Yuan Siming, Zhu Yang, Dai Yi, Wang Yu, Jin Duo, Liu Manman, Tang Liqin, Arnesano Fabio, Natile Giovanni, Liu Yangzhong
Department of Pharmacy, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Department of Chemistry, University of Science and Technology of China, Hefei, Anhui, China.
Dipartimento di Chimica, Università di Bari "A. Moro", via E. Orabona 4, 70125, Bari, Italy.
Angew Chem Int Ed Engl. 2022 Jan 21;61(4):e202114250. doi: 10.1002/anie.202114250. Epub 2021 Dec 16.
Pt prodrugs can overcome resistance and side effects of conventional Pt anticancer therapies. By F-labeling of a Pt prodrug (Pt-FBA, FBA=p-fluorobenzoate), the activation under physiological conditions could be investigated. Unlike single-electron reductants, multi-electron agents can efficiently promote the two electrons reduction of Pt to Pt . The activation of Pt-FBA in cell lysate is highly dependent upon the type of cancer cells. When administered to E. coli, Pt-FBA is reduced intracellularly and free FBA can shuttle out of the cell. The reduction rate greatly increases by inducing metallothionein overexpression and is lowered by addition of Zn ions. When injected into mice, Pt-FBA undergoes fast reduction in the bloodstream accompanied by metabolic degradation of FBA; nevertheless, unreduced Pt-FBA can accumulate to detectable levels in liver and kidneys. The F NMR approach has the advantage of avoiding the interference of all background signals.
铂前药可以克服传统铂类抗癌疗法的耐药性和副作用。通过对一种铂前药（Pt-FBA，FBA = 对氟苯甲酸酯）进行¹⁹F标记，可以研究其在生理条件下的活化情况。与单电子还原剂不同，多电子试剂可以有效地促进铂的两电子还原为Pt²⁺。Pt-FBA在细胞裂解物中的活化高度依赖于癌细胞的类型。当给予大肠杆菌时，Pt-FBA在细胞内被还原，游离的FBA可以穿梭出细胞。通过诱导金属硫蛋白过表达，还原速率大大增加，而添加锌离子则会降低还原速率。当注入小鼠体内时，Pt-FBA在血液中迅速还原，同时伴随着FBA的代谢降解；然而，未还原的Pt-FBA可以在肝脏和肾脏中积累到可检测的水平。¹⁹F NMR方法具有避免所有背景信号干扰的优点。
