To cage or to be caged? The cytotoxic species in ruthenium-based photoactivated chemotherapy is not always the metal.

In metal-based photoactivated chemotherapy (PACT), two photoproducts are generated by light-triggered photosubstitution of a metal-bound ligand: the free ligand itself and an aquated metal complex. By analogy with cisplatin, the aquated metal complex is usually presented as the biologically active species, as it can typically bind to DNA. In this work, we show that this qualitative assumption is not necessarily valid by comparing the biological activity, log P, and cellular uptake of three ruthenium-based PACT complexes: [Ru(bpy)2(dmbpy)]2+, [Ru(bpy)2(mtmp)]2+, and [Ru(Ph2phen)2(mtmp)]2+. For the first complex, the photoreleased dmbpy ligand is responsible for the observed phototoxicity, whereas the second complex is not phototoxic, and for the third complex it is the ruthenium bis-aqua photoproduct that is the sole cytotoxic species.