Photo-induced activation of metal complexes in living cells for photodynamic therapy (PDT) and photo-activated chemotherapy (PACT)

Elaboration of new generations of more effective and safer metal-based anticancer agents, has been stimulated by the severe side effects encountered by patients undergoing chemotherapeutic treatments. In this search, ruthenium complexes have shown encouraging potential, demonstrating a wide antiproliferative profile against cancer cells. Seminal studies conducted in our labs have resulted in the development of ruthenium(II)-based new anticancer agents, which showed distinct cytotoxicity mechanisms. First, a substitutionally-inert bis(dppz)-Ru(II) complex has been synthetized that impairs the mitochondrial membrane potential of cells leading to apoptosis. A follow- up structure-activity relationship analysis investigating the impact of lipophilicity, charge and size-based modification revealed the presence of carboxylic acid functionality as indispensable to confer cytotoxicity to the Ru(II) complex. This complex was successfully inactivated by protecting the carboxylate functionality with a photolabile protecting group. The anticancer activity could be regained by UV-A irradiation (2.58 J/cm2). Second, a seemingly harmless ruthenium(II) complex was prepared. It targets the cell nucleus and causes significant damage to DNA, such as single-strand breaks (SSBs) and purines oxidation upon UV-A irradiation (1.29 J/cm2). After 24 h, double- strand breaks (DSBs) are also created that lead overall to cell death. Collectively, these findings are an important progress towards developing a new class of metal-based anticancer agents, which have the potential to overcome the drawbacks of the current platinum-based drugs