Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs. To address this challenge, we developed a smart theranostic prodrug system that combines a fluorophore and an anticancer drug, specifically 6-diazo-5-oxo-l-norleucine (DON), using a thioketal linkage (TK). This system enables imaging, chemotherapy, photodynamic therapy, and on-demand drug release upon radiation exposure. The optimized prodrug, DON-TK-BM3, incorporating cyanine dyes as the fluorophore, displayed potent reactive oxygen species release and efficient tumor cell killing. Unlike the parent drug DON, DON-TK-BM3 exhibited no toxicity toward normal cells. Moreover, DON-TK-BM3 demonstrated high tumor accumulation and reduced side effects, including gastrointestinal toxicity, in mice. This study provides a practical strategy for designing prodrugs of metabolic inhibitors with significant toxicity stemming from their lack of tissue selectivity.

癌症靶向代谢治疗的最新进展受到与此类药物相关的相当大的毒性的限制。为了应对这一挑战，我们开发了一种智能治疗诊断前药系统，该系统使用硫缩酮键（TK）结合荧光团和抗癌药物，特别是6-重氮-5-氧代-l-正亮氨酸（DON）。该系统可实现成像、化疗、光动力疗法以及辐射暴露时的按需药物释放。优化的前药 DON-TK-BM3，结合花青染料作为荧光团，表现出有效的活性氧释放和有效的肿瘤细胞杀伤作用。与母体药物 DON 不同，DON-TK-BM3 对正常细胞没有毒性。此外，DON-TK-BM3 在小鼠体内表现出较高的肿瘤蓄积性和较低的副作用，包括胃肠道毒性。这项研究为设计代谢抑制剂的前药提供了一种实用的策略，这些抑制剂由于缺乏组织选择性而具有显着的毒性。