Photocytoxicity in vitro studies of ruthenium (II) complexes inducing cell death through targeting DNA

Abstract

Photodynamic therapy (PDT) has been proven to be an important and effective therapy method with good spatial and temporal accuracy in clinical cancer treatment. Among many PDT candidates, Ru(II)-based compounds have received more attention due to their excellent photochemical and photophysical properties, high singlet oxygen (1O2) photogeneration, and DNA affinities. In this study, three ruthenium(II) complexes (RC1, RC2, RC3) have been designed by varying the aromatic plane area of the main ligand to adjust their 1O2 photogeneration, DNA affinities, DNA photodamage, and photocytoxicity. All complexes display no cytotoxicity in the dark against Hela, A549, HepG2, and BEL-7402 cells. RC1 displays no photocytotoxicity against all tumor cells. RC2 and RC3 showed high photocytotoxicity against BEL-7402 cells. The cellular uptake, cell migration, colonies assay, apoptosis analysis, and cell cycle analysis of RC2 and RC3 confirmed that the ruthenium(II) complexes might effectively enter the cancer cells, and lead to BEL-7402 cells apoptosis through DNA damage pathway. DNA photocleavage, DNA binding, and 1O2 measurement experiments demonstrated the DNA damage caused by RC2 and RC3 under light, compared to RC1, might be due to their high DNA affinities, large 1O2 quantum yields, and large lipophilicity by varying the aromatic plane area of the main ligand. Time dependent density functional theory (TDDFT) calculated results further show that two complexes exhibit the photocytotoxicity possibly via type II photoreaction mechanism because of the larger ΔS-T than O2 and strong SOC between Sn and Tm. Hence, rational design of ruthenium(II) complexes by increasing DNA affinities, 1O2 quantum yields and lipophilicity can be regarded as an effective approach for enhanced photodynamic therapy (PDT).