Abstract

Ferroptosis is a regulated cell death pathway which depends on iron. Ferroptosis can be induced by limiting intracellular glutathione (GSH) synthesis, or inhibiting the activity of GPX4, or increasing intracellular accumulation of PE-AA-OOH, all of which involve NADPH. Therefore, NADPH depletion, excessive PE-AA-OOH, and GPX4 deficiency are generally considered to be the main characteristics of ferroptosis. In this research, the novel self-assembly nanomicelles modified by maltose ligand (Malt-PEG-Abz@RSL3) with superior nano characteristics were designed and fabricated. Malt-PEG-Abz@RSL3 micelles achieved active targeted drug delivery due to the high expression of glucose transporter (GLUT) and high uptake by HepG2 cells. Maltose-polyethylene glycol broke to release RSL3 for inhibiting GPX4 activity when Malt-PEG-Abz@RSL3 micelles entered the cells. Meanwhile, key coenzyme NADPH that participated in synthesis of GSH and Trx(SH)₂ was depleted by azobenzene moiety, resulting in decreasing GSH and Trx(SH)₂, which dually induced ferroptosis in tumour cells and promoted cell apoptosis.

摘要

铁死亡是一种受调节的细胞死亡途径，它依赖于铁。铁死亡可通过限制细胞内谷胱甘肽 (GSH) 合成，或抑制 GPX4 的活性，或增加 PE-AA-OOH 的细胞内积累来诱导，所有这些都涉及 NADPH。因此，NADPH 耗竭、PE-AA-OOH 过多和 GPX4 缺乏通常被认为是铁死亡的主要特征。本研究设计并制备了具有优异纳米特性的麦芽糖配体（Malt-PEG-Abz@RSL3）修饰的新型自组装纳米胶束。由于葡萄糖转运蛋白 (GLUT) 的高表达和 HepG2 细胞的高摄取，Malt-PEG-Abz@RSL3 胶束实现了主动靶向给药。当 Malt-PEG-Abz@RSL3 胶束进入细胞时，麦芽糖-聚乙二醇破裂释放 RSL3 抑制 GPX4 活性。同时，参与GSH和Trx(SH)合成的关键辅酶NADPH₂被偶氮苯部分耗尽，导致GSH和Trx(SH) ₂降低，从而双重诱导肿瘤细胞的铁死亡并促进细胞凋亡。