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.

中文翻译：

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电子接受胶束消耗减少烟酰胺腺嘌呤二核苷酸磷酸和损害两个抗氧化级联的肥大病诱发的肿瘤根除。

各种细胞内抗氧化剂，尤其是谷胱甘肽和硫氧还蛋白，已经损害了促肥性抗肿瘤治疗。两者都是谷胱甘肽过氧化物4（GPX4）的辅因子，它们通过催化脂质过氧化物的还原而抗氧化应激。据推测，定制的聚合物胶束可以通过在缺氧条件下减少谷胱甘肽和硫氧还蛋白。目的是设计低氧反应性胶束，以选择性增强实体瘤中肥大细胞的死亡。该聚合物包含亲水性聚乙二醇（PEG），该亲水性聚乙二醇通过偶氮苯接头与硝基咪唑共轭的多肽相连。定制的聚合物可以自组装成纳米级胶束，以封装RAS选择性致死小分子3（共价GPX4抑制剂）。在缺氧条件下，偶氮苯部分使PEG脱落并增强了4T1细胞中的胶束摄取。同样，用减少的烟酰胺腺嘌呤二核苷酸磷酸酯（NADPH）作为辅因子，过表达的硝基还原酶会还原硝基咪唑部分，从而导致NADPH的瞬时消耗。这损害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。进一步验证了铁质胶束在消耗NADPH，谷胱甘肽和硫氧还蛋白方面的选择性效能在体内在4T1肿瘤异种移植物的小鼠模型。这项工作强调了缺氧反应性聚合物在增强肥大细胞诱导剂抵抗实体瘤的效力方面的作用，而对健康器官没有其他副作用。