A redox-triggered C-centered free radicals nanogenerator for self-enhanced magnetic resonance imaging and chemodynamic therapy

Abstract

Current chemodynamic therapy (CDT) has been restricted by the requirement of strongly acidic conditions, insufficient endogenous H₂O₂ and upregulated cellular antioxidant defense. To overcome these obstacles, the carrier-free Fe(III)-ART nanoparticle is developed via coordination driven self-assembly of Fe³⁺ and hydrolyzed ART and evaluated as a redox-triggered C-centered free radicals nanogenerator for self-enhanced magnetic resonance imaging and chemodynamic therapy. The carrier-free Fe(III)-ART NPs can be triggered by intracellular GSH to release ART and Fe³⁺, which is further reduced to Fe²⁺ that catalyzed the endoperoxide of ART to generate C-centered free radicals. Notably, unlike current CDT, such a free radical generation process is without reliance on pH or endogenous H₂O₂. Meanwhile, the concurrent GSH depletion can diminish the antioxidation of tumors and enhance CDT. The C-centered free radicals-mediated apoptosis and GSH depletion-induced ferrotosis act in synergy, leading to potent tumor growth inhibition and superior anticancer efficacy in vitro and in vivo. Moreover, Fe(III)-ART NPs exhibit redox-triggered T₂ relaxivity and contribute to activatable MRI-guided CDT. The development of biodegradable Fe(III)-ART NPs with superior anticancer efficacy, favorable pharmacokinetics and good biocompatibility provides a promising strategy to break through the bottlenecks of traditional CDT and greatly promotes the development of next-generation cancer theranostics.

Keywords: Artemisinin; C-centered free radicals; Fenton reaction; Ferroptosis; Glutathione.