Department of Chemistry, Shanghai Stomatological Hospital & School of Stomatology, State Key Laboratory of Molecular Engineering of Polymers, iChem, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, School of Chemistry and Materials, Fudan University, Shanghai 200433, P. R. China.
Nano Lett. 2024 Jan 31;24(4):1284-1293. doi: 10.1021/acs.nanolett.3c04293. Epub 2024 Jan 17.
Despite its effectiveness in eliminating cancer cells, ferroptosis is hindered by the high natural antioxidant glutathione (GSH) levels in the tumor microenvironment. Herein, we developed a spatially asymmetric nanoparticle, FeO@DMS&PDA@MnO-SRF, for enhanced ferroptosis. It consists of two subunits: FeO nanoparticles coated with dendritic mesoporous silica (DMS) and PDA@MnO (PDA: polydopamine) loaded with sorafenib (SRF). The spatial isolation of the FeO@DMS and PDA@MnO-SRF subunits enhances the synergistic effect between the GSH-scavengers and ferroptosis-related components. First, the increased exposure of the FeO subunit enhances the Fenton reaction, leading to increased production of reactive oxygen species. Furthermore, the PDA@MnO-SRF subunit effectively depletes GSH, thereby inducing ferroptosis by the inactivation of glutathione-dependent peroxidases 4. Moreover, the SRF blocks Xc transport in tumor cells, augmenting GSH depletion capabilities. The dual GSH depletion of the FeO@DMS&PDA@MnO-SRF significantly weakens the antioxidative system, boosting the chemodynamic performance and leading to increased ferroptosis of tumor cells.
尽管铁死亡在消除癌细胞方面非常有效，但它受到肿瘤微环境中高天然抗氧化剂谷胱甘肽 (GSH) 水平的阻碍。在此，我们开发了一种空间不对称纳米粒子 FeO@DMS&PDA@MnO-SRF，用于增强铁死亡。它由两个亚单位组成：用树枝状介孔硅 (DMS) 和负载索拉非尼 (SRF) 的聚多巴胺 (PDA) 包覆的 FeO 纳米粒子。FeO@DMS 和 PDA@MnO-SRF 亚单位的空间隔离增强了 GSH 清除剂和铁死亡相关成分之间的协同作用。首先，增加的 FeO 亚单位暴露增强了 Fenton 反应，导致活性氧的产生增加。此外，PDA@MnO-SRF 亚单位有效耗尽 GSH，从而通过失活谷胱甘肽依赖性过氧化物酶 4 诱导铁死亡。此外，SRF 阻断肿瘤细胞中的 Xc 转运，增强 GSH 耗竭能力。FeO@DMS&PDA@MnO-SRF 的双重 GSH 耗竭显著削弱了抗氧化系统，增强了化学动力学性能，并导致肿瘤细胞中铁死亡的增加。
