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

Amplifying intracellular oxidative stress effectively destroys cancer cells. In addition, iron-mediated Fenton reaction converts endogenous HO 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 (FeO-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 HO via NAD(P)H: quinone oxidoreductase 1 (NQO1) catalysis. Subsequently, the iron ions released from the ionization of FeO in the acidic environment selectively convert HO 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 FeO-HSA@Lapa nanoparticles (NPs) exhibit perfect targeting capability, prolonged blood circulation, and increased tumor accumulation. Furthermore, FeO-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.