Tumor-Specific Expansion of Oxidative Stress by Glutathione Depletion and Use of a Fenton Nanoagent for Enhanced Chemodynamic Therapy

Abstract

Amplifying intracellular oxidative stress effectively destroys cancer cells. In addition, iron-mediated Fenton reaction converts endogenous H₂O₂ to produce hypertoxic hydroxyl radical (^•OH), resulting in irreversible oxidative damage to combat tumor cells. This method is known as chemodynamic therapy (CDT). Overexpressed glutathione (GSH) in tumor cells efficiently scavenges ^•OH, significantly reducing the curative effects of CDT. To overcome this challenge and enhance intracellular oxidative stress, iron oxide nanocarriers loaded with β-lapachone (Lapa) drugs (Fe₃O₄-HSA@Lapa) were constructed and had both Fenton-like agents and GSH depletion properties to amplify intracellular oxidative stress. Release of Lapa selectively increases tumor site-specific generation of H₂O₂ via NAD(P)H: quinone oxidoreductase 1 (NQO1) catalysis. Subsequently, the iron ions released from the ionization of Fe₃O₄ in the acidic environment selectively convert H₂O₂ into highly toxic ^•OH by Fenton reaction, dramatically improving CDT with minimal systemic toxicity due to low NQO1 expression in normal tissues. Meanwhile, released Lapa consumes GSH in the tumor, amplifying oxidative stress and enhancing the efficacy of CDT. Designed Fe₃O₄-HSA@Lapa nanoparticles (NPs) exhibit perfect targeting capability, prolonged blood circulation, and increased tumor accumulation. Furthermore, Fe₃O₄-HSA@Lapa NPs effectively enhance the inhibition of tumor growth and reduce the side effects of anticancer drugs. This work establishes a remarkably enhanced tumor-selective CDT against NQO1-overexpressing tumors by significantly inducing intratumoral oxidative stress with minimal side effects.