Biodegradable nanotherapeutic with simultaneously GSH depletion and H2O2 supplying for enhanced synergistic chemotherapy/chemodynamic therapy

Chemodynamic therapy (CDT) has been exploited as an emerging therapeutic modality for cancer treatment. However, insufficient intracellular H2O2 levels and ultrahigh glutathione (GSH) in the tumor microenvironment (TME) severely restrict CDT efficacy. To address these concerns, in this work, a self-reinforcing biodegradable nanotherapeutic was developed to modulate the TME to amplify CDT. The nanotherapeutic (GOD-FeCaP@TPZ, abbreviated GFCT) was fabricated through a mild one-step biomineralization process using the enzyme catalyst glucose oxidase (GOD) as a template to form biodegradable iron-doped calcium phosphate nanoparticles, followed by the loading of the prodrug tirapazamine (TPZ). When GFCT decomposes and releases Fe3+ in the acidic TME, the delivered GOD can effectively catalyze the oxidization of glucose to enhance the subsequent Fenton-like reaction by promoting intracellular acidity (via the production of gluconic acid) and improving the generation of H2O2. Moreover, the released iron constantly depletes GSH by self-cyclic valence alterations in Fe(III) and Fe(II) and then triggers H2O2 to produce •OH through an Fe(II)-mediated Fenton-like reaction. Moreover, the elevated level of hypoxia induced by GOD-mediated glucose oxidization can activate the prodrug TPZ for effective chemotherapy, thus achieving remarkable synergistic therapeutic outcomes. This work provides another paradigm to augment antitumor efficacy via modulation of the TME.