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

Liubov M Lifshits; John A Roque 3rd; Elamparuthi Ramasamy; Randolph P Thummel; Colin G Cameron; Sherri A McFarland

doi:10.1016/j.jpap.2021.100067

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

J Photochem Photobiol. 2021 Dec:8:100067. doi: 10.1016/j.jpap.2021.100067. Epub 2021 Sep 15.

Authors

Liubov M Lifshits¹, John A Roque 3rd^{1

2}, Elamparuthi Ramasamy¹, Randolph P Thummel³, Colin G Cameron¹, Sherri A McFarland¹

Affiliations

¹ Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, Texas, 76019-0065 United States.
² Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, North Carolina 27402, USA.
³ Department of Chemistry, University of Houston, 112 Fleming Building, Houston, Texas, 77204-5003, USA.

Abstract

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.

Keywords: Ruthenium; intraligand (IL); melanoma; metal-to-ligand charge transfer (MLCT); near-infrared (NIR); photodynamic therapy.

Grants and funding

R01 CA222227/CA/NCI NIH HHS/United States