Preclinical Assessment of Enhanced Chemodynamic Therapy by an FeMnO <i> _x </i> -Based Nanocarrier: Tumor-Microenvironment-Mediated Fenton Reaction and ROS-Induced Chemotherapeutic for Boosted Antitumor Activity

Abstract

In recent studies, iron-containing Fenton nanocatalysts have demonstrated significant promise for clinical use due to their effective antitumor activity and low cytotoxicity. A new approach was reported in this work utilizing cation exchange synthesis to fabricate FeMnO<i>_x</i> nanoparticles (NPs) that boost Fenton reactions and responses to the tumor microenvironment (TME) for chemodynamic therapy (CDT) and chemotherapy (CT). Within the TME, the redox metal pair of Fe²⁺/Mn²⁺ helps break down endogenous hydrogen peroxide (H₂O₂) into very harmful hydroxyl radicals (•OH) while simultaneously deactivating glutathione (GSH) to boost CDT performance. To further enhance the therapeutic potential, FeMnO<i>_x</i> NPs were encapsulated with thioketal-linked camptothecin (CPT-TK-COOH), a reactive oxygen species (ROS)-responsive prodrug, achieving a high CPT-loading capacity of up to 51.1%. Upon ROS generation through the Fenton reaction, the prodrug TK linkage was disrupted, releasing 80% of the CPT payload within 48 h. Notably, FeMnO_<i>x</i>@CPT exhibited excellent dual-modal imaging capabilities, enabling magnetic resonance and fluorescence imaging for image-guided therapy. In vitro studies showed the cytocompatibility of FeMnO_<i>x</i> NPs using MDA-Mb-231 and 4T1 cells, but in the presence of H₂O₂, they induced significant cytotoxicity, resulting in 80% cell death through CDT and CT effects. Upon intravenous administration, FeMnO_<i>x</i>@CPT displayed remarkable tumor accumulation, which enhanced tumor suppression in xenografts through improved CDT and CT effects. Moreover, no significant adverse effects were observed in the FeMnO_<i>x</i> NP-treated animals. In the current study, the FeMnO_<i>x</i>@CPT anticancer platform, with its boosted •OH-producing capability and ROS-cleavable drug release, has been validated utilizing in vitro and animal studies, suggesting its capacity as a viable strategy for clinical trials.