Zhang Wen-Xin, Li You, Ke Di, Gao Yi-Ru, Fei Teng, Wang Guo-Qing, Shu Yang, Wang Jian-Hua
Department of Chemistry, College of Sciences, Northeastern University, Box 332, Shenyang 110819, China.
College of Life and Health Sciences, Northeastern University, Shenyang 110819, China.
Biomater Sci. 2023 Oct 10;11(20):6906-6918. doi: 10.1039/d3bm01000g.
Ferroptosis is a non-apoptotic form of regulated cell death. The efficiency of ferroptosis is restrained in the tumor microenvironment (TME) by overexpression of glutathione (GSH) and insufficient production of hydrogen peroxide (HO). In this work, theranostic nanoparticles Ce-aMOFs@Fe-EGCG, termed MEFs, are developed by coating uniform Ce-based amorphous metal-organic frameworks (Ce-aMOFs) with epigallocatechin gallate (EGCG) and Fe. Fe is chelated by the adjacent phenol hydroxyl groups in EGCG. In the tumor cell interior, overexpressed GSH and weak acidic medium degrade the coating to release Fe and EGCG accompanied by exposure of Ce-aMOFs. Fe and EGCG consume GSH along with turning Fe into Fe. Ce-aMOFs act as a nanozyme possessing dual-enzymatic activities, superoxide dismutase (SOD)- and phosphatase-like activities. In the TME, Ce-aMOFs catalyze the conversion of endogenous superoxide (O˙) into HO, and Fe catalyzes HO to generate toxic hydroxyl radicals (˙OH), which may further induce tumor cell death through ferroptosis. In addition, the phosphatase-like activity of Ce-aMOFs may sustainably dephosphorylate NADPH and effectively inhibit intracellular biosynthesis of GSH. Therefore, MEFs ensure down-regulation of intracellular GSH levels and up-regulation of oxidative pressure, which enhance the ferroptosis effect.
铁死亡是一种非凋亡形式的程序性细胞死亡。在肿瘤微环境（TME）中，谷胱甘肽（GSH）的过度表达和过氧化氢（HO）的产生不足会抑制铁死亡的效率。在这项工作中，通过用表没食子儿茶素没食子酸酯（EGCG）和铁包覆均匀的铈基非晶态金属有机框架（Ce-aMOFs），开发了一种可用于诊断和治疗的纳米颗粒Ce-aMOFs@Fe-EGCG，称为MEFs。铁被EGCG中相邻的酚羟基螯合。在肿瘤细胞内部，过表达的GSH和弱酸性介质会降解包覆层，释放出铁和EGCG，同时Ce-aMOFs暴露出来。铁和EGCG消耗GSH并将铁转化为亚铁。Ce-aMOFs作为一种具有双酶活性的纳米酶，具有超氧化物歧化酶（SOD）和磷酸酶样活性。在TME中，Ce-aMOFs催化内源性超氧化物（O˙）转化为HO，铁催化HO生成有毒的羟基自由基（˙OH），这可能通过铁死亡进一步诱导肿瘤细胞死亡。此外，Ce-aMOFs的磷酸酶样活性可能持续使NADPH去磷酸化，并有效抑制细胞内GSH的生物合成。因此，MEFs可确保细胞内GSH水平下调和氧化压力上调，从而增强铁死亡效应。
