Multifunctional CuFe2O4@HA as a GSH-depleting nanoplatform for targeted photothermal/enhanced-chemodynamic synergistic therapy

Abstract

Chemodynamic therapy (CDT), which converts overexpressed hydrogen peroxide (H₂O₂) in tumor cells to hydroxyl radicals (•OH) by Fenton reactions, is considered a prospective strategy in anticancer therapy. However, the high level of glutathione (GSH) and poor Fenton catalytic efficiency contribute to the suboptimal efficiency of CDT. Herein, we present a multifunctional nanoplatform (CuFe₂O₄@HA) that can induce GSH depletion and combine with photothermal therapy (PTT) to enhance antitumor efficacy. CuFe₂O₄@HA nanoparticles could release Cu²⁺ and Fe³⁺ after entering tumor cells by targeting hyaluronic acid (HA). Subsequently, Cu²⁺ and Fe³⁺ were reduced to Cu⁺ and Fe²⁺ by GSH, where Cu⁺/Fe²⁺ significantly catalyzed H₂O₂ to produce a higher level of •OH, and the depletion of GSH disrupted the antioxidant capacity of the tumor. Therefore, depleting GSH substantially enhances the level of •OH in tumor cells. In addition, CuFe₂O₄@HA nanoparticles have considerable absorption in the near-infrared (NIR) region, which can stimulate excellent PTT effects. More importantly, the heat generated by PTT can further enhance the Fenton catalysis efficiency. In vitro and in vivo experiments have demonstrated the excellent tumor-killing effect of CuFe₂O₄@HA nanoparticles. This strategy overcomes the problem of insufficient CDT efficacy caused by GSH overexpression and poor catalytic efficiency. Moreover, this versatile nanoplatform provides a reference for self-enhanced CDT and PTT/CDT synergistic targeted therapy.

Keywords: Chemodynamic therapy; CuFe(2)O(4); GSH depletion; Photothermal therapy; Targeting.