Sorafenib-Loaded Copper Peroxide Nanoparticles with Redox Balance Disrupting Capacity for Enhanced Chemodynamic Therapy against Tumor Cells.

Chemodynamic therapy (CDT) is a promising hydroxyl radical (•OH)-mediated tumor therapeutic method with desirable tumor specificity and minimal side effects. However, the efficiency of CDT is restricted by the pH condition, insufficient HO level, and overexpressed reductive glutathione (GSH), making it challenging to solve these problems simultaneously to improve the efficacy of CDT. Herein, a kind of polyvinylpyrrolidone-stabilized, sorafenib-loaded copper peroxide (CuO-PVP-SRF) nanoparticle (NPs) was designed and developed for enhanced CDT against tumor cells through the synergetic pH-independent Fenton-like, HO self-supplying, and GSH depletion strategy. The prepared CuO-PVP-SRF NPs can be uptaken by 4T1 cells to specifically release Cu, HO, and SRF under acidic conditions. The intracellular GSH can be depleted by SRF-induced system xc dysfunction and Cu-participated redox reaction, causing the inactivation of GPX4 and generating Cu. A great amount of •OH was produced in this reducing capacity-disrupted condition by the Cu-mediated Fenton-like reaction, causing cell apoptosis and lipid hydroperoxide accumulation-induced ferroptosis. They display an excellent 4T1 cell killing outcome through the improved •OH production capacity. The CuO-PVP-SRF NPs display elevated therapeutic efficiency of CDT and show good promise in further tumor treatment applications.