School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
Department of Obstetrics and Gynecology, Fengxian Hospital, Southern Medical University, Shanghai 201499, China.
Theranostics. 2019 Aug 12;9(20):5755-5768. doi: 10.7150/thno.36163. eCollection 2019.
Severe multidrug resistance (MDR) often develops in the process of chemotherapy for most small molecule anticancer drugs, which results in clinical chemotherapy failures. Here, a nanodrug is constructed through the self-assembly of amphiphilic drug-inhibitor conjugates (ADIC) containing a redox-responsive linkage for reversing the multidrug resistance (MDR) in cancer treatment. Specifically, hydrophilic anticancer irinotecan (Ir) and hydrophobic P-gp protein inhibitor quinine (Qu) are linked by a redox responsive bridge for overcoming MDR of tumors. Ir-ss-Qu is able to self-assemble into nanoparticles (NPs) in water and shows the longer blood retention half-life compared with that of free Ir or Qu, which facilitates drug accumulation in tumor site. After endocytosis of Ir-ss-Qu NPs by drug-resistant tumor cells, the disulfide bond in the linkage between Ir and Qu is cleaved rapidly induced by glutathione (GSH) to release anticancer drug Ir and inhibitor Qu synchronously. The released Qu can markedly reduce the expression of P-gp in drug-resistant tumor cells and inhibits P-gp to pump Ir out of the cells. The increased concentration of intracellular Ir can effectively improve the therapeutic efficacy. Such redox-responsive Ir-ss-Qu NPs, as a drug delivery system, exhibit very high cytotoxicity and the most effective inhibitory to the growth of drug-resistant breast cancer compared with that of free therapeutic agents and .
严重的多药耐药性（MDR）在大多数小分子抗癌药物的化疗过程中经常发生，导致临床化疗失败。 在这里，通过自组装包含氧化还原响应性连接物的两亲性药物-抑制剂缀合物（ADIC）构建纳米药物，用于逆转癌症治疗中的多药耐药性（MDR）。 具体而言，亲水性抗癌伊立替康（Ir）和疏水性 P-糖蛋白抑制剂奎宁（Qu）通过氧化还原响应桥连接以克服肿瘤的 MDR。 Ir-ss-Qu 能够在水中自组装成纳米颗粒（NPs），与游离的 Ir 或 Qu 相比，具有更长的血液保留半衰期，有利于药物在肿瘤部位积累。 Ir-ss-Qu NPs 被耐药肿瘤细胞内吞后，连接 Ir 和 Qu 之间的二硫键在谷胱甘肽（GSH）的快速诱导下迅速断裂，同步释放抗癌药物 Ir 和抑制剂 Qu。 释放的 Qu 可以显著降低耐药肿瘤细胞中 P-糖蛋白的表达，并抑制 P-糖蛋白将 Ir 泵出细胞。 细胞内 Ir 浓度的增加可以有效提高治疗效果。 作为药物递送系统，这种氧化还原响应性 Ir-ss-Qu NPs 与游离治疗剂相比，对耐药乳腺癌的生长具有非常高的细胞毒性和最有效的抑制作用。
