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

A family of complexes of the type [Ru(tpbn)(IP-R)(4-pic)]Cl (tbpn=2,2'-(4-(-butyl)pyridine-2,6-diyl)bis(1,8-napthyridine); 4-pic=4-picoline; IP-R=imidazo[4,5-][1,10]phenanthroline attached to an aromatic group R for - and H for ) were prepared as near-infrared (NIR) absorbing coordination complexes to test whether triplet intraligand excited states (IL) of higher energy than the lowest-lying triplet metal-to-ligand charge transfer excited states (MLCT) could effectively generate cytotoxic singlet oxygen (O) 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 MLCT state estimated at 1.5 eV. Complexes - absorbed NIR light, with their longest-wavelength peak maxima occurring near 725 nm that extended out to 800 nm. The O quantum yields for the aromatic-containing compounds were extremely small (Φ=0.07), with correspondingly modest in vitro photocytotoxicities. All compounds were nontoxic without a light trigger, with dark EC values >60 μM and most values closer to 100 or greater. EC 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 IL energies and values for Φ or PI demonstrate that IL states with energies above the lowest-lying MLCT states do not contribute to the overall excited state dynamics responsible for potent PDT effects in previous studies. Lowest-lying MLCT states in this family of NIR-absorbing photosensitizers do not produce the requisite O for effective in vitro photocytotoxic effects, underscoring the need to install IL states that are lower in energy than the lowest-lying MLCT states in order the create potent NIR-activatable Ru(II) complexes for PDT.