A Mitochondria‐Targeted Ferroptosis Inducer Activated by Glutathione‐Responsive Imaging and Depletion for Triple Negative Breast Cancer Theranostics

作者：Hongbo Gan, Xie Huang, Xi Luo, Jinlin Li, Banghui Mo, Lizhi Cheng, Qiuxia Shu, Zaizhi Du, Hong Tang, Wei Sun, Liting Wang, Shenglin Luo, Songtao Yu · 发表于：Advanced Healthcare Materials · 年份：2023 · DOI：10.1002/adhm.202300220 · 被引用次数：43 · 研究领域：Nanoplatforms for cancer theranostics、Ferroptosis and cancer prognosis、Advanced Nanomaterials in Catalysis

Ferroptosis is a new type of iron-dependent programmed cell death characterized by glutathione (GSH) depletion, selenoprotein glutathione peroxidase 4 (GPX4) inactivation, and lipid peroxides accumulation. Mitochondria, as the main source of intracellular energy supply and reactive oxygen species (ROS) generation, play a central role in oxidative phosphorylation and redox homeostasis. Therefore, targeting cancer-cell mitochondria and attacking redox homeostasis is expected to induce robust ferroptosis-mediated anticancer effects. In this work, a theranostic ferroptosis inducer (IR780-SPhF), which can simultaneously achieve the imaging and therapy of triple-negative breast cancer (TNBC) by targeting mitochondria is presented. It is developed from a mitochondria-targeting small molecule (IR780) with cancer-preferential accumulation, enabling it to react with GSH by nucleophilic substitution, resulting in mitochondrial GSH depletion and redox imbalance. More interestingly, IR780-SPhF exhibits GSH-responsive near-infrared fluorescence emission and photoacoustic imaging characteristics, further facilitating diagnosis and treatment with real-time monitoring of TNBC with a highly elevated GSH level. Both in vitro and in vivo results demonstrate that IR780-SPhF exhibits potent anticancer effect, which is significantly stronger than cyclophosphamide, a classic drug commonly recommended for TNBC patients in clinic. Hence, the reported mitochondria-targeted ferroptosis inducer may repre...