pH敏感性的聚离子复合物胶束对化疗药物的共递送

doi:10.6040/j.issn.1671-7554.0.2017.875

摘要/Abstract

摘要： 目的利用pH敏感的聚离子复合物胶束实现紫杉醇(PTX)与阿霉素(DOX)的共递送,并对其进行体内外评价。方法制备普朗尼克F127-壳聚糖(F127-CS)复合物与乌头酸酐-阿霉素(CA-DOX)前药,利用静电作用使其形成F127-CS/CA-DOX聚离子复合物胶束。将上述胶束与普朗尼克P105混合,制备混合胶束,并将难溶性药物PTX包裹在胶束中形成共载药胶束。测量胶束的粒径、载药量、临界胶束浓度。通过体外释放实验、体外细胞实验与体内药效学实验对胶束进行评价。结果成功制备具有pH敏感性的共载药胶束。胶束的平均粒径为179.3 nm,临界胶束浓度为0.039 mg/mL。两种药物的体外释放皆呈pH依赖性。细胞实验显示,胶束中的药物可有效地被细胞摄取。体内药效学实验显示,共载药胶束有较强的抑瘤作用与较低毒性。结论共载药胶束具有pH敏感释放特性且对癌细胞有较强的抑制作用和较低的毒性,是一种具有潜力的共递送给药系统。

关键词: 紫杉醇, 阿霉素, 聚离子复合物胶束, 混合胶束, 共载药, pH敏感性

Abstract: Objective To achieve co-delivery of paclitaxel(PTX)and doxorubicin(DOX)by pH-sensitive polyion complex micelles, and to evaluate its effects in vitro and in vivo. Methods Amphiphilic polyelectrolyte/prodrug micelles were constructed via synergistic electrostatic interactions between slightly positively charged pluronic F127-chitosan copolymer(F127-CS)and negatively charged cis-aconityl-doxorubicin(CA-DOX)prodrug. Mixed micelles were prepared using pluronic P105(P105)and F127-CS/CA-DOX, and poorly water-soluble anticancer drug PTX was incorporated into mixed micelles to realize the co-delivery of DOX and PTX. The particle size of micelles was measured and the critical micelle concentration(CMC)was observed by the pyrene fluorescence probe method. Finally, the characteristics of micelles such as in vitro drug release, in vitro cell uptake and in vivo pharmacodynamics studies were evaluated. Results The pH-sensitive micelles were prepared successfully. The average particle diameter of the micelles was 179.3 nm and the CMC was 0.039 mg/mL. DOX and PTX release from polymeric micelles followed a pH-dependent manner. The results of cell uptake studies exhibited that both DOX and PTX could be delivered into cells by P105/F127-CS/CA-DOX mixed micelles effectively. The in vivo pharmacodynamics studies of drug-loaded P105/F127-CS/CA-DOX micelles showed that the co-delivery micelles had a strong inhibitory effect on tumors with a lower toxicity. Conclusion The co-delivery micelles are pH-sensitive and have a strong inhibitory effect on cancer with a lower toxicity on normal tissues; it is potential for co-delivery of PTX and DOX.

Key words: Paclitaxel, Doxorubicin, Polyion complex micelles, Mixed micelles, Co-delivery, pH-sensitivity

中图分类号:

R944.9

朱艺馨,范晓慧,陈颜,李凌冰. pH敏感性的聚离子复合物胶束对化疗药物的共递送[J]. 山东大学学报 (医学版), 2018, 56(6): 21-28.

ZHU Yixin, FAN Xiaohui, CHEN Yan, LI Lingbing. Cooperative pH-sensitivity polyion complex micelles for co-delivery of doxorubicin and paclitaxel[J]. Journal of Shandong University (Health Sciences), 2018, 56(6): 21-28.

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