Dual-prodrug cascade activation for chemo/chemodynamic mutually beneficial combination cancer therapy

The combination of chemodynamic therapy (CDT) and chemotherapy has shown promise for achieving improved cancer treatment outcomes. However, due to the lack of synergy rationale, a simple one-plus-one combination therapy remains suboptimal in overcoming the obstacles of each treatment approach. Herein, we report a nanoplatform consisting of a pH-sensitive ferrocene- and cinnamaldehyde-based polyprodrug and a hydrogen peroxide-responsive doxorubicin (DOX) prodrug. Under an acidic tumor environment, the cinnamaldehyde polyprodrug will be activated to release free cinnamaldehyde, which can increase the intracellular hydrogen peroxide level and enhance the Fenton reaction. Subsequently, due to the collapse of nanoparticle structures, the DOX prodrug will be released and activated under a hydrogen peroxide stimulus. Meanwhile, the quinone methide produced during DOX prodrug activation can consume glutathione, an important antioxidant, and thus in turn enhance the efficacy of CDT. This design of a nanoplatform with dual-prodrug cascade activation provides a promising mutually beneficial cooperation mode between chemotherapy and CDT for enhancing antitumor efficacy.