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In this perspective article, we present the recent achievements in the application of ruthenium complexes as photosensitizers and as photoactivatable prodrugs.

Photodynamic Therapy (PDT) is an emerging technique to treat certain types of cancer, bacterial, fungal, and viral infections, and skin diseases. In past years, different research groups developed new ruthenium-containing photosensitizers (PSs) with tuned photophysical and biological properties to better fit the requirements of PDT. In this Account, we report and discuss the latest results in this research area, emphasizing particularly our own research. For example, inspired by the DNA intercalating complex [Ru(bpy)(dppz)] (bpy = 2,2'-bipyridine; dppz = (dipyrido[3,2-a:2',3'-c]phenazine), a series of ruthenium complexes bearing differently functionalized dppz ligands were synthesized to target DNA. The introduction of the substituents on the dppz ligand did not reduce much the affinity of the complexes to DNA but highly affected their cellular uptake. The most effective complex in this series, [Ru(bpy)(dppz-7-OMe)], showed IC values in the low micromolar range against several types of cancer cells upon light irradiation and, importantly, a high phototoxic index (PI) of >150. This value is comparable to or even better than several PSs used in clinics under comparable experimental conditions. This compound was found to localize in the nucleus and to induce DNA damage in HeLa cells upon light irradiation. Interestingly, cells in the mitotic phase were found to be more affected and to have a different mechanism of cell death (apoptosis) upon light irradiation than those in the interphase (paraptosis). To take advantage of that, the PS was combined with a cell cycle inhibitor to synchronize cells in the mitotic phase, further improving the phototoxicity by a factor of 3.6. In addition, our group recently demonstrated that [Ru(bphen)(benzene-1,2-dislufinate)] (bphen = 4,7-diphenyl-1,10-phenanthroline) localizes in mitochondria and has an IC value of 0.62 μM with a PI of over 80 in HeLa cells upon light irradiation at 420 nm. Interestingly, this complex was also found to efficiently kill Gram-positive Staphylococcus aureus under light irradiation. Antimicrobial PDT (aPDT) is another field of research where Ru(II) polypyridyl complexes can play an interesting role to fight antibiotics resistance. [Ru(dqpCOMe)(ptpy)] (dqpCOMe = 4-methylcarboxy-2,6-di(quinolin-8-yl)pyridine), ptpy = 4'-phenyl-2,2':6',2″-terpyridine) is additionally efficient against Gram-negative Escherichia coli. The efficacy of positively charged Ru(II) PSs is related to their affinity to the negatively charged membrane of Gram-negative bacteria. A drawback of many Ru(II) polypyridyl PSs is their low absorption in the biological optical window (600-900 nm) where light penetration depth into tissue is the highest. The lowest energy transition in the UV/Vis spectra of Ru(II) polypyridyl complexes is usually a metal-to-ligand charge-transfer band. To shift the absorption into this range, tuning of the ligand system, for example, by extending π-systems, has been described in the literature. Another approach to make excitation in the optical biological windo...