Overcoming Multidrug Resistance by Codelivery of MDR1-Targeting siRNA and Doxorubicin Using EphA10-Mediated pH-Sensitive Lipoplexes: In Vitro and In Vivo Evaluation
Overcoming Multidrug Resistance by Codelivery of MDR1-Targeting siRNA and Doxorubicin Using EphA10-Mediated pH-Sensitive Lipoplexes: In Vitro and In Vivo Evaluation
复制标题
使用 EphA10 介导的 pH 敏感脂质复合物同时递送 MDR1 靶向 siRNA 和阿霉素来克服多药耐药性：体外和体内评估
DOI：
10.1021/acsami.8b01806
复制
发表时间：
2018-06-27
影响因子：
9.5
通讯作者：
Zhao, Xiuli
中科院分区：
文献类型：
--
作者：
Zhang, Jiulong;Du, Zhouqi;Zhao, Xiuli
P-糖蛋白（P-gp）过度表达导致的多药耐药（MDR）严重阻碍了化疗的疗效。抗肿瘤药物与siRNA的共递送是近年来克服P-gp相关MDR的有效策略。本研究设计了一种具有pH敏感性和主动靶向性的多功能药物递送系统，成功地将MDR 1-siRNA和DOX负载于其中。所得载体EphA 10抗体偶联的pH敏感性阿霉素（DOX）、MDR 1-siRNA偶联的脂质复合物（简称DOX + siRNA/ePL）具有良好的理化性质，具有较高的血清稳定性。DOX + siRNA/ePL在人乳腺癌细胞系/阿霉素耐药（MCF-7/ADR）细胞中表现出增加的细胞摄取、增强的P-gp下调功效以及更好的细胞毒性。细胞内共定位研究结果表明，DOX + siRNA/ePL具有pH响应性的快速内体逃逸能力，且具有时间依赖性。同时，体内抗肿瘤活性表明，DOX + siRNA/ePL经静脉给药进入血液系统后，可延长循环时间，并通过受体介导的内吞作用在肿瘤细胞中特异性蓄积。组织学研究进一步证实DOX + siRNA/ePL在体内具有抑制细胞增殖、诱导细胞凋亡和下调P-gp表达的作用。因此，DOX + siRNA/ePL有望成为克服MDR效应的合适的共递送系统。
The therapeutic efficacy of chemotherapy is dramatically hindered by multidrug resistance (MDR), which is induced by the overexpression of P-glycoprotein (P-gp). The codelivery of an antitumor drug and siRNA is an effective strategy recently applied in overcoming P-gp-related MDR In this study, a multifunctional drug delivery system with both pH-sensitive feature and active targetability was designed, in which MDR1-siRNA and DOX were successfully loaded. The resulting carrier EphA10 antibody-conjugated pH-sensitive doxorubicin (DOX), MDR1-siRNA coloading lipoplexes (shortened as DOX + siRNA/ePL) with high serum stability had favorable physicochemical properties. DOX + siRNA/ePL exhibited an incremental cellular uptake, enhanced P-gp downregulation efficacy, as well as a better cell cytotoxicity in human breast cancer cell line/adriamycin drug-resistant (MCF-7/ADR) cells. The results of the intracellular colocalization study indicated that DOX + siRNA/ePL possessed the ability for pH-responsive rapid endosomal escape in a time-dependent characteristic. Meanwhile, the in vivo antitumor activities suggested that DOX + siRNA/ePL could prolong the circulation time as well as specifically accumulate in the tumor cells via receptor-mediated endocytosis after intravenous administration into the blood system. The histological study further demonstrated that DOX + siRNA/ePL could inhibit the proliferation, induce apoptosis effect, and downregulate the P-gp expression in vivo. Altogether, DOX + siRNA/ePL was expected to be a suitable codelivery system for overcoming the MDR effect.