A novel type of functional epirubicin liposomes modified with DSPE-PEG_(2000)-cyclopamine conjugate for eliminating heterogeneous breast cancer cells  

环巴胺-磷脂共聚物修饰的功能化表阿霉素脂质体及其在异质性乳腺癌中的体外治疗效应（英文）

作　　者：胡英杰[1] 张靖莹 刘磊[1] 阎妍[1] 沐黎敏 白婧[1] 吴佳栓 吕万良[1] 

机构地区：[1]北京大学医学部药学院天然药物及仿生药物国家重点实验室分子药剂学与新释药系统北京市重点实验室,北京100191

出　　处：《Journal of Chinese Pharmaceutical Sciences》2017年第4期255-264,共10页中国药学（英文版）

基　　金：National Basic Research Program of China(973 Program,Grant No.2013CB932501);the National Science Foundation of China(Grant No.81373343,81673367)

摘　　要：Common chemotherapy is unable to eliminate the heterogeneous side population of cancer cells （such as cancer stem-like cells）, resulting in poor prognosis. The heterogeneity of cancer cells causes an extensive multidrug resistance through the aberrantly active Hedgehog （Hh） signaling pathway. Cyclopamine is a chemical compound that can block Hh signaling pathway, and a combination use of cyclopamine with anticancer drug would be beneficial for killing heterogeneous cancer cells. In the present study, we aimed to develop a kind type of fimctional drug liposomes for eliminating heterogeneous cancer, The study was performed on human breast cancer cells. A distearoylphosphoethanolamine polyethylene glycol （DSPE-PEG2000）-cyclopamine conjugate was newly synthesized by a nucleophilic substitution reaction, and confirmed by MALDI-TOF mass. An HPLC method was established and validated for qualification of epirubicin. Functional epimbicin liposomes were successful constructed by modifying with DSPE-PEG2o00-cyclopamine, displaying a particle size in nano-scale （approximately 98 nm） and a high epirubicin encapsulation （〉97%）. The CD44＋/CD24-side population was characterized in defining heterogeneous breast cancer cells. As compared with regular epirubicin liposomes, fimctional epirubicin liposomes exhibited an evidently enhanced cellular drug uptake and a significant killing effect in overall breast cancer cells. In conclusion, the functional epirubicin liposomes could be a useful drug delivery carrier for eliminating heterogeneous breast cancer cells.普通化学药物治疗难以根除具有耐药性的异质性侧群癌细胞,因而临床预后效果不理想。异质性侧群癌细胞是导致多药耐药性的主要原因之一,其耐药性与相关信号通路如Hedgehog(Hh)通路的异常激活有关。环巴胺是一种可阻断Hh通路的化合物,其联合应用抗癌药可望有效增强对异质性癌细胞的杀伤效果。本研究旨在构建一种可杀伤异质性癌细胞的环巴胺-磷脂共聚物修饰的功能化载药脂质体。研究主要以人乳腺细胞为评价模型。研究结果显示,通过亲核替换法合成了一种新的功能材料二硬磷脂酰乙醇胺-聚乙二醇-环巴胺(DSPE-PEG_(2000)-cyclopamine)共聚物,经基质辅助激光解析电离飞行时间质谱(MALDI-TOF-MS)测定,证实了合成结果;为了对新制剂进行定量,建立了表阿霉素高效液相色谱法,并对方法学进行了有效性验证;采用新合成的功能性材料对脂质体膜进行修饰,制备了功能性表阿霉素脂质体,其粒径为98 nm,在脂质体中阿霉素的包封率>97%;采用CD44+/CD24-癌细胞表型免疫标记方法,对人乳腺癌MCF-7细胞的异质性进行了表征;与普通表阿霉素脂质体相比,功能性表阿霉素脂质体显著增强了药物在异质性乳腺癌细胞中的摄取效应以及杀伤效应。因此,构建的功能性脂质体为异质性乳腺癌细胞的根除提供了一种可选择的新策略。

关 键 词：Cyclopamine conjugate Epirubin Liposomes HETEROGENEITY Breast cancer 

分 类 号：R943[医药卫生—药剂学]