Proton Nanomodulators for Enhanced Mn 2+ -mediated Chemodynamic Therapy of Tumors via HCO 3 − Regulation

Author:

Yang Peng1,Liu Shaojie1,Chen Zhuang1,Liu Weijing1,Yang Zuo1,Yan Haohao1,Rao Zhiping1,Zhang Xianghan1,Zhang Ruili1,Wang Zhongliang1

Affiliation:

1. Ministry of Education, Xidian University

Abstract

Abstract

Background Mn2+-mediated chemodynamic therapy (CDT) has been emerged as a promising cancer therapeutic modality that relies heavily on HCO3 level in the system. Although the physiological buffers (H2CO3/HCO3) provide certain amounts of HCO3, the acidity of the tumor microenvironment (TME) would seriously affect the HCO3 ionic equilibrium (H2CO3 ⇌ H+ + HCO3). As a result, HCO3 level in the tumor region is actually insufficient to support effective Mn2+-mediated CDT. Results In this study, a robust nanomodulator MnFe2O4@ZIF-8 (PrSMZ) with the capability of in situ self-regulation HCO3 is presented to enhance therapeutic efficacy of Mn2+-mediated CDT. Under an acidic tumor microenvironment, PrSMZ could act as a proton sponge to shift the HCO3 ionic equilibrium to the positive direction, significantly boosting the generation of the HCO3. Most importantly, such HCO3 supply capacity of PrSMZ could be finely modulated by its ZIF-8 shell thickness, resulting in a 1000-fold increase in reactive oxygen species (ROS) generation. Enhanced ROS-dependent CDT efficacy is further amplified by a glutathione (GSH)-depletion ability and the photothermal effect inherited from the inner core MnFe2O4 of PrSMZ to exert the remarkable antitumor effect on mouse models. Conclusions This work addresses the challenge of insufficient HCO3 in the TME for Mn2+-mediated Fenton catalysts and could provide a promising strategy for designing high-performance Mn2+-mediated CDT agents to treat cancer effectively.

Publisher

Research Square Platform LLC

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