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Triggered ferroptotic polymer micelles for reversing multidrug resistance to chemotherapy

胶束 癌细胞 人口 多重耐药 脂质过氧化 体内 化学 药理学 生物化学 细胞生物学 癌症研究 癌症 生物 氧化应激 医学 遗传学 抗生素 水溶液 生物技术 物理化学 环境卫生
作者
Min Gao,Jian Deng,Fang Liu,Aiping Fan,Yujuan Wang,Hui‐Yuan Wu,Dan Ding,Deling Kong,Zheng Wang,Dan Peer,Yanjun Zhao
出处
期刊:Biomaterials [Elsevier]
卷期号:223: 119486-119486 被引量:168
标识
DOI:10.1016/j.biomaterials.2019.119486
摘要

Drug-tolerant persister cancer cells (PCCs) play an important role in the development of multidrug resistance (MDR) to anti-cancer drugs. This is due to the strong link between PCCs formation and epithelial-mesenchymal transition (EMT), as well as the low numbers of PCCs. In addition, PCC removal by traditional cytotoxic agents is poor due to the intrinsic high MDR activity in these cells. As a novel programmed cell death pathway, ferroptosis shows high potency to eliminate cells at the EMT state via manipulating intracellular redox homeostasis. The aim of this work was to utilize triggered ferroptotic polymer micelles for PCCs removal and MDR reversal both in vitro and in vivo. The micelles were made of arachidonic acid-conjugated amphiphilic copolymer that can enable rapid cargo release upon free radical-triggering in the tumor microenvironment. A potent ferroptotic inducer, RSL3 was encapsulated in the micelles to target the glutathione peroxidase 4 (GPX4). In the model resistant human ovarian adenocarcinoma cells, the RSL3 micelles were 30-fold more toxic than activatable control micelles due to the ferroptotic machinery. The lipid peroxidation-induced intracellular glutathione level reduction also made a contribution, which enhanced the potency of RSL3 for ferroptosis induction and enabled the drug-loaded micelles all-active. As an index of PCCs population, the level of CD133+ and aldehyde dehydrogenase (ALDH+) biomarker was significantly lower for the ferroptotic micelles in contrast to the control. The potency of ferroptotic micelles regarding PCCs reduction was proved by the in vitro soft agar colony forming assay. The in vivo anti-tumor efficacy of triggered micelles was further demonstrated in tumor-bearing nude mice in terms of PCCs biomarkers, tumor growth inhibition, mice survival, and GPX4 inhibition. This work demonstrates a novel strategy to overcome cancer MDR via the tailored ferroptotic micelles, which opens new avenues for managing resistant tumors.
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