Evaluation of the Medicinal Potential of Two Ruthenium(II) Polypyridine Complexes as One‐ and Two‐Photon Photodynamic Therapy Photosensitizers

Abstract

Two [Ru(phen) dppz] derivatives (phen=1,10-phenantroline, dppz=dipyrido[3,2-a:2',3'-c]phenazine) with different functional groups on the dppz ligand [dppz-7,8-(OMe) (1), dppz-7,8-(OH) (2)] have been synthesized, characterized and investigated as photosensitizers (PSs) for photodynamic therapy (PDT) against cancer. Both complexes showed intense red phosphorescence and promising singlet oxygen ( O ) quantum yields of 75 % (1) and 54 % (2) in acetonitrile. Complex 1 (logP =-0.52, 2.4 nmol Ru per mg protein) was found to be more lipophilic, having also a higher cellular uptake efficiency compared to 2 (logP =-0.20, 0.9 nmol Ru per mg protein). Complex 1 localized evenly in HeLa cells whereas 2, was mainly visualized in the cell membrane by confocal microscopy. In the dark, complex 1 (IC =36.5 μm) was found to be more toxic than complex 2 (IC >100 μm) on a HeLa cells monolayer. Importantly, in view of PDT applications, both complexes were found to be non-toxic in the dark towards multicellular HeLa spheroids (IC >100 μm). Upon one-photon irradiation (420 nm, 9.27 J cm ), 1 exhibited higher phototoxicity (IC =3.1 μm) than 2 (IC =16.7 μm) on HeLa cell monolayers. When two-photon irradiation (800 nm, 9.90 J cm ) was applied, only 1 (IC =9.5 μm) was found to be active toward HeLa spheroids. This study demonstrates that the functional group on the intercalative ligand has a strong influence on the cellular localization and anticancer activity of Ru polypyridyl complexes.

New Designs for Phototherapeutic Transition Metal Complexes

“…However, multiphoton PDT also has limitations, posing new challenges for its clinical application. Unlike one photon PDT that can be easily carried out with low power lasers and LEDs, two photon PDT requires higher power lasers for successful photosensitization . Although the area irradiated with 2‐photon light can be highly specific, the volume of irradiated tissue is very small (≈1 μm 3 ), which will necessiate new rastering techniques if wide areas are to be treated.…”

Highly Charged Ruthenium(II) Polypyridyl Complexes as Effective Photosensitizer in Photodynamic Therapy

“…PDT relies on the use of a photosensitizer agent (PS), that can be triggered by irradiation with low‐energy light to generate cytotoxic species, such as reactive oxygen species (ROS), thus providing a complete spatial and temporal control over the generation of the toxic molecule . Generally, light‐activated PSs can react with the molecular oxygen leading to the formation of ROS through two distinct pathways.…”

The Antimicrobial Activity of Mononuclear Ruthenium(II) Complexes Containing the dppz Ligand

“…Although [Ru(bpy) 2 (dppz)] 2+ and [Ru(phen) 2 (dppz)] 2+ bind DNA strongly, they have generally exhibited low cytotoxicity against eukaryotic cells, with a number of studies indicating that the low cytotoxicity was due to their poor cellular uptake . Puckett and Barton demonstrated that these complexes enter eukaryotic cells by passive diffusion, and that the uptake can be enhanced by increasing the lipophilicity of the complex, for example, by substituting the bpy or phen ligands with 4,7‐diphenyl‐1,10‐phenanthroline (DIP) .…”

“…To increase the antimicrobial activity of [Ru(2,9‐Me 2 phen) 2 (dppz)] 2+ , the 2,9‐Me 2 phen ligands could be replaced with a more lipophilic ligand such as DIP. However, this would also significantly increase the toxicity of the ruthenium complex to eukaryotic systems . In addition, a number of studies have also demonstrated that the cellular localisation of polypyridylruthenium(II) complexes in eukaryotic cells is significantly modulated by the lipophilicity .…”