The activation mechanism of Pt(IV) prodrugs in biological tissues: using X-ray Absorption Spectroscopy study to track reduction kinetics

Pt(II) complexes (like cisplatin, oxaliplatin and carboplatin) still belong to the most important anticancer drugs. However, their application has severe adverse effects and drug resistance is common. To improve the tumor specificity, we have developed albumin-targeted Pt(IV) prodrugs, which have an improved anticancer activity and are being (pre)clinically developed towards first in man clinical trials. We showed that the prodrugs accumulate in malignant tissues, where they enter the cancer cells by endocytosis. The drugs are activated by reduction, releasing the active Pt(II)-drug. The experiments proposed here are aimed at exploiting X-ray Absorption Spectroscopy to determine the Pt oxidation state and its local environment of the anticancer agents in solution, within cancer cells and (tumor) tissues. This will allow us to better understand the behavior of the new Pt(IV) prodrugs in biological systems and to unravel the activation by reduction processes of Pt(IV) complexes.