State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, P. R. China.
Angew Chem Int Ed Engl. 2022 Nov 25;61(48):e202206074. doi: 10.1002/anie.202206074. Epub 2022 Oct 27.
Lipid peroxides accumulation induced ferroptosis is an effective cell death pathway for cancer therapy. However, the hypoxic condition of tumor microenvironment significantly suppresses the efficacy of ferroptosis. Here, we design a novel nanoplatform to overcome hypoxia-induced ferroptosis resistance. Specifically, we synthesize a novel kind of perfluorocarbon (PFOB)@manganese oxide (MnOx) core-shell nanoparticles (PM-CS NPs). Owing to the good carrier of O as fuel, PM-CS NPs can induce higher level of ROS generation, lipid peroxidation and GSH depletion, as well as lower activity of GPX4, compared with MnOx NPs alone. Moreover, the supplement of O can relieve tumor hypoxia to break down the storage of intracellular lipid droplets and increase expression of ACSL4 (a symbol for ferroptosis sensitivity). Furthermore, upon stimulus of GSH or acidity, PM-CS NPs exhibit the "turn on" F-MRI signal and activatable T /T -MRI contrast for correlating with the release of Mn. Finally, PM-CS NPs exert high cancer inhibition rate for ferroptosis based therapy via synergetic combination of O -mediated enhancement of key pathways of ferroptosis.
脂质过氧化物积累诱导的铁死亡是癌症治疗的一种有效的细胞死亡途径。然而，肿瘤微环境的缺氧条件显著抑制了铁死亡的疗效。在这里，我们设计了一种新的纳米平台来克服缺氧诱导的铁死亡耐药性。具体来说，我们合成了一种新型的全氟碳（PFOB）@氧化锰（MnOx）核壳纳米粒子（PM-CS NPs）。由于 O 作为燃料的良好载体，与单独的 MnOx NPs 相比，PM-CS NPs 可以诱导更高水平的 ROS 生成、脂质过氧化和 GSH 耗竭，以及更低的 GPX4 活性。此外，O 的补充可以缓解肿瘤缺氧，分解细胞内脂质滴的储存，并增加 ACSL4（铁死亡敏感性的标志）的表达。此外，在 GSH 或酸度的刺激下，PM-CS NPs 表现出“开启”F-MRI 信号和可激活的 T/T-MRI 对比，与 Mn 的释放相关。最后，PM-CS NPs 通过 O 介导的铁死亡关键途径的增强协同作用，发挥高的基于铁死亡的癌症抑制率。
