Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China; Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, 750004, China.
The Affiliated Tumor Hospital of General Hospital of Ningxia Medical University, Yinchuan, 750004, China.
Colloids Surf B Biointerfaces. 2018 Oct 1;170:330-340. doi: 10.1016/j.colsurfb.2018.06.024. Epub 2018 Jun 18.
The drug efflux mediated by P-glycoprotein (P-gp) transporter is a major factor responsible for multidrug resistance (MDR) of paclitaxel (PTX). The efficient intracellular PTX delivery is a promising strategy for overcoming the MDR of tumor cells. A CD44 receptor targeting and endosome-pH sensitive dual functionalized hyaluronic acid-deoxycholic acid-histidine (HA-DOCA-His) micellar formulation was developed to overcome MDR, and a CD44 receptor targeting hyaluronic acid-deoxycholic acid (HA-DOCA) micelles was used as a comparison. Compared with Taxol solution and HA-DOCA micelles, the cytotoxicity of PTX loaded in HA-DOCA-His micelles against drug-resistant tumor cells was improved significantly and possessed superior MDR-overcoming performance; this phenomenon is due to the increased intracellular PTX delivery by CD44 receptor-mediated endocytosis pathway and endosome-pH sensitivity-mediated PTX triggering release. Upon pharmacokinetic study, PTX/HA-DOCA-His micelles demonstrated longer blood circulation time, larger AUC, decreased V and CL than the Taxol solution. More importantly, PTX/HA-DOCA-His micelles were more effective in tumor growth inhibition in MCF-7/Adr tumor-bearing mice compared with PTX/HA-DOCA micelles and Taxol solution. Dual targeting strategy-functionalized HA-DOCA-His micelles demonstrated excellent MDR-reversing ability for therapeutic efficacy and improvement on MDR tumors, thereby providing an effective targeting strategy for PTX delivery of nano-drug delivery system in MDR cancer chemotherapy.
P-糖蛋白（P-gp）转运介导的药物外排是导致紫杉醇（PTX）多药耐药（MDR）的主要因素。有效的细胞内 PTX 递药是克服肿瘤细胞 MDR 的一种有前途的策略。本研究设计了一种靶向 CD44 受体且具有内体- pH 敏感双重功能的透明质酸-去氧胆酸-组氨酸（HA-DOCA-His）胶束制剂，以克服 MDR，并使用靶向 CD44 受体的透明质酸-去氧胆酸（HA-DOCA）胶束作为对照。与紫杉醇溶液和 HA-DOCA 胶束相比，载 PTX 的 HA-DOCA-His 胶束对耐药肿瘤细胞的细胞毒性显著提高，且具有优越的 MDR 逆转性能；这一现象归因于通过 CD44 受体介导的内吞途径和内体-pH 敏感介导的 PTX 触发释放增加了细胞内 PTX 的递送。药代动力学研究表明，PTX/HA-DOCA-His 胶束的血液循环时间更长、AUC 更大、V 和 CL 更小，优于紫杉醇溶液。更重要的是，与 PTX/HA-DOCA 胶束和紫杉醇溶液相比，PTX/HA-DOCA-His 胶束在 MCF-7/Adr 荷瘤小鼠中更有效地抑制肿瘤生长。靶向双重功能化的 HA-DOCA-His 胶束在提高治疗效果和改善 MDR 肿瘤方面表现出优异的 MDR 逆转能力，从而为 MDR 癌症化疗中纳米药物递送系统的 PTX 递送提供了一种有效的靶向策略。
