Engineering Research Center for Biomedical Materials, School of Life Sciences, Anhui University, Anhui Key Laboratory of Modern Biomanufacturing, Hefei, Anhui Province 230601, China.
Engineering Research Center for Biomedical Materials, School of Life Sciences, Anhui University, Anhui Key Laboratory of Modern Biomanufacturing, Hefei, Anhui Province 230601, China.
Eur J Pharm Sci. 2020 Apr 15;146:105275. doi: 10.1016/j.ejps.2020.105275. Epub 2020 Feb 20.
The antitumor activity of doxorubicin (DOX) is often limited owing to the occurrence of multidrug resistance (MDR) during treatment. Herein, we developed hybrid polymeric micelles, which consisted of pluronic F127 as long-circulating helper in blood, and phenylboronic ester-grafted pluronic P123 (PHE) as efflux and detoxification regulator to efficiently deliver DOX and reverse MDR in vivo. Hybrid F127/PHE micelles exhibited higher stability and drug encapsulation (~80%) than simple F127/P123 micelles due to its lower CMC, and displayed in vitro drug release in a hydrogen peroxide (HO)-sensitive manner. Besides, DOX-loaded hybrid micelles (F127/PHE-DOX) possessed higher cell-killing ability and induce more apoptotic in MDR-cells than other groups, which was probably because it not only could greatly increase intracellular drug concentration by inhibiting P-gp mediated drug efflux, but also promote reactive oxygen species (ROS) generation by decreasing glutathione (GSH) levels. Besides, in vivo evaluation indicated that F127/PHE-DOX could well accumulate at tumor regions and exhibit the strongest tumor growth inhibition (TGI 87.87%) accompanied with low side effects. As a result, F127/PHE micelles had great potentials as a platform for anticancer drugs delivery and tumor MDR reversal in clinical application.
多柔比星（DOX）的抗肿瘤活性常因治疗过程中发生多药耐药（MDR）而受到限制。在此，我们开发了一种杂化聚合物胶束，由长循环助溶剂泊洛沙姆 F127 和苯硼酸酯接枝的泊洛沙姆 P123（PHE）组成，可有效在体内递送 DOX 并逆转 MDR。杂化 F127/PHE 胶束由于其较低的 CMC，表现出比简单 F127/P123 胶束更高的稳定性和药物包封率（~80%），并表现出对过氧化氢（HO）敏感的体外药物释放。此外，载 DOX 的杂化胶束（F127/PHE-DOX）在 MDR 细胞中具有更高的细胞杀伤能力和诱导更多的细胞凋亡能力，这可能是因为它不仅可以通过抑制 P-糖蛋白介导的药物外排来大大增加细胞内药物浓度，还可以通过降低谷胱甘肽（GSH）水平来促进活性氧（ROS）的产生。此外，体内评价表明 F127/PHE-DOX 可以很好地在肿瘤部位聚集，并表现出最强的肿瘤生长抑制（TGI 87.87%），同时副作用较低。因此，F127/PHE 胶束具有作为抗癌药物递送和肿瘤 MDR 逆转的平台在临床应用中的巨大潜力。
