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

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 Mn3O4 and GOD (denoted as Mn3O4@PDOMs-GOD) is ingeniously designed for enhanced ST and chemodynamic therapy (CDT). Specifically, the internalized Mn3O4@PDOMs-GOD in tumor cells consumes intracellular glucose and oxygen (O-2) under the catalysis of GOD to generate hydrogen peroxide (H2O2), which is subsequently decomposed by Mn3O4 to liberate O-2. This cyclically regenerated O-2 will form a virtuous cycle of O-2 and H2O2 compensation to enhance the ST outcome. Meanwhile, Mn3O4 can oxidize and deplete the overexpressed GSH in the tumor microenvironment (TME) to release Mn2+, which then catalyzes H2O2 into highly toxic hydroxyl radicals (center dot OH) to accomplish chemodynamic therapy (CDT). Both in vitro and in vivo experiment results demonstrate the significant antitumor efficacy of Mn3O4@PDOMs-GOD by the cooperatively enhanced ST and CDT, suggesting the feasibility to develop promising therapeutic platforms with higher treatment efficacies.

Automated summary

In this study, a glutathione-responsive organosilica hybrid micelle system was developed for enhanced starvation therapy and chemodynamic therapy. The system utilizes the catalytic activity of glucose oxidase to consume glucose and oxygen within tumor cells, generating hydrogen peroxide which is then decomposed to release oxygen. Simultaneously, the system can deplete glutathione in the tumor microenvironment and catalyze hydrogen peroxide to generate highly toxic hydroxyl radicals for chemodynamic therapy. The results demonstrate the significant antitumor efficacy of this system in both in vitro and in vivo experiments.