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Published on: March 15, 2024
A Mitochondria-Targeted Ferroptosis Inducer Activated by Glutathione-Responsive Imaging and Depletion for Triple
Hongbo Gan1, Xie Huang2, Xi Luo1
1Department of Oncology, Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Chongqing, 400038, China.
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 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 represent a promising candidate and a prospective strategy for efficient cancer treatment.
Insights
A novel theranostic ferroptosis inducer, IR780-SPhF, targets cancer mitochondria to deplete glutathione (GSH) and induce cell death. This approach shows potent anticancer effects against triple-negative breast cancer (TNBC) and enables real-time imaging.
Area of Science:
- Biomedical Engineering
- Oncology
- Nanotechnology
Background:
- Ferroptosis is an iron-dependent programmed cell death pathway involving glutathione (GSH) depletion and lipid peroxidation.
- Mitochondria are crucial for cellular redox homeostasis and are implicated in ferroptosis.
- Triple-negative breast cancer (TNBC) presents a significant therapeutic challenge, often requiring novel treatment strategies.
Purpose of the Study:
- To develop a theranostic agent for simultaneous imaging and therapy of TNBC.
- To investigate mitochondria-targeted ferroptosis induction as an anticancer strategy.
- To create a glutathione (GSH)-responsive agent for real-time monitoring of treatment efficacy.
Main Methods:
- Synthesis of a mitochondria-targeting ferroptosis inducer (IR780-SPhF) from a known mitochondria-targeting molecule (IR780).
- Evaluation of IR780-SPhF's ability to deplete mitochondrial GSH and induce ferroptosis in vitro and in vivo.
- Assessment of IR780-SPhF's near-infrared fluorescence and photoacoustic imaging capabilities.
- Comparison of IR780-SPhF's anticancer efficacy against cyclophosphamide in TNBC models.
Main Results:
- IR780-SPhF effectively targets mitochondria and accumulates preferentially in cancer cells.
- The agent induces mitochondrial GSH depletion and redox imbalance, leading to ferroptosis.
- IR780-SPhF exhibits GSH-responsive fluorescence and photoacoustic imaging properties for real-time TNBC monitoring.
- In vitro and in vivo studies show IR780-SPhF possesses potent anticancer activity superior to cyclophosphamide.
Conclusions:
- IR780-SPhF is a promising theranostic agent for TNBC, leveraging mitochondria-targeted ferroptosis.
- The GSH-responsive imaging capability allows for real-time monitoring of therapeutic response.
- This mitochondria-targeted ferroptosis inducer represents a novel and effective strategy for cancer treatment.
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