<sup>19</sup>F NMR Allows the Investigation of the Fate of Platinum(IV) Prodrugs in Physiological Conditions
Siming Yuan, Yang Zhu, Yi Dai, Yu Wang, Duo Jin, Manman Liu, Liqin Tang, Fabio Arnesano, Giovanni Natile, Yangzhong Liu
Abstract
Abstract Pt IV prodrugs can overcome resistance and side effects of conventional Pt II anticancer therapies. By 19 F‐labeling of a Pt IV 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 IV to Pt II . 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 II 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 19 F NMR approach has the advantage of avoiding the interference of all background signals.