Near Infrared-Activatable Platinum-Decorated Gold Nanostars for Synergistic Photothermal/Ferroptotic Therapy in
Andrea C Del Valle1, Chih-Kuang Yeh1, Yu-Fen Huang1,2
1Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan, 30013, R.O.C.
Abstract:
Ferroptotic cell death results from glutathione peroxidase 4 (GPX4) inactivation and/or glutathione (GSH) depletion. Elevated GSH levels are often found in multidrug-resistant (MDR) tumor cells, reducing their sensitivity to chemotherapeutic drugs and the efficacy of treatment. MDR cells also acquire a dependency on GPX4, reducing their oxidative stress and promoting their survival. Therefore, the depletion of GSH and inactivation of GPX4 has the potential to be a superior treatment strategy for MDR tumors. Platinum-decorated gold nanostars (Pt-AuNS) are presented as a novel metal nanoprodrug for ferroptotic therapy against MDR tumors. Under dark conditions, the synthesized Pt-AuNS exhibit negligible levels of toxicity. Upon exposure of the Pt-AuNS to near-infrared (NIR) light, active metallic (Pt and Au) species are released, subsequently inducing cytotoxicity. The mechanism of action is attributed to GSH depletion and GPX4 inactivation, accumulating lipid hydroperoxides, which in turn leads to ferroptosis. In in vivo xenograft, the MDR cancer model confirmed the NIR light-activation of Pt-AuNS prodrugs, resulting in efficient ferroptotic therapeutic action against MDR tumors without long-term side effects. The findings lay the groundwork for using Pt-AuNS prodrugs responsive to NIR light as ferroptosis-inducing agents in chemo-resistant cancer cells and demonstrate their potential for use in future clinical applications.
Insights
Platinum-decorated gold nanostars (Pt-AuNS) offer a novel ferroptosis therapy for multidrug-resistant (MDR) tumors. NIR light activates Pt-AuNS to deplete glutathione (GSH) and inactivate GPX4, selectively killing resistant cancer cells.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Multidrug-resistant (MDR) tumors exhibit elevated glutathione (GSH) and GPX4 dependency, conferring resistance to chemotherapy.
- Ferroptosis, a cell death pathway triggered by GSH depletion and GPX4 inactivation, presents a potential therapeutic strategy for MDR tumors.
- Targeting ferroptosis offers a novel approach to overcome chemoresistance in cancer treatment.
Purpose of the Study:
- To develop and evaluate platinum-decorated gold nanostars (Pt-AuNS) as a novel nanoprodrug for ferroptosis induction in MDR tumors.
- To investigate the mechanism of action of Pt-AuNS, focusing on GSH depletion and GPX4 inactivation under near-infrared (NIR) light.
- To assess the in vivo efficacy and safety of NIR-activated Pt-AuNS in a preclinical MDR cancer model.
Main Methods:
- Synthesis and characterization of platinum-decorated gold nanostars (Pt-AuNS).
- In vitro assessment of Pt-AuNS cytotoxicity and mechanism of action (GSH depletion, GPX4 inactivation, lipid peroxidation) upon NIR light irradiation.
- In vivo evaluation of Pt-AuNS efficacy in an MDR tumor xenograft model, assessing tumor growth inhibition and potential side effects.
Main Results:
- Pt-AuNS exhibited minimal toxicity in the dark but potent cytotoxicity upon NIR light exposure.
- NIR-activated Pt-AuNS effectively induced ferroptosis by depleting GSH and inactivating GPX4 in MDR cancer cells.
- In vivo studies demonstrated significant suppression of MDR tumor growth with NIR-activated Pt-AuNS, showing good tolerability and no long-term side effects.
Conclusions:
- NIR light-activated Pt-AuNS serve as an effective ferroptosis-inducing nanoprodrug against MDR tumors.
- The developed Pt-AuNS demonstrate a promising therapeutic strategy for overcoming chemoresistance by targeting ferroptosis.
- Pt-AuNS hold potential for future clinical applications in treating drug-resistant cancers.
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