载阿霉素星型多臂PLGA-PEG嵌段共聚物纳米胶束的构建  

Study on doxoru bicin-loaded star-shaped multi-arm PLGA-PEG-NH2 nanomicelles

作　　者：陈旼旼[1] 赵顺新[2] 金旭[3] 宋存先[1] 张政朴[2] 马桂蕾[1] 

机构地区：[1]中国医学科学院北京协和医学院生物医学工程研究所,天津市生物材料重点实验室,天津300192 [2]南开大学高分子化学研究所,功能高分子材料教育部重点实验室,天津300071 [3]首都医科大学附属北京天坛医院麻醉科,北京100050

出　　处：《国际生物医学工程杂志》2012年第3期146-150,I0002,共6页International Journal of Biomedical Engineering

基　　金：国家自然科学基金资助项目（50873114,50903093）;天津市自然科学基金资助项目（10JCYBJC01700）;北京市自然科学基金资助项目（7102052）

摘　　要：目的 利用星型多臂端氨基聚乙丙交酯/聚乙二醇[4s-（ PLGA-PEG-NH2）]两亲性嵌段共聚物作为载体材料,构建抗肿瘤药物阿霉素纳米胶束载药体系.方法 合成聚合物4s-（ PLGA-PEG-NH2）,通过核磁共振氢谱（1H NMR）和凝胶渗透色谱（GPC）对其组成、结构及相对分子质量进行表征；采用溶剂挥发法制备阿霉素（DOX）聚合物纳米胶束,并通过透射电子显微镜（TEM）、粒径分析仪及荧光分析法对载药纳米胶束进行表征；对阿霉素载药纳米胶束在HeLa细胞中的摄取及细胞毒性进行了初步评价.结果 1H NMR与GPC测定结果表明：合成的共聚物符合设计的4s-（ PLGA-PEG-NH2）结构；能成功物理包埋DOX药物分子在水溶液中自组装成核-壳结构的纳米胶束,载药量约为7.5％,包埋率约为75.2％,Zeta电位为-17.6 mV;体外细胞实验显示：载阿霉素星型4臂聚合物纳米胶束[DOX-loaded 4s-（PLGA-PEG-NH2）micelles]比载阿霉素线性聚合物纳米胶束[DOX-loaded linear-（ PLGA-PEG-PLGA）micelles]可更有效地被HeLa细胞摄取,并对HeLa细胞的毒性更强.结论 4s-（ PLGA-PEG-NH2）阿霉素载药纳米胶束可有效提高HeLa细胞的摄取率以及对HeLa细胞的杀伤率,提示其可作为一类新型的抗肿瘤药物递送载体.Objective To develop doxorubicine-loaded nanomicelles based on a type of novel star- shaped 4-arm PLGA-PEG-NH2 amphiphilic block eopolymers. Methods 4s-（PLGA-PEG-NH2） synthesized by 4s-PLGA and （H2N-PEG-NH2） according to N, N＇-dicyclohexylearbodiimide（DCC） condensation reaction was demonstrated by IH NMR spectroscopy and gel permeation chromatography（GPC）; DOX-loaded 4s-（PLGA-PEG- NH2） nanomieelles were self-assembled by doxorubicin（DOX） and 4s-（PLGA-PEG-NH2） via emulsion-solvent evaporation method and characterized in terms of morphology, particle size and size distribution, drug loading, encapsulation efficacy, cell uptake and cytotoxicity studies. Results 4s-（PLGA-PEG-NH2） were capable of self- assembling into ＂core-shell＂ nanomieelles structure and encapsulating DOX into their hydrophobic cores. The mean size of DOX-loaded 4s-（PLGA-PEG-NH2） was nanometer size; drug loading and encapsulation efficacy were around 7.5% and 75.2%, respectively. Mean surface charge of the mieelles was around -17.6 mV. In vitro cell uptake and eytotoxieity studies indicated that comparing to the DOX-loaded Iinear-（PLGA-PEG-PLGA） nanomicelles, DOX-loaded 4s-（PLGA-PEG-NH2） nanomieelles showed better performance in uptaking by HeLa cells and higher cytotoxicity to cancer cells. Conclusion 4s-（PLGA-PEG-NH2） amphiphilic block eopolymers can be successfully used in encapsulating DOX, self-assembling ＂core-shell＂ nanomicelles in aqueous solvent. Therefore, 4s-（PLGA-PEG-NH2） eopolymers can be considered as a promising drug carrier in effectively carrying hydrophobic drug, improving the efficacy while reducing the side effect.

关 键 词：阿霉素 聚合物纳米胶束 星型多臂聚乙丙交酯/聚乙二醇 两亲性嵌段共聚物 

分 类 号：R318.08[医药卫生—生物医学工程] R979.1[医药卫生—基础医学]