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

Chemodynamic therapy (CDT), as an emerging therapeutic strategy, kills cancer cells by converting in-tracellular hydrogen peroxide (H2O2) into cytotoxic oxidizing hydroxyl radicals ( center dot OH). However, the ther-apeutic 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 construc-tion of polyphenol-metal nanoparticles (NPs) via a phenol-metal coordination strategy. The unique-ness 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 consump-tion, 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 chemother-apy, starvation therapy, and CDT for synergistic enhanced anticancer efficiency, which shows great poten-tial for clinical translations. Statement of significance Chemodynamic therapy (CDT) generally suffers from compromised therapeutic efficiency due to insuf-ficient 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 nanoplat-form, DOX@POAD-Fe@GOD nanoparticles (NPs) via a phenol-metal coordination strategy. This nanoplat-form integrates multiple supramolecular dynamic interactions not only for simultaneously safe encapsu-lation 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 .(c) 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.