Reactive oxygen species activated by mitochondria-specific camptothecin prodrug for enhanced chemotherapy

Abstract

Camptothecin (CPT) has attracted much attention due to its potent antitumor activities. However, the undesirable physicochemical proper-ties, including poor water solubility, unstable lactone ring, and severe adverse effects, limit its further application. In this study, two water-solu-ble prodrugs, CPT-lysine and CPT-arginine, were designed and synthesized by conjugating lysine or arginine with CPT, improving its solubility, pharmacokinetic properties, and tumor penetration. Importantly, the introduction of arginine into CPTR contributed to the mitochondria-spe-cific delivery, which increased mitochondrial reactive oxygen species generation, induced mitochondria dysfunction, and enhanced cell apop-tosis and in vivo anti-cancer effect. This strategy is believed to hold great potential for organelle-specific synergistic anti-tumor therapy.