Electron-Accepting Micelles Deplete Reduced Nicotinamide Adenine Dinucleotide Phosphate and Impair Two Antioxidant Cascades for Ferroptosis-Induced Tumor Eradication
Electron-Accepting Micelles Deplete Reduced Nicotinamide Adenine Dinucleotide Phosphate and Impair Two Antioxidant Cascades for Ferroptosis-Induced Tumor Eradication
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DOI：
10.1021/acsnano.0c00764
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发表时间：
2020-11-24
期刊：
影响因子：
17.1
通讯作者：
Zhao, Yanjun
中科院分区：
文献类型：
--
作者：
Guo, Xuliang;Liu, Fang;Zhao, Yanjun
细胞内抗氧化剂，尤其是谷胱甘肽和硫氧还蛋白，影响了嗜铁性抗肿瘤治疗。两者都是谷胱甘肽过氧化物4 （GPX4）的辅助因子，通过催化脂质过氧化物的减少来对抗氧化应激。推测在缺氧条件下，定制聚合物胶束可通过减少谷胱甘肽和硫氧还蛋白来增强其抗肿瘤作用。目的是设计低氧反应胶束选择性增强实体肿瘤中铁细胞死亡。该聚合物含有亲水性聚乙二醇（PEG），由偶氮苯连接剂与硝基咪唑共轭多肽连接。这种定制的聚合物可以自组装成纳米级胶束，包裹ras选择性致死小分子3（一种共价GPX4抑制剂）。在缺氧条件下，偶氮苯片段使4T1细胞中的PEG脱落并增强胶束摄取。同样，硝基咪唑部分被过表达的硝基还原酶还原，还原的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）作为辅因子，导致NADPH瞬间耗尽。这破坏了谷胱甘肽和硫氧还蛋白的氧化还原循环，导致细胞内谷胱甘肽和硫氧还蛋白减少。在4T1肿瘤异种移植小鼠模型中，进一步验证了紧铁胶束在消耗NADPH、谷胱甘肽和硫氧还蛋白方面的选择性效力。这项工作强调了低氧反应聚合物在增强铁诱导剂对抗实体肿瘤的效力而不对健康器官产生额外副作用方面的作用。
Ferroptotic antitumor therapy has been compromised by various intracellular antioxidants, particularly glutathione and thioredoxin. Both are cofactors of glutathione peroxide 4 (GPX4) that act against oxidative stress via catalyzing the reduction of lipid peroxides. It was postulated that tailored polymer micelles could enhance ferroptotic antitumor efficacy via diminishing glutathione and thioredoxin under hypoxia. The aim was to engineer hypoxia-responsive micelles for selective enhancement of ferroptotic cell death in solid tumor. The polymer contains hydrophilic poly(ethylene glycol) (PEG) that is linked by azobenzene linker with nitroimidazole-conjugated polypeptide. The tailored polymer could self-assemble into nanoscale micelles to encapsulate RAS-selective lethal small molecule 3, a covalent GPX4 inhibitor. Under hypoxia, the azobenzene moiety enabled PEG shedding and enhanced micelles uptake in 4T1 cells. Likewise, the nitroimidazole moiety was reduced by the overexpressed nitroreductase with reduced nicotinamide adenine dinucleotide phosphate (NADPH) as the cofactor, resulting in transient depletion of NADPH. This impaired both the glutathione and thioredoxin redox cycle, leading to diminished intracellular glutathione and thioredoxin. The selective potency of ferroptotic micelles in depleting NADPH, glutathione and thioredoxin was further verified in vivo in the 4T1 tumor xenograft mice model. This work highlights the role of hypoxia-responsive polymers in enhancing the potency of ferroptotic inducers against solid tumors without additional side effects to healthy organs.