Chemodynamic therapy agent optimized mesoporous TiO2 nanoparticles for Glutathione-Enhanced and Hypoxia-Tolerant synergistic Chemo-Sonodynamic therapy

Abstract

Sonodynamic therapy (SDT) can generate reactive oxygen species to kill cancer cells by activating sonosensitizers under ultrasound (US) irradiation. Nevertheless, its application is greatly limited by low quantum yield of sonosensitizers, high levels of endogenous glutathione (GSH) and tumor hypoxia. Herein, a GSH-activated sonosensitizers with synergistic therapy effect (chemodynamic therapy (CDT) and SDT) are developed by depositing Fe(III)-artemisinin infinite coordination polymers (Fe(III)-ART CPs) in pores of mesoporous TiO₂ nanoparticles (NPs). The formed Fe(III)-ART-TiO₂ NPs have high sono-induced electron-hole separation efficiency because the deposited Fe(III)-ART CPs can provide isolated intermediate bands to capture sono-induced electrons in TiO₂ NPs. Meanwhile, Fe³⁺ in Fe(III)-ART-TiO₂ NPs are reduced to Fe²⁺ by GSH with oxygen-deficient sites generated to further capture sono-induced electrons in TiO₂ NPs. Based on this, the reaction efficiency between water molecules and sono-induced holes is high enough to generate numerous hydroxyl radicals (•OH) without oxygen participated for overcoming tumor hypoxia. Additionally, through consuming GSH, the generated Fe²⁺ can catalyze ART to produce C-centered free radicals for CDT. Owing to these characteristics, Fe(III)-ART-TiO₂ NPs show significant tumor suppression ability and good biocompatibility in vivo. The strategy of using CDT agent to modify sonosensitizers offers new options to improve SDT effect without introducing harmful substances.

Keywords: Chemodynamic therapy; Electron-hole separation; Glutathione depletion; Sonodynamic therapy; Tumor hypoxia.