Glutathione-Responsive Chemodynamic Therapy of Manganese(III/IV) Cluster Nanoparticles Enhanced by Electrochemical Stimulation via Oxidative Stress Pathway

Escalating the level of reactive oxygen species (ROS) in a tumor microenvironment is one of the effective strategies to improve the efficacy of anticancer therapy. In this work, manganese cluster nanoparticles (Mn12) encapsulated with heparin (Mn12-heparin) were developed as a chemodynamic therapeutic agent for cancer treatment by raising ROS levels in tumor cells via cascade reactions. The manganese cluster is a cluster of mixed valence (III/IV) with acetate as the ligand. The cluster is readily subject to reduction by glutathione (GSH) to release Mn(II), which reacts with H2O2 to generate hydroxyl radicals via a Fenton-like pathway. The generation of hydroxyl radicals could be enhanced by the stimulation of an external alternative electric field during which GSH acts as an electron mediator to enhance the release of Mn(II) from the cluster. The relatively high levels of both H2O2 and GSH and the acidic environment in tumor cells strengthen its specificity when the manganese cluster system is employed to suppress or eliminate tumors. Both in vitro and in vivo results suggest that, in addition to the cytotoxicity imposed by the raised ROS level due to the presence of Mn(II) species, the depletion of endogenous GSH leads indirectly to the inhibition of glutathione peroxidase 4 (GPX4), consequently raising the lipid peroxidation (LPO) level to cause ferroptosis. The apoptosis and ferroptosis jointly render the manganese-based agent potent efficacy with tumor-targeting specificity in antitumor treatment under electric stimulation.