叶酸介导的雷公藤甲素外泌体靶向给药系统抗恶性黑色素瘤体内外评价  

In vitro and in vivo evaluation of folate-mediated triptolide exosome targeted delivery system against malignant melanoma

作　　者：顾永卫 姜良弟 杜月[2,3] 李爱雪 刘继勇 GU Yong-wei;JIANG Liang-di;DU Yue;LI Ai-xue;LIU Ji-yong(Department of Pharmacy,Fudan University Shanghai Cancer Center,Shanghai 200032,China;College of Pharmacy,Shandong University of Traditional Chinese Medicine,Jinan 250355,China;Department of Pharmacy,Children's Hospital Affiliated to Shanghai Jiao Tong University,Shanghai 200062,China)

机构地区：[1]复旦大学附属肿瘤医院药剂科,上海200032 [2]山东中医药大学药学院,山东济南250355 [3]上海交通大学附属儿童医院药学部,上海200062

出　　处：《药学学报》2021年第12期3224-3232,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81873011,82074272);上海市科委优秀学术带头人计划项目(21XD1403400)。

摘　　要：本研究以人恶性黑色素瘤A375细胞来源的外泌体为载体,以肿瘤细胞表面高表达的叶酸受体为靶点,以中药雷公藤甲素为模型药物,制备外泌体靶向给药系统FA-Exo/TPL,并对其体外特性和体内抑瘤效果进行表征和评价。采用梯度离心法收集外泌体,叶酸靶向修饰后包载药物,制备成的FA-Exo/TPL粒径在100 nm左右,呈茶托状双层膜结构,对药物具有较高的包封率和载药量。体外研究显示,FA-Exo/TPL可被黑色素瘤细胞大量摄取,从而增强了药物抑制细胞增殖和促进细胞凋亡的作用。体内实验结果表明,FA-Exo/TPL能有效抑制肿瘤组织的生长,延长荷瘤裸鼠的生存期,且能显著降低药物的系统毒性,起到增效减毒的作用。动物福利和实验过程均遵循复旦大学附属肿瘤医院动物伦理委员会的规定。本研究为雷公藤甲素抗恶性黑色素瘤的制剂学研究提供了新的思路和方法。In this study,exosomes were extracted from human malignant melanoma cell A375.Folic acid(FA)receptor was used as target and triptolide(TPL)was used as model drug to prepare exosome targeted drug delivery system,FA-Exo/TPL.The physicochemical properties and antitumor effect were evaluated in vivo and in vitro.Gradient centrifugation method was applied to collect exosomes.Then,exosome was modified with FA for loading TPL.The particle sizes of the FA-Exo/TPL were about 100 nm with a double-layer membrane structure like a tray.It is characteristic of high encapsulation efficiency and drug loading.In vitro experiments showed that FA-Exo/TPL could be effectively uptaken by A375 cells,thus significantly inhibiting proliferation and promoting apoptosis the cells.In vivo experiment results showed that FA-Exo/TPL could effectively inhibit the growth of tumor tissue,prolong the model mice life cycle,and significantly reduce the systemic toxicity of the free drug,playing a synergistic and toxic role.Animal welfare and experimental procedures follow the regulations of the Animal Ethics Committee of Fudan University Shanghai Cancer Center.This study provides a new strategies and methods for the preparation of TPL against malignant melanoma.

关 键 词：雷公藤甲素 外泌体 叶酸 靶向给药系统 恶性黑色素瘤 

分 类 号：R943[医药卫生—药剂学]