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

Abstract

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 H2O2 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 (CuO2-PVP-SRF) nanoparticle (NPs) was designed and developed for enhanced CDT against tumor cells through the synergetic pH-independent Fenton-like, H2O2 self-supplying, and GSH depletion strategy. The prepared CuO2-PVP-SRF NPs can be uptaken by 4T1 cells to specifically release Cu2+, H2O2, and SRF under acidic conditions. The intracellular GSH can be depleted by SRF-induced system xc– dysfunction and Cu2+-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 CuO2-PVP-SRF NPs display elevated therapeutic efficiency of CDT and show good promise in further tumor treatment applications.

Advances in H2O2-supplying materials for tumor therapy: synthesis, classification, mechanisms, and applications

“…49,50 A PVP-stabilized sorafenib-loaded copper peroxide (CuO 2 ) nanoparticle was fabricated to induce lipid hydroperoxide accumulation-induced ferroptosis. 51 The • OH generated by CDT may be eliminated to decrease the therapy effects on the performance of reduced glutathione (GSH). 52,53 Some studies have shown that metal ions can enhance CDT effects by depleting GSH to develop antitumor capacity.…”

Synergy effects of copper ion in doxorubicin-based chelate prodrug for cancer chemo-chemodynamic combination therapy

“…Copper ion is widely used in CDT since Cu + can participate in Fenton-like reaction to generate ·OH (Qiu et al., 2022 ; Chen et al., 2022 ; Wang et al., 2022 ). At the same time, it was also reported that Cu 2+ can mediate effective loading of DOX, which is based on the complexation of drugs with metal ions.…”

Hemoglobin-Decorated Boron-Carbon Nanosheets with Catalytic Ability and Near-Infrared II Light Response for Tumor Photothermal-Chemodynamic Therapy

“…Chemodynamic therapy (CDT) has been recognized as a promising tumor therapeutic method. − The principle is using specific valence metal ions (such as iron ions, manganese ions, etc.) to react with endogenous high-concentration hydrogen peroxide (H 2 O 2 ) in tumor tissues to produce strong oxidizing hydroxyl radicals ( • OH) for tumor cell killing. , However, the reaction conditions always limit the therapeutic effect of CDT. , It has been reported that the efficacy of the Fenton reaction can be promoted at the elevated temperature condition. The photothermal effect leads to an increase in the temperature of tumor tissue, − which can accelerate the production of • OH.…”

“…6,35 However, the reaction conditions always limit the therapeutic effect of CDT. 33,36 It has been reported that the efficacy of the Fenton reaction can be promoted at the elevated temperature condition. The photothermal effect leads to an increase in the temperature of tumor tissue, 37−40 which can accelerate the production of • OH.…”