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A strategy of “adding fuel to the flames” enables a self-accelerating cycle of ferroptosis-cuproptosis for potent antitumor therapy

Affiliations
  • 1School of Biomedical Engineering, Southern Medical University, 1023 Sha-Tai South Road, Guangzhou, Guangdong, 510515, China.
  • 2Medical Imaging Center, Nanfang Hospital, Southern Medical University, 1023 Sha-Tai South Road, Guangzhou, Guangdong, 510515, China.
  • 3School of Biomedical Engineering, Southern Medical University, 1023 Sha-Tai South Road, Guangzhou, Guangdong, 510515, China. Electronic address: gzccm@smu.edu.cn.
  • 4Department of Radiology, Zhuhai People’s Hospital, Zhuhai Clinical Medical College of Jinan University, Zhuhai, 519000, China. Electronic address: yuxiangrong@jnu.edu.cn.
  • 5School of Biomedical Engineering, Southern Medical University, 1023 Sha-Tai South Road, Guangzhou, Guangdong, 510515, China. Electronic address: sz@smu.edu.cn.

Published on:

July 9, 2024

Abstract

Cuproptosis in antitumor therapy faces challenges from copper homeostasis efflux mechanisms and high glutathione (GSH) levels in tumor cells, hindering copper accumulation and treatment efficacy. Herein, we propose a strategy of “adding fuel to the flames” for potent antitumor therapy through a self-accelerating cycle of ferroptosis-cuproptosis. Disulfiram (DSF) loaded hollow mesoporous copper-iron sulfide (HMCIS) nanoparticle with conjugation of polyethylene glycol (PEG) and folic acid (FA) (i.e., DSF@HMCIS-PEG-FA) was developed to swiftly release DSF, HS, Cu, and Fe in the acidic tumor microenvironment (TME). The hydrogen peroxide (HO) levels and acidity within tumor cells enhanced by the released HS induce acceleration of Fenton (Fe) and Fenton-like (Cu) reactions, enabling the powerful tumor ferroptosis efficacy. The released DSF acts as a role of “fuel”, intensifying catalytic effect (“flame”) in tumor cells through the sustainable Fenton chemistry (i.e., “add fuel to the flames”). Robust ferroptosis in tumor cells is characterized by serious mitochondrial damage and GSH depletion, leading to excess intracellular copper that triggers cuproptosis. Cuproptosis disrupts mitochondria, compromises iron-sulfur (Fe-S) proteins, and elevates intracellular oxidative stress by releasing free Fe. These interconnected processes form a self-accelerating cycle of ferroptosis-cuproptosis with potent antitumor capabilities, as validated in both cancer cells and tumor-bearing mice.

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