叶酸介导的普鲁兰多糖-阿霉素聚合物前药的制备及生物学性能初探

目的：制备叶酸介导的普兰多糖-阿霉素聚合物前药（FA-MP-DOX）,实现阿霉素药物的靶向控制释放。方法：将普鲁兰多糖用马来酸酐进行修饰后,通过酰胺键键合阿霉素制备得到普鲁兰多糖-阿霉素（MP-DOX）,继而酯键键合叶酸制备得到叶酸介导的普鲁兰多糖-阿霉素聚合物前药（FA-MP-DOX）。红外光谱、核磁共振光谱表征聚合物药物的结构,动态透析法模拟体外释药特性,监测不同pH值聚合物药物中阿霉素的释药特性,同时采用人口腔表皮样癌细胞（KB细胞）测定聚合物药物体系的细胞毒性。结果：①经核磁共振表征FA-MP-DOX聚合物合成完成。②在pH2.5、pH5.0及pH7.4的PBS缓冲体系16h中,阿霉素药物累积释放率分别为49.1%,30.3%和15.3%,证实FA-MP-DOX中阿霉素的释放具有pH依赖性。③细胞实验证实FA-MP-DOX的细胞毒性高于阿霉素和MP-DOX。结论：FA-MP-DOX聚合物药物有望成为阿霉素智能型控释和靶向性药物载体。

Prodrug of Folate-mediated Pullulan - doxorubicin Polymer： Preparation, Characterization and Biological Evaluation

Objective： To prepare A novel folate-decorated maleilated pullulan-doxorubicin conjugate （abbreviated as FA-MP-DOX） for targeted releasing. Methods： The structure of this conjugate was confirmed by 1H-NMR. Furthermore, the conjugation efficiency, drug release property and stability of the conjugate were determined. The cellular uptake and cytotoxicity were assessed by using human oral epidermoid carcinoma KB cells as in vitro cell model. Results： ① The conjugates were preparated successfully. ② In vitro DOX release from FA-MP-DOX conjugate occurred at a faster rate at acidic pH compared with neutral pH （7.4）. the released free DOX after 16 h of incubation at pH 2.5, 5.0 and 7.4 was 49.1%, 30.3% and 15.3%, respectively. ③The FA-MP-DOX conjugates were much more toxic against KB cells, compared with either free DOX or MP-DOX conjugate（P0.05）. Conclusion： FA-MP-DOX conjugate could be used as a promising doxorubicin carrier for its targeted and intracellular delivery.