GSH-Responsive Organosilica Hybrid Nanosystem as a Cascade Promoter for Enhanced Starvation and Chemodynamic Therapy.

Abstract

Glucose oxidase (GOD)-mediated starvation therapy (ST) that causes intratumoral glucose depletion is a promising strategy for tumor treatment. However, the ultimate efficacy is inevitably limited by tumor hypoxia, as oxygen is a key component in the consumption of glucose by GOD. In this study, a kind of glutathione (GSH)-responsive organosilica hybrid micelles loaded with Mn₃ O₄ and GOD (denoted as Mn₃ O₄ @PDOMs-GOD) is ingeniously designed for enhanced ST and chemodynamic therapy (CDT). Specifically, the internalized Mn₃ O₄ @PDOMs-GOD in tumor cells consumes intracellular glucose and oxygen (O₂ ) under the catalysis of GOD to generate hydrogen peroxide (H₂ O₂ ), which is subsequently decomposed by Mn₃ O₄ to liberate O₂ . This cyclically regenerated O₂ will form a virtuous cycle of O₂ and H₂ O₂ compensation to enhance the ST outcome. Meanwhile, Mn₃ O₄ can oxidize and deplete the overexpressed GSH in the tumor microenvironment (TME) to release Mn²⁺ , which then catalyzes H₂ O₂ into highly toxic hydroxyl radicals (·OH) to accomplish chemodynamic therapy (CDT). Both in vitro and in vivo experiment results demonstrate the significant antitumor efficacy of Mn₃ O₄ @PDOMs-GOD by the cooperatively enhanced ST and CDT, suggesting the feasibility to develop promising therapeutic platforms with higher treatment efficacies.