Prodrug-Based Nanoreactors with Tumor-Specific In Situ Activation for Multisynergistic Cancer Therapy

Efficient drug delivery into tumor cells while bypassing many biological barriers is still a challenge for cancer therapy. By taking advantage of the palladium (Pd)-mediated in situ activation of a prodrug and the glucose oxidase (GOD)-based β-d-glucose oxidation reaction, we developed a multisynergistic cancer therapeutic platform that combined doxorubicin (DOX)-induced chemotherapy with GOD-mediated cancer-orchestrated oxidation therapy and cancer starvation therapy. In the present work, we first synthesized DOX prodrugs (pDOXs) and temporarily assembled them with β-cyclodextrins to reduce their toxic side effects. Then, a nanoreactor was constructed by synthesizing Pd⁰ nanoparticles in situ within the pores of mesoporous silica nanoparticles for the conversion of pDOX into the active anticancer drug. Furthermore, GOD was introduced to decrease the pH of the tumor microenvironment and induce cancer-orchestrated oxidation/starvation therapy by catalyzing β-d-glucose oxidation to form hydrogen peroxide (H₂O₂) and gluconic acid. Our study provides a new strategy that employs a cascade chemical reaction to achieve combined orchestrated oxidation/starvation/chemotherapy for the synergistic killing of cancer cells and the suppression of tumor growth.