Enhanced Chemodynamic Therapy Mediated by a Tumor‐Specific Catalyst in Synergy with Mitophagy Inhibition Improves the Efficacy for Endometrial Cancer

Abstract

AbstractChemodynamic therapy (CDT) relies on the tumor microenvironment (e.g., high H2O2 level) responsive Fenton‐like reactions to produce hydroxyl radicals (·OH) against tumors. However, endogenous H2O2 is insufficient for effective chemodynamic responses. An NAD(P)H: quinone oxidoreductase 1 (NQO1)high catalase (CAT)low therapeutic window for the use of NQO1 bioactive drug β‐lapachone (β‐Lap) is first identified in endometrial cancer (EC). Accompanied by NADH depletion, NQO1 catalyzes β‐Lap to produce excess H2O2 and initiate oxidative stress, which selectively suppress NQO1high EC cell proliferation, induce DNA double‐strand breaks, and promote apoptosis. Moreover, shRNA‐mediated NQO1 knockdown or dicoumarol rescues NQO1high EC cells from β‐Lap‐induced cytotoxicity. Arginine‐glycine‐aspartic acid (RGD)‐functionalized iron‐based metal‐organic frameworks (MOF(Fe)) further promote the conversion of the accumulated H2O2 into highly oxidative ·OH, which in turn, exacerbates the oxidative damage to RGD‐positive target cells. Furthermore, mitophagy inhibition by Mdivi‐1 blocks a powerful antioxidant defense approach, ultimately ensuring the anti‐tumor efficacy of stepwise‐amplified reactive oxygen species signals. The tumor growth inhibition rate (TGI) is about 85.92%. However, the TGI of MOF(Fe)‐based synergistic antitumor therapy decreases to only 50.46% in NQO1‐deficient KLE tumors. Tumor‐specific chemotherapy and CDT‐triggered therapeutic modality present unprecedented therapeutic benefits in treating NQO1high EC.