The emerged apoptosis/ferroptosis synergistic platinum-based therapy has attracted a lot of attention but is far from clinic use due to high systemic toxicity. Herein, a series of novel precise carrier-free self-assembled platinum(IV) nanoparticles with lipid regulation effect named FSPNPs (5NPs–8NPs) were constructed via connecting fenofibrate acid (FA) to cisplatin or oxaliplatin-derived platinum(IV)-intermediates with disulfide bonds. FSPNPs can be stimulated by high-glutathione/ascorbic acid and acidity environment to produce an “explosion-like” cascade release process. Cell-activity showed precision of FSPNPs, which accumulated more in tumor cells and inhibited cell proliferation. Especially, 5NPs have higher cell selectivity than cisplatin. FSPNPs downregulated glutathione/glutathione peroxidase 4, increased reactive oxygen species/lipid peroxidation/malondialdehyde, induced DNA damage/S-phase arrest, and regulated p53/Bcl-2/Bax to trigger the apoptosis/ferroptosis hybrid pathway. The released FA and derivates were docked into the peroxisome proliferator-activated receptor α with activating cholesterol metabolism to destroy membrane integrity. FSPNPs also showed good biocompatibility and superior antitumor activity with no observable tissue damage.

中文翻译：

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用于细胞凋亡/铁死亡协同肿瘤治疗的精确无载体 Pt（IV）-纳米炸弹：一种获得良好化疗和低毒性的新有效方法


出现的细胞凋亡/铁死亡协同铂类疗法引起了很多关注，但由于全身毒性高，远未用于临床。在此，通过将非诺贝酸 （FA） 连接到具有二硫键的顺铂或奥沙利铂衍生的铂 （IV） 中间体，构建了一系列具有脂质调节作用的新型精确无载体自组装铂 （IV） 纳米颗粒，命名为 FSPNP （5NPs–8NPs）。FSPNPs 可以受到高谷胱甘肽/抗坏血酸和酸度环境的刺激，产生“爆炸状”级联释放过程。细胞活性显示 FSPNPs 的精确性，FSPNPs 在肿瘤细胞中积累更多并抑制细胞增殖。特别是，5个 NPs 的细胞选择性高于顺铂。FSPNPs 下调谷胱甘肽/谷胱甘肽过氧化物酶 4，增加活性氧/脂质过氧化/丙二醛，诱导 DNA 损伤/S 期阻滞，并调节 p53/Bcl-2/Bax 触发细胞凋亡/铁死亡杂交途径。释放的 FA 和衍生物与过氧化物酶体增殖物激活的受体α对接，激活胆固醇代谢以破坏膜完整性。FSPNPs 还显示出良好的生物相容性和卓越的抗肿瘤活性，没有可观察到的组织损伤。