聚乙二醇1000维生素E琥珀酸酯-米托蒽醌前药胶束的制备及其抗肿瘤活性  

Preparation and antitumor activity of mitoxantrone conjugated D-α-tocopherylpolyethylene glycol 1000 succinate prodrug micelle

作　　者：高雅晗 平其能[1] 宗莉[2] 

机构地区：[1]中国药科大学天然药物活性组分与药效国家重点实验室,南京210009 [2]中国药科大学药剂学教研室,南京210009

出　　处：《中国药科大学学报》2016年第3期311-316,共6页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.81273467)~~

摘　　要：为了提高化疗药物的抗肿瘤疗效,将米托蒽醌(MTO)与聚乙二醇1000维生素E琥珀酸酯(TPGS)通过丁二酸连接臂化学键合形成前体药物(TPGS-MTO)。该前药在水中能够自组装形成胶束,HPLC测定MTO的载药量为(18.61±0.24)%;粒径电位仪测得的胶束粒径为(25.61±0.92)nm,多分散指数PDI为0.22±0.04,Zeta电位为-(3.98±0.09)m V;透射电镜(TEM)显示胶束为均匀的类球形结构;体外生理环境下24 h内粒径无明显变化;体外研究显示胶束在生理条件下无突释现象,24 h释放量为9.04%,随着p H降低,释放速率加快;细胞摄取实验表明,TPGS-MTO胶束可有效促进MCF-7细胞对药物的摄取,6 h的摄取量较MTO溶液提高1.18倍。MTT法结果显示,胶束对乳腺癌细胞MCF-7和MCF-7/MDR均具有明显的抗肿瘤作用,尤其对耐药株细胞,TPGS-MTO表现出优于MTO的抑制效果。TPGS-MTO有望开发为一种水溶性抗肿瘤前药制剂,提高其抗肿瘤活性。To improve the theraputic effect of chemotherapeutic drugs, D-α-tocopheryl polyethylene glycol 1000 succinate（TPGS）was employed as a carrier of mitoxantrone（MTO）. MTO was successfully conjugated to TPGS via succinic anhydride to prepare TPGS-MTO prodrug. The prodrug was then self-assembled into TPGS-MTO micelle, with the particle size of（25. 61±0. 92）nm, the polydispersity of 0. 22±0. 04 and the Zeta potential of -（3. 98±0. 09）mV. The micelle was homogeneous spheres under the observation of transmission electron microscope（TEM）. The drug loading capacity（DLC）was（18. 61±0. 24）% by HPLC. Meanwhile, the particle size of TPGS-MTO micelle remained stable in 24 h. TPGS-MTO showed a controlled drug release profile with only 9. 04% MTO being detected in 24 h in neutral conditions, and faster release was achieved by decreasing pH in media. Cellular uptake experiments showed that micelle was 1. 18 times more effective than parent drug after 6 h incubation on MCF-7 cells. The cytotoxicity of micelle on MCF-7 and MCF-7/MDR cells was detected by MTT, both with anti-tumor activity, especially on MCF-7/MDR cells. In conclusion, TPGS-MTO prodrug micelle could be a potential formulation of higher therapeutic effects and fewer side-effects than MTO itself.

关 键 词：聚乙二醇1000维生素E琥珀酸酯 米托蒽醌 前药 胶束 抗肿瘤 

分 类 号：R943[医药卫生—药剂学]