A Mitochondria-Targeted Ferroptosis Inducer Activated by Glutathione-Responsive Imaging and Depletion for Triple Negative Breast Cancer Theranostics.
Advanced healthcare materials(2023)
Abstract
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 effect. In this work, we present a theranostic ferroptosis inducer (IR780-SPhF), which can simultaneously achieve the imaging and therapy of triple-negative breast cancer (TNBC) by targeting mitochondria. It is developed from a mitochondria-targeting small molecule (IR780) with cancer-preferential accumulation, enables 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 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 (CTX), a classic drug commonly recommended for TNBC patients in clinic. Hence, our reported mitochondria-targeted ferroptosis inducer may represent a promising candidate and a prospective strategy for efficient cancer treatment. This article is protected by copyright. All rights reserved.
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Key words
breast cancer
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