Chemotherapy remains a primary cancer treatment. However, the poor selectivity of conventional small-molecule chemotherapeutic agents often leads to severe side effects against normal cells and tissues, limiting their clinical application. To address this challenge, tumor-microenvironment-activated prodrugs represent a promising strategy for enhancing selectivity and efficacy. Herein, we developed a charge-reversal prodrug, PIX-DMMA, synthesized through the reaction between primary amino groups of pixantrone (PIX) and 2,3-dimethylmaleic anhydride (DMMA). PIX-DMMA is activated under tumor extracellular pH (∼6.5), releasing the o-PIX while simultaneously undergoing charge reversal from negative to positive, thereby enhancing cellular uptake. Drug release kinetics at pH 6.5 were verified via NMR spectroscopy. In vitro studies demonstrated that prodrug activation at pH 6.5 confers significant tumor selectivity and potent cytotoxicity toward cancer cells. Furthermore, in vivo studies in LoVo tumor-bearing mice showed significant tumor growth inhibition without significant systemic toxicity. This acid-triggered charge-reversal prodrug represents a promising strategy for selective cancer therapy.
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