F-19 NMR Allows the Investigation of the Fate of Platinum(IV) Prodrugs in Physiological Conditions

Pt-IV prodrugs can overcome resistance and side effects of conventional Pt-II anticancer therapies. By F-19-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 F-19 NMR approach has the advantage of avoiding the interference of all background signals.