Adjudin-loaded redox-sensitive paclitaxel-prodrug micelles for overcoming multidrug resistance with efficient targeted Colon cancer therapy
Adjudin-loaded redox-sensitive paclitaxel-prodrug micelles for overcoming multidrug resistance with efficient targeted Colon cancer therapy
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DOI：
10.1080/10717544.2020.1797245
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发表时间：
2020-01-01
期刊：
影响因子：
6
通讯作者：
Li, Shiqing
中科院分区：
文献类型：
--
作者：
Chen, Deli;Ge, Sitang;Li, Shiqing
多药耐药（MDR）是结肠癌化疗失败的主要原因。最近的研究表明，化疗药物和线粒体抑制剂的组合可能是一个有前途的策略，以帮助克服MDR。然而，为了使这种方法在临床上有效，重要的是这两种药物可以以最佳比例主动并同时递送到肿瘤细胞中，并在细胞内完全释放药物。为了应对这些挑战，我们设计并制备了一种叶酸受体靶向和氧化还原响应的药物递送系统（FA-ss-P/A），其能够共同递送紫杉醇（PTX）和调节素（ADD）以逆转结肠癌MDR。PTX前药通过二硫键将PTX与糊精缀合而获得。然后，将叶酸（FA）修饰在PTX前药上。最后，将线粒体抑制剂ADD封装在PTX前药形成的胶束中。随后的一系列体内外实验表明，FA-ss-P/A可通过增加细胞摄取、抑制PTX外排和改善药物释放来有效逆转MDR。
Multidrug resistance (MDR) is the primary cause for the failure of chemotherapy in the treatment of colon cancer. Recent research has indicated that the combination of a chemotherapeutic agent and a mitochondrial inhibitor might represent a promising strategy to help overcome MDR. However, for this approach to be clinically effective, it is important that the two drugs can be actively and simultaneously delivered into tumor cells at an optimal ratio and completely released drug within cells. To address these challenges, we designed and prepared a folate receptor-targeted and redox-responsive drug delivery system (FA-ss-P/A) that was able to co-deliver paclitaxel (PTX) and adjudin (ADD) to reverse colon cancer MDR. The PTX prodrug was obtained by conjugating PTX to dextrin via a disulfide-linkage. Then, folic acid (FA) was modified on the PTX prodrug. Finally, ADD, a mitochondrial inhibitor, was encapsulated in the PTX prodrug-formed micelles. A series of in vitro and in vivo experiments subsequently demonstrated that FA-ss-P/A can effectively reverse MDR by increasing cell uptake, inhibiting PTX efflux, and improving drug release.