel, Jean Jacques Peron, et al. Synthesis and hydrolytic degradation of graft copolymers containing poly(lactic acid) side chains: in vitro release studies of bioactive molecules. Polymer Degradation and Stability, 2002, 76(3): 411
[15] Perez C, Sanchez A, Putnam D, et al. Poly(lactic acid)-poly(ethylene glycol) nanoparticles as new carriers for the delivery of plasmid DNA, Journal of Controlled Release, 2001, 75(2): 211
[16] Baras B, Benoit MA, Gillard J. Parameters influencing the antigen release from spray-dried poly(DL-lactide) microparticles. International Journal of Pharmaceutics, 2000, 200(1): 4781
[17] Tze-Wen Chung, Yi-You Huang, Yi-Ze Liu. Effects of the rate of solvent evaporation on the characteristics of drug loaded PLLA and PDLLA microspheres. International Journal of Pharmaceutics, 2001, 212(2): 161
[18] Tommy Tarvainen, Teija Karjalainen, Minna Malin, et al. Degradation of and drug release from a novel 2,2-bis(2-oxazoline) linked poly(lactic acid) polymer. Journal of Controlled Release, 2002, 81(3): 251
[19] Hiroshi Tsuji, Hitoshi Sasaki, Hiroko Sato, et al. Neuron attachment properties of carbon negative-ion implanted bioabsorbable polymer of poly-lactic acid. Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, 2002, 191(1-4): 815
[20] Ekiss, Bertoti I, Vargha-Butler EI. XPS and wettability characterization of modified poly(lactic acid) and poly(lactide/glycolic acid) films. Journal of Colloid and Interface Science, 2002, 245(1): 91
[21] Ouchi, Tatsuro, et al. Design of lactide copolymers as biomaterials. Polymer Chemistry, 2004, 42(3): 453
[22]葛建华,王迎军,郑裕东等,PLA-PEG-PLA嵌段共聚物的合成及研究,材料科学与工程学报,2003,21(6):817
[23]宋谋道,朱吉亮,张邦华等,聚乙二醇改性聚乳酸的研究,高分子学报,1998,4:454~458
[24]吴之中,聚乳酸—聚乙二醇嵌段共聚物及其交联聚氨酯弹性体的性能研究,信阳师范学院学报(自然科学版),1999,12(2):166～169
[25] Achim Gopferich, Susam J Peter, Andrea Lucke, et al. Modulation of marrow stromal cell function using poly(D,L-lactic acid)-block-poly(ethylene glycol)-monomethyl ether surfaces. Journal of Biomedical Materials Research, 1999, 46(3): 390~398
[26] Metters AT, Anseth KS, Bowman CN. Fundamental studies of a novel, biodegradable PEG-b-PLA hydrogel. Polymer, 2000, 41(11): 3993
[27]全大萍,高建文,寥凯荣等,聚乳酸—聚乙二醇—聚乳酸三嵌段共聚物的降解性能,功能高分子学报,2002,15(4):391
[28] Dong Keun Han, Jeffrey A Hubbell. Synthesis of polymer network scaffolds from L-lactide and poly(ethylene glycol) and their interaction with cells. Macromolecules, 1997, 30: 6077
[29] Wenna Chen, Weijun Luo, Shenguo Wang, et al. Synthesis and properties of poly(L-lactide)-poly(ethylene glycol) multiblock copolymers by coupling triblock copolymers. Polymers for Advanced Technologies, 2003, 14(3~5): 245~253
[30]熊成东,戴琦,邓先模等,聚乳酸—聚乙二醇嵌段共聚物的合成及表征,化学通报,1994,5(4):59~61
[31] Deng XM, Xiong CD, Cheng LM. Studies on the block copolymerization of D,L-lactide and poly(ethylene glycol) with aluminum complex catalyst. Journal of Applied Polymer Science, 1995, 55(8): 1193~l196
[32]吴桐,何勇,韦嘉,范仲勇,李速明,聚乳酸—聚乙二醇嵌段共聚物结晶行为研究,高等学校化学学报,2006,27(11):2193~2197
[33]王方,赵耀明,汪朝阳,聚乙二醇对直接合成聚乳酸—聚乙二醇的影响,合成树脂及塑料,2005,22(2):31
[34] Sheth M, Kumar RA, Dave V, et al. Biodegradable polymer blends of poly(lactic acid) and poly(ethylene glycol). Journal of Applied Polymer Science, 1997, 66(8): 1495
[35]刘斌,张基昌,陈宏勃等,生物可降解冠状动脉支架涂层材料聚乙二醇—聚乳酸—聚谷氨酸共聚物的生物相容性研究,中国实验诊断学,2006,10(9):975
[36]孔航,潘可风,吴志刚,聚乳酸—聚乙二醇的制备及骨修复实验研究,现代口腔医学杂志,2006,20(5):501
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