Photodynamic therapy (PDT) is a cancer therapy that operates with greater selectivity than conventional chemotherapy by the combination of a photosensitizer and visible light irradiation. Localization of irradiation allows for specificity by selectively activating the photosensitizer in the tissue of interest, while leaving healthy cells undamaged. However, PDT drawbacks remain and in this document the photophysical properties and DNA interactions of dirhodium, ruthenium, and osmium complexes are investigated for their abilities to address some of the shortcomings of current cancer photochemotherapies.
A series of dirhodium(II,II) complexes of the type cis-[Rh2(μ-O2CCH3)2(dppn)(L)]2+, where dppn = benzo[i]dipyrido-[3,2-a:2′,3′-h]quinoxaline and L = 2,2′-bipyridine (bpy), 1,10-phenanthroline (phen), dipyrido[3,2-f:2′3′-h]quinoxaline (dpq), dipyrido[3,2-a:2′,3′-c]phenazine (dppz), and dppn, was synthesized and its photophysical properties investigated. The ability of the complexes to bind and photocleave DNA was also probed, along with their toxicity and photocytotoxicity toward human skin cells. Nanosecond time-resolved absorption measurements established that the lowest energy excited state in the series is dppn-localized 3ππ* in DMSO. All complexes except the bis-dppn complex photocleave DNA efficiently via a mechanism that is mostly mediated by reactive oxygen species. The DNA photocleavage by the bis-dppn complex is significantly lower than that measured for the others, however, it exhibits the largest increase between toxicity and photocytotoxicity within the series.
A discussion of three new complexes [Ru(bpy)2(dpqp)]2+ (dpqp = pyrazino[2′,3′:5,6]pyrazino-[2,3-f][1,10]phenanthroline), [Ru(bpy)2(dppn)]2+, and [Os(bpy)2(dppn)]2+ is also presented. These complexes provide improvement to current PDT shortcomings by utilizing longer lifetimes, dual mechanisms of reactivity, and longer wavelengths of absorption, respectively. [Ru(bpy)2(dpqp)]2+ exhibits strong luminescence in water at room temperature, a striking deviation from that of the related non-emissive “DNA light-switch” prototype [Ru(bpy)2(dppz)]2+ under similar conditions. The combination of its strong DNA binding affinity and relatively long-lived triplet metal-to-ligand charge-transfer (3MLCT) excited state in water results in more efficient DNA photocleavage by [Ru(bpy)2(dpqp)]2+ than [Ru(bpy)2(dppz)]2+. Irradiation of [Ru(bpy)2(dppn)]2+ with visible light results in nearly complete DNA cleavage within 30 s (Lirr ≥ 455 nm), likely from the combination of guanine oxidation from the 3MLCT state and photoproduction of 1O2 from population of the 3ππ*. [Os(bpy)2(dppn)]2+ generates 1O2 with a quantum yield of 0.42 upon irradiation from its low-lying 3ππ* excited state, which results in efficient DNA cleavage with irradiation Lirr ≥ 645 nm.
The new complexes cis-[Rh2(μ-O2CCH3)2(C6H5CN)42+] and cis-[Rh2(μ-O2CCH3)2(4F-C6H5CN)42+] were synthesized and studied as potential photo-cisplatin analogs. Theoretical calculations were performed to assist in the understanding of the electronic structures of the complexes. Both complexes were inert to ligand exchange in the dark in H2O, CH3CN, and CH2Cl2. cis-[Rh2(μ-O2CCH3)2(4F-C6H5CN)42+], however, showed photosubstitution of its four equatorial 4F-C6H5CN ligands for CH3CN with Lirr ≥ 455 nm in 25 min, whereas tirr > 2 hr was required for cis-[Rh2(μ-O2CCH3)2(C6H5CN)42+]. The photosubstitution of the complexes with H2O was also investigated to assess their biological viability. Both complexes exhibit reduced ligand substitution in water due to their hydrophobicity and the π-stacking of the benzonitrile ligands. The photoinduced DNA binding of cis-[Rh2(μ-O2CCH3)2(C6H5CN)42+] was investigated by gel electrophoresis and compared to cis-[Rh2(μ-O2CCH3)2(CH3CN)62+], a complex known to covalently bind DNA upon irradiation.