【作者】 徐艳敏；

【导师】 孟凤华；

【作者基本信息】 苏州大学 ， 高分子化学与物理， 2010， 硕士

【摘要】 本论文设计、制备了还原敏感可逆交联的生物可降解的聚合物胶束。通过在聚乙二醇(PEG)和聚己内酯(PCL)之间引入可交联的基团,硫辛酸,在少量DTT的催化下,可在形成的胶束的界面发生交联,得到稳定的胶束,但在模拟体内还原环境中它很快解离,引起药物的触发释放。(1)通过PEG-SH和PCL-丙烯酸酯的迈克尔加成反应,合成了中间含有DTT的PEG-DTT-PCL。然后,酯化反应把硫辛酸接到DTT的两个羟基上,从而得到在PEG和PCL界面上有两个硫辛酸功能团的嵌段聚合物PEG-L2-PCL。核磁氢谱和凝胶色谱测试显示PEG-L2-PCL嵌段聚合物具有可控的组成且聚合物分子量分布为1.36.在水溶液中PEG-L2-PCL形成胶束的粒径在20 -150 nm之间,临界胶束浓度为16 mg/L。加入硫辛酸官能团7.6%的DTT后,稀释、加入生理浓度盐和有机溶剂聚合物胶束仍然很稳定,但当加入10mM DTT后,聚合物胶束很快解交联。在体外释放研究显示,交联后胶束10h阿霉素仅释放了15%,未交联胶束在0.5h内释放了约80%,交联胶束在加入10mM DTT后,9h释放了75%.(2)通过序贯RAFT聚合反应,合成了中间含有寡聚HEMA的三嵌段共聚物聚乙二醇(PEG)-P(HEMA)-P(HEMA-g-PLA)。然后,用同样的酯化反应把硫辛酸接到中间PHEMA链段上得到不同取代度的聚合物PEG-PHEMA-Lx-(PHEMA-g-PLA)。通过改变中间链段PHEMA上硫辛酸的取代度,研究了改变交联程度对胶束稳定性的影响。核磁氢谱和凝胶色谱测试显示PEG-PHEMA-Lx-(PHEMA-g-PLA)嵌段聚合物具有可控的组成且聚合物分子量分布较窄。在水溶液中PEG-PHEMA-Lx-(PHEMA-g-PLA)形成胶束的粒径在50 -150 nm之间,加入硫辛酸官能团10%的DTT后,稀释和有机溶剂后交联聚合物胶束仍然很稳定,但当加入10mM DTT后,聚合物胶束3h内解交联。更多还原

【Abstract】 In this thesis, the reduction-sensitive reversibly interfacial crosslinked micelle was prepared. By introducing crosslinkably groups, lipoic acid, in between the biodegradable biocompatible PEG-PCL, the micelles can be reversibly crosslinked in the interface of the micelles as catalyzed by DTT. Thus crosslinked micelles demonstrated markedly enhanced stability, while they dissociated in mimicking intracellular reductive environment.(1) In the first part, the block polymer of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) containing two lipoyl functional groups at their interface (PEG-L2-PCL) was synthesized. 1H NMR and gel permeation chromatography (GPC) measurements shows that PEG-L2-PCL block copolymer had a controlled composition and a polydispersity index (PDI) of 1.36. PEG-L2-PCL formed micelles with sizes ranging from 20 to 150 nm in aqueous solutions, wherein a critical micelle concentration (CMC) of 16 mg/L was determined. The micelles were readily crosslinked by adding 7.6 mol.% dithiothreitol (DTT) relative to lipoyl groups. Notably, micelles after crosslinking demonstrated markedly enhanced stability against dilution, physiological salt concentration and organic solvent. In the presence of 10 mM DTT, however, micelles were subject to rapid de-crosslinking. In vitro release studies showed minimal release of DOX from crosslinked micelles at a concentration of 10 mg/L (C < CMC), wherein less than 15 % DOX was released in 10 h. In contrast, rapid release of DOX was observed for DOX-loaded non-crosslinked micelles under otherwise the same conditions (ca. 80 % release in 0.5 h). In the presence of 10 mM DTT mimicking intracellular reductive environment, sustained release of DOX from crosslinked micelles was achieved, in which 75 % DOX was released in 9 h. (2) In the second part, the block polymer of poly(ethylene glycol)-poly(2-Hydroxyethyl methacrylate)-poly(2-Hydroxyethyl methacrylate- g - polylactide) (PEG-PHEMA-P(HEMA-g-PLA)11 containing two lipoyl functional groups on the side chain (PEG-PHEMA-Lx-P(HEMA-g-PLA)11) was synthesized. 1H NMR and GPC measurements showed that PEG-PHEMA-P(HEMA-g-PLA) block copolymer had a controlled composition and a polydispersity index (PDI) of 1.12. PEG-PHEMA-Lx-P(HEMA-g-PLA)11 formed micelles with sizes ranging from 50 to 150 nm in aqueous solutions. The micelles were readily crosslinked by adding 10 mol.% dithiothreitol (DTT) relative to lipoyl groups. Notably, micelles after crosslinking demonstrated markedly enhanced stability against dilution and organic solvent. In the presence of 10 mM DTT mimicking intracellular reductive environment, the micelles de- crosslinked in 3h.更多还原