A multivalent polyphenol-metal-nanoplatform for cascade amplified chemo-chemodynamic therapy

Chemodynamic therapy (CDT), as an emerging therapeutic strategy, kills cancer cells by converting intracellular hydrogen peroxide (H₂O₂) into cytotoxic oxidizing hydroxyl radicals (⋅OH). However, the therapeutic efficiency of CDT is compromised due to the insufficient endogenous H₂O₂ and metal catalysts in tumor cells. The use of multivalent polyphenols with multiple hydroxyl functions provides a facile yet robust means for efficient CDT augmentation. For this purpose, we reported herein the construction of polyphenol-metal nanoparticles (NPs) via a phenol-metal coordination strategy. The uniqueness of this study is the preparation of only one polymer construct with multivalency that can afford various supramolecular interactions for simultaneous "one-pot" loading of different therapeutic species, i.e., doxorubicin (DOX), glucose oxidases (GOD), and Fe³⁺ and further co-self-assembly into a stabilized nanomedicine for cascade amplified chemo-chemodynamic therapy. Specifically, the tumor intracellular acidic pH-triggered DOX release could serve for chemotherapy as well as enhance the intracellular H₂O₂ level. Together with the extra H₂O₂ and gluconic acid produced by the GOD-triggered glucose consumption, DOX@POAD-Fe@GOD NPs promoted Fe³⁺participation in the Fe-mediated Fenton reaction for cascade amplified chemo-chemodynamic therapy. Notably, this formulation displayed a greater anti-tumor effect with a tumor inhibition ratio 1.6-fold higher than that of free DOX in a BALB/c mice model bearing 4T1 tumors. Overall, the multivalent polyphenol-metal nanoplatform developed herein integrates chemotherapy, starvation therapy, and CDT for synergistic enhanced anticancer efficiency, which shows great potential for clinical translations. STATEMENT OF SIGNIFICANCE: Chemodynamic therapy (CDT) generally suffers from compromised therapeutic efficiency due to insufficient endogenous H₂O₂ and metal catalysts in tumor cells. To develop a facile yet robust strategy for efficient CDT augmentation, we reported herein construction of a multivalent polyphenol-metal nanoplatform, DOX@POAD-Fe@GOD nanoparticles (NPs) via a phenol-metal coordination strategy. This nanoplatform integrates multiple supramolecular dynamic interactions not only for simultaneously safe encapsulation of doxorubicin (DOX), Fe³⁺, and glucose oxidases (GOD), but also for cascade amplified chemo-chemodynamic therapy. Specifically, the intracellular acidic pH-triggered dissociation of DOX@POAD-Fe@GOD NPs promoted the release of Fe³⁺, DOX, and GOD for significantly increased ROS levels that can accelerate Fenton reactions for cascaded chemotherapy, starvation therapy, and CDT with amplified antitumor efficiency in vivo.