π-π堆叠和化学交联共同作用的聚合物胶束的构建及表征  

Development and characterization ofπ-πstacked and chemical crosslinked polymeric micelles

作　　者：吕晓霖 武颖丽 杨宇 公续金 刘晏娜 姚庆强 LYU Xiaolin;WU Yingli;YANG Yu;GONG Xujin;LIU Yanna;YAO Qingqiang(School of Pharmaceutical Sciences&Institute of Materia Medica,Shandong First Medical University&Shandong Academy of Medical Sciences,Jinan 250117,Shandong,China;NHC Key Laboratory of Biotechnology Drugs(Shandong Academy of Medical Sciences),Jinan 250117,Shandong,China;Key Lab for Rare&Uncommon Diseases of Shandong Province,Jinan 250117,Shandong,China;Jining Medical University,Jining 272067,Shandong,China)

机构地区：[1]山东第一医科大学药学院(药物研究所),山东济南250117 [2]国家卫生健康委生物技术药物重点实验室(山东省医学科学院),山东济南250117 [3]山东省罕见病重点实验室,山东济南250117 [4]济宁医学院,山东济宁272067

出　　处：《山东大学学报（医学版）》2023年第9期1-9,共9页Journal of Shandong University:Health Sciences

基　　金：山东省自然科学基金(ZR202103020117);山东第一医科大学学术提升计划(2019LJ003)。

摘　　要：目的合成能实现π-π堆叠和化学交联共同作用的两亲性嵌段共聚物PEG-b-P(TMC-COOH)-b-P(CL-Bz),提高胶束在血液循环中的稳定性以及药物在胶束中的滞留。方法通过含有苄基侧链的碳酸酯单体(TMC-Bz)构建了PEG-b-P(TMC-Bz)嵌段。然后,通过PEG-b-P(TMC-Bz)末端羟基引发使含有苯环侧链的己内酯单体(CL-Bz)开环聚合,生成PEG-b-P(TMC-Bz)-b-P(CL-Bz)。最后,在Pd/C作用下脱去P(TMC-Bz)中的苄基,构建出PEG-b-P(TMC-COOH)-b-P(CL-Bz)。对合成的单体及聚合物进行核磁共振氢谱(^(1)H NMR)及凝胶渗透色谱(GPC)表征。另外,通过动态光散射(DLS)对基于该聚合物制备的(交联)空胶束及载药胶束进行表征,并通过GPC对交联反应时间以及交联剂用量对交联度的影响进行了探索。结果成功合成了PEG-b-P(TMC-COOH)-b-P(CL-Bz)聚合物。用该聚合物制备的交联聚合物胶束粒径较小(~80 nm)且均一,而且对紫杉醇的包封率可以达到90%以上。基于聚合物中活化的羧基和交联剂胱胺二盐酸盐中的氨基的交联反应在12 h之内结束,且交联程度随着交联剂用量的增大而增大。结论成功构建了能实现π-π堆叠和化学交联共同作用的PEG-b-P(TMC-COOH)-b-P(CL-Bz)聚合物胶束给药系统。Objective To improve the stability of micelles in blood circulation and the retention of drugs in micelles by synthesizing amphiphilic block copolymer PEG-b-P(TMC-COOH)-b-P(CL-Bz).Methods PEG-b-P(TMC-Bz)block was firstly synthesized by carbonate monomers(TMC-Bz)containing benzyl side chains.Then,PEG-b-P(TMC-Bz)-b-P(CL-Bz)containing benzyl side chains was synthesized using hydroxyl end groups of PEG-b-P(TMC-Bz)as initiator.Finally,the benzyl group in P(TMC-Bz)was removed under Pd/C to obtain PEG-b-P(TMC-COOH)-b-P(CL-Bz).The synthesized monomers and polymers were characterized by nuclear magnetic resonance hydrogen spectroscopy(^(1)H NMR)and gel permeation chromatography(GPC).In addition,the empty and drug-loaded crosslinked micelles prepared by the resulting polymer were characterized by dynamic light scattering(DLS),and the effects of crosslinking reaction time and the amount of crosslinking agent on crosslinking degree were explored by GPC.Results PEG-b-P(TMC-COOH)-b-P(CL-Bz)polymer was successfully synthesized.The crosslinked polymer micelles prepared had a small and uniform particle size(about 80 nm),and the loading efficiency of paclitaxel in the micelles reached more than 90%.The crosslinking reaction based on the activated carboxyl group in the polymer and the amino group in the crosslinker cystamine dihydrochloride ended within 12 h,and the degree of crosslinking increased with the increase of the amount of crosslinker.Conclusion The PEG-b-P(TMC-COOH)-b-P(CL-Bz)polymeric micelles as a drug delivery system were successfully developed,which can realize the interaction ofπ-πstacking and chemical crosslinking.

关 键 词：聚合物合成 开环聚合 化学交联 Π-Π堆积 聚合物胶束 

分 类 号：R94[医药卫生—药剂学]