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药物诱导的自组装纳米囊泡通过自噬抑制和递送同步逆转多柔比星耐药性。

Drug-induced self-assembled nanovesicles for doxorubicin resistance reversal via autophagy inhibition and delivery synchronism.

机构信息

Ministry of Educational (MOE) Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China.

出版信息

Theranostics. 2022 May 13;12(8):3977-3994. doi: 10.7150/thno.70852. eCollection 2022.

DOI:10.7150/thno.70852
PMID:35664062
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9131275/
Abstract

As a classical autophagy inhibitor, CQ has been supposed to increase the sensitivity of tumors to chemotherapeutics. However, there exists a quite huge gap between laboratory research and clinical application, which is related to the distinct pharmacokinetic behavior of CQ to a great extent. Based on amphiphilic copolymer PPAP, a pH-responsive drug-induced self-assembled nanovesicle, named DC-DIV/C, was constructed to load DOX⋅HCl and CQ. The physicochemical properties of DC-DIV/C were characterized. To validate the cooperative action and delivery synchronism of DOX⋅HCl and CQ, cytotoxicity, apoptosis, cellular uptake and autophagy assay were investigated in DOX⋅HCl resistant cancer cells. The pharmacokinetic character and antitumor effect of DC-DIV/C were evaluated on rats and nude mice bearing xenograft drug-resistant K562/ADR tumors, respectively. DC-DIV/C could simultaneously encapsulate DOX·HCl and CQ at the optimal ratio of 1:2. In vitro and in vivo tests confirmed that DC-DIV/C acted as an excellent vehicle for the synchronous delivery of DOX⋅HCl and CQ during the process of blood circulation, cellular uptake and intracellular release. Furthermore, CQ accomplished autophagy inhibition to reduce the IC of DOX⋅HCl resistant cancer cells. Consequently, DC-DIV/C exhibited the extremely improved anti-tumor effect with 84.52% TIR on K562/ADR tumor. This study provides a promising and powerful strategy to achieve enhanced treatment outcomes for the precise combination therapy.

摘要

作为一种经典的自噬抑制剂，CQ 被认为可以提高肿瘤对化疗药物的敏感性。然而，实验室研究与临床应用之间存在着相当大的差距，这在很大程度上与 CQ 截然不同的药代动力学行为有关。基于两亲性嵌段共聚物 PPAP，构建了一种 pH 响应的药物诱导自组装纳米囊泡，命名为 DC-DIV/C，用于装载 DOX·HCl 和 CQ。对 DC-DIV/C 的理化性质进行了表征。为了验证 DOX·HCl 和 CQ 的协同作用和递药同步性，在 DOX·HCl 耐药癌细胞中进行了细胞毒性、凋亡、细胞摄取和自噬实验。分别在荷瘤耐药 K562/ADR 肿瘤大鼠和裸鼠中评价了 DC-DIV/C 的药代动力学特征和抗肿瘤作用。DC-DIV/C 可以在最佳比例 1:2 同时包载 DOX·HCl 和 CQ。体外和体内实验证实，DC-DIV/C 在血液循环、细胞摄取和细胞内释放过程中是一种同时递运 DOX·HCl 和 CQ 的优秀载体。此外，CQ 完成自噬抑制以降低 DOX·HCl 耐药癌细胞的 IC。因此，DC-DIV/C 对 K562/ADR 肿瘤表现出了极好的抗肿瘤效果，TIR 为 84.52%。本研究为精确联合治疗提供了一种有前途的、强大的策略，以实现治疗效果的增强。

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