DNA‐Damage‐Response‐Targeting Mitochondria‐Activated Multifunctional Prodrug Strategy for Self‐Defensive Tumor Therapy

Abstract We report a novel multifunctional construct, M1 , designed explicitly to target the DNA damage response in cancer cells. M1 contains both a floxuridine (FUDR) and protein phosphatase 2A (PP2A) inhibitor combined with a GSH‐sensitive linker. Further conjugation of the triphenylphosphonium moiety allows M1 to undergo specific activation in the mitochondria, where mitochondria‐mediated apoptosis is observed. Moreover, M1 has enormous effects on genomic DNA ascribed to FUDR's primary function of impeding DNA/RNA synthesis combined with diminishing PP2A‐activated DNA repair pathways. Importantly, mechanistic studies highlight the PP2A obtrusion in FUDR/5‐fluorouracil (5‐FU) therapy and underscore the importance of its inhibition to harbor therapeutic potential. HCT116 cell xenograft‐bearing mice that have a low response rate to 5‐FU show a prominent effect with M1 , emphasizing the importance of DNA damage response targeting strategies using tumor‐specific microenvironment‐activatable systems.