The vital roles of metals in nutrients and medicines are not accessible to purely organic compounds.

The Pt(IV) prodrug trans, trans, trans-[Pt(pyridine) 2 (N 3 ) 2 (OH) 2 ] (Pt1) and its coumarin derivative trans, trans, trans-[Pt(pyridine) 2 (N 3 ) 2 (OH)(coumarin-3-carboxylate)] (Pt2) are promising agents for photoactivated chemotherapy. These complexes are inert in the dark but release Pt(II) species and radicals upon visible light irradiation, resulting in photocytotoxicity toward cancer cells. Here, we have used synchrotron techniques to investigate the in-cell behavior of these prodrugs and visualize, for the first time, changes in cellular morphology and Pt localization upon treatment with and without light irradiation. We show that photoactivation of Pt2 induces remarkable cellular damage with extreme alterations to multiple cellular components, including formation of vacuoles, while also significantly increasing the cellular accumulation of Pt species compared to dark conditions. X-ray absorption near-edge structure (XANES) measurements in cells treated with Pt2 indicate only partial reduction of the prodrug upon irradiation, highlighting that phototoxicity in cancer cells may involve not only Pt(II) photoproducts but also photoexcited Pt(IV) species.

Most metallodrugs are prodrugs that can undergo ligand exchange and redox reactions in biological media. Here we have investigated the cellular stability of the anticancer complex [OsII[(η6‐p‐cymene)(RR/SS‐MePh‐DPEN)] [1] (MePh‐DPEN=tosyl‐diphenylethylenediamine) which catalyses the enantioselective reduction of pyruvate to lactate in cells. The introduction of a bromide tag at an unreactive site on a phenyl substituent of Ph‐DPEN allowed us to probe the fate of this ligand and Os in human cancer cells by a combination of X‐ray fluorescence (XRF) elemental mapping and inductively coupled plasma‐mass spectrometry (ICP‐MS). The BrPh‐DPEN ligand is readily displaced by reaction with endogenous thiols and translocated to the nucleus, whereas the Os fragment is exported from the cells. These data explain why the efficiency of catalysis is low, and suggests that it could be optimised by developing thiol resistant analogues. Moreover, this work also provides a new way for the delivery of ligands which are inactive when administered on their own.