Ruthenium Photosensitizers for NIR PDT Require Lowest-Lying Triplet Intraligand (³IL) Excited States

A family of complexes of the type [Ru(tpbn)(IP-R)(4-pic)]Cl₂ (tbpn=2,2'-(4-(tert-butyl)pyridine-2,6-diyl)bis(1,8-napthyridine); 4-pic=4-picoline; IP-R=imidazo[4,5-f][1,10]phenanthroline attached to an aromatic group R for 2-8 and H for 1) were prepared as near-infrared (NIR) absorbing coordination complexes to test whether triplet intraligand excited states (³IL) of higher energy than the lowest-lying triplet metal-to-ligand charge transfer excited states (³MLCT) could effectively generate cytotoxic singlet oxygen (¹O₂) and elicit in vitro photodynamic therapy (PDT) effects. Aromatic groups ranged from benzene to anthracene, with corresponding triplet state energies that were all significantly higher (approximately 3.7-1.8 eV) than the ³MLCT state estimated at 1.5 eV. Complexes 1-8 absorbed NIR light, with their longest-wavelength peak maxima occurring near 725 nm that extended out to 800 nm. The ¹O₂ quantum yields for the aromatic-containing compounds were extremely small (Φ_Δ=0.07), with correspondingly modest in vitro photocytotoxicities. All compounds were nontoxic without a light trigger, with dark EC₅₀ values >60 μM and most values closer to 100 or greater. EC₅₀ values with visible light were 5-6 (PI=15-20), 7-10 (PI=8-11), and 10-15 μM (PI=6-8) in SKMEL28, A375, and B16F10 cancer cell lines, respectively. With NIR light, these values were even less: 11-16 (PI=5-9), 16-50 (PI=2-6), and 15-19 μM (PI=4-6) in SKMEL28, A375, and B16F10 cancer cell lines, respectively. While measurable, the modest activities and absence of any trend between the ³IL energies and values for Φ_Δ or PI demonstrate that ³IL states with energies above the lowest-lying ³MLCT states do not contribute to the overall excited state dynamics responsible for potent PDT effects in previous studies. Lowest-lying ³MLCT states in this family of NIR-absorbing photosensitizers do not produce the requisite ¹O₂ for effective in vitro photocytotoxic effects, underscoring the need to install ³IL states that are lower in energy than the lowest-lying ³MLCT states in order the create potent NIR-activatable Ru(II) complexes for PDT.