Highly Charged Ruthenium(II) Polypyridyl Complexes as Lysosome‐Localized Photosensitizers for Two‐Photon Photodynamic Therapy

Abstract

Photodynamic therapy (PDT) is a noninvasive medical technique that has received increasing attention over the last years and been applied for the treatment of certain types of cancer. However, the currently clinically used PDT agents have several limitations, such as low water solubility, poor photostability, and limited selectivity towards cancer cells, aside from having very low two-photon cross-sections around 800 nm, which limits their potential use in TP-PDT. To tackle these drawbacks, three highly positively charged ruthenium(II) polypyridyl complexes were synthesized. These complexes selectively localize in the lysosomes, an ideal localization for PDT purposes. One of these complexes showed an impressive phototoxicity index upon irradiation at 800 nm in 3D HeLa multicellular tumor spheroids and thus holds great promise for applications in two-photon photodynamic therapy.

Ruthenium-based PACT compounds based on an N,S non-toxic ligand: a delicate balance between photoactivation and thermal stability

“…The increased cytotoxicity of the compound by light irradiation was generally attributed to the formation of the bis-aqua complex cis-[Ru(bpy) 2 (OH 2 ) 2 ] 2+ , which may interact with nuclear DNA by analogy with the mode-of-action of cisplatin. However, we and others demonstrated recently that the second photoproduct obtained upon irradiation of [Ru(bpy) 2 (dmbpy)] 2+ in water, i.e. the free dmbpy ligand, is the actual cytotoxic species [8,9].…”

“…Whereas in Photodynamic Therapy (PDT) cytotoxicity is obtained by the photochemical generation of reactive oxygen species (ROS) such as singlet oxygen [1,2,3], in metal-based PACT a new cytotoxic drug is formed in situ via photosubstitution of at least one of the ligands of the original pro-drug [4,5]. In many reported examples, ruthenium PACT agents are based on complexes of the [Ru(bpy) 2 (dmbpy)] 2+ family, where bpy is 2,2'-bipyridine and dmbpy is the sterically hindering ligand 6,6'-dimethyl-2,2'-bipyridine, which increases the distortion of the coordination octahedron [6,7]. In such strained complexes, the triplet metal-centered excited state ( 3 MC) of the ruthenium complex is lowered and can thus be thermally populated from the photochemically generated triplet metal-to-ligand charge-transfer state ( 3 MLCT), leading to photosubstitution of dmbpy by two solvent molecules.…”

“…In addition, many ruthenium complexes coordinated to thioethers show selective photosubstitution of the thioether ligand because these types of ligands become more weakly bound in the excited states than nitrogen-based ligands [11,12]. [Ru(bpy) 2 (mtmp)]Cl 2 and [Ru(Ph 2 phen) 2 (mtmp)]Cl 2 (Ph 2 phen = 4,7-diphenyl-1,10-phenantroline and mtmp = 2-methylthiomethyl pyridine), for example, efficiently photosubstitute the non-toxic N,S ligand mtmp in water [8]. In A549 cancer cells, the former hardly entered the cell because of its too high hydrophilicity, while the latter already showed a strong cytotoxicity in the dark due to its high lipophilicity.…”

“…In the present study, we systematically varied the number of bpy and dmbpy ligands in a series of ruthenium complexes also bearing a 3-(methylthio)propylamine chelating ligand (mtpa). The complexes [Ru(bpy) 2 6 ) 2 ), were prepared (Figure 1), their stereochemistry fully characterized, and their cytotoxicity in the dark and under light irradiation evaluated. The effect of the number of methyl groups on the photochemistry, lipophilicity, and cytotoxicity of these complexes is discussed.…”

“…The effect of the number of methyl groups on the photochemistry, lipophilicity, and cytotoxicity of these complexes is discussed. 2 Cl 2 ], respectively, with the mtpa ligand, to afford racemic mixtures. The stereochemistry of these complexes is challenging to establish.…”