Ferroptosis is an iron-dependent, non-apoptotic cell death induced by an overload of iron initiated through Fenton and Haber–Weiss reactions. These two reactions lead to lethal levels of intracellular reactive oxygen species (ROS) and lipid peroxidation. In contrast, glutathione (GSH) and glutathione peroxidase 4 (GPX4) suppress ferroptosis by inhibiting lipid peroxidation. Herein, the ferric ion (Fe³⁺) carriers, poly(glycerol sebacate dithiodiglycolate) nanoparticles (PGSDTG NPs), were prepared via nanoprecipitation. The GSH/pH-dual sensitive Fe³⁺/PGSDTG NPs would disintegrate via the cleavage of disulfide and ester bonds in the presence of GSH and acidic conditions. The cleaved polymer segments along with released Fe³⁺ rendered cancer cells showing ferroptosis characteristics including ROS production, transferrin receptor 1 (TfR1) expression, and iron accumulation after treatment with Fe³⁺/PGSDTG NPs. The PGSDTG NPs played an important role in ferroptosis by triggering the oxidation of intracellular GSH and reducing the GPX4 expression. An in vivo experiment also showed that Caenorhabditis elegans (C. elegans) exhibited a shortened lifespan after treatment with NPs. These results indicated that the PGSDTG NPs were potential GSH/pH-sensitive metal ion carriers for anticancer treatment by inducing ferroptosis.

中文翻译：

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GSH/pH 敏感聚（癸二酸二硫代二甘醇酸甘油酯）纳米粒子通过与 Fe3+ 配合作为铁死亡诱导剂

铁死亡是一种铁依赖性、非凋亡性细胞死亡，由芬顿反应和哈伯-韦斯反应引发的铁过载引起。这两种反应导致细胞内活性氧 (ROS) 和脂质过氧化达到致命水平。相反，谷胱甘肽 (GSH) 和谷胱甘肽过氧化物酶 4 (GPX4) 通过抑制脂质过氧化来抑制铁死亡。在此，通过纳米沉淀制备了三价铁离子（Fe ^{3+ ）载体，聚（癸二酸二硫代二甘醇酸甘油酯）纳米颗粒（PGSDTG NPs）。}GSH/pH 双敏感 Fe ³⁺ /PGSDTG NP 在 GSH 和酸性条件下会通过二硫键和酯键的裂解而分解。裂解的聚合物片段与释放的 Fe ³⁺一起使癌细胞表现出铁死亡特征，包括 ROS 产生、转铁蛋白受体 1 (TfR1) 表达以及用 Fe ³⁺ /PGSDTG NP 处理后的铁积累。PGSDTG NPs 通过触发细胞内 GSH 氧化并减少 GPX4 表达，在铁死亡中发挥重要作用。体内实验还表明，使用 NP 处理后，秀丽隐杆线虫( C. elegans ) 的寿命缩短。这些结果表明，PGSDTG NPs 是潜在的 GSH/pH 敏感金属离子载体，可通过诱导铁死亡进行抗癌治疗。