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NIR-Absorbing Ru^II Complexes Containing α-Oligothiophenes for Applications in Photodynamic Therapy.

ABSTRACT: The design of near-infrared (NIR)-active photosensitizers (PSs) for light-based cancer treatments such as photodynamic therapy (PDT) has been a challenge. While several NIR-Ru^II scaffolds have been reported, this approach has not been proven in cells. This is the first report of NIR-Ru^II PSs that are phototoxic to cancer cells, including highly pigmented B16F10 melanoma cells. The PS family incorporated a bis(1,8-naphthyridine)-based ligand (tpbn), a bidentate thiophene-based ligand (nT; n=0-4), and a monodentate 4-picoline ligand (4-pic). All compounds absorbed light >800 nm with maxima near 730 nm. Transient absorption (TA) measurements indicated that n=4 thiophene rings (4T) positioned the PDT-active triplet intraligand charge transfer (³ ILCT) excited state in energetic proximity to the lowest-lying triplet metal-to-ligand charge transfer (³ MLCT). 4T had low-micromolar phototoxicity with PI_vis and PI_733nm values as large as 90 and 12, respectively. Spectroscopic studies suggested that the longer-lived (τ_TA =3-6 μs) ³ ILCT state was accessible from the ³ MLCT state, but energetically uphill in the overall photophysics. The study highlights that phototoxic effects can be achieved with NIR-absorbing Ru^II PSs as long as the reactive ³ ILCT states are energetically accessible from the low-energy ³ MLCT states. It also demonstrates that tissue-penetrating NIR light can be used to activate the PSs in highly pigmented cells where melanin attenuates shorter wavelengths of light.

SUBMITTER: Lifshits LM

PROVIDER: S-EPMC7736147 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The photophysical and photobiological properties of a new class of cyclometalated ruthenium(II) compounds incorporating π-extended benzo[ h]imidazo[4,5- f]quinoline (IBQ) cyclometalating ligands (C^N) bearing thienyl rings ( n = 1-4, compounds 1-4) were investigated. Their octanol-water partition coefficients (log Po/w) were positive and increased with n. Their absorption and emission energies were red-shifted substantially compared to the analogous Ru(II) diimine (N^N) complexes. They displayed C^N-based intraligand (IL) fluorescence and triplet excited-state absorption that shifted to longer wavelengths with increasing n and N^N-based metal-to-ligand charge transfer (MLCT) phosphorescence that was independent of n. Their photoluminescence lifetimes (τem) ranged from 4-10 ns for 1IL states and 12-18 ns for 3MLCT states. Transient absorption lifetimes (τTA) were 5-8 μs with 355 nm excitation, ascribed to 3IL states that became inaccessible for 1-3 with 532 nm excitation (1-3, τTA = 16-17 ns); the 3IL of 4 only was accessible by lower energy excitation, τTA = 3.8 μs. Complex 4 was nontoxic (EC50 > 300 μM) to SK-MEL-28 melanoma cells and CCD1064-Sk normal skin fibroblasts in the dark, while 3 was selectively cytotoxic to melanoma (EC50= 5.1 μM) only. Compounds 1 and 2 were selective for melanoma cells in the dark, with submicromolar potencies (EC50 = 350-500 nM) and selectivity factors (SFs) around 50. The photocytotoxicities of compounds 1-4 toward melanoma cells were similar, but only compounds 3 and 4 displayed significant phototherapeutic indices (PIs; 3, 43; 4, >1100). The larger cytotoxicities for compounds 1 and 2 were attributed to increased cellular uptake and nuclear accumulation, and possibly related to the DNA-aggregating properties of all four compounds as demonstrated by cell-free gel mobility-shift assays. Together, these results demonstrate a new class of thiophene-containing Ru(II) cyclometalated compounds that contain both highly selective chemotherapeutic agents and extremely potent photocytotoxic agents.

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NIR-Absorbing Ru^II Complexes Containing α-Oligothiophenes for Applications in Photodynamic Therapy.

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NIR-Absorbing RuII Complexes Containing α-Oligothiophenes for Applications in Photodynamic Therapy.

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OmicsDI is part of the ELIXIR infrastructure

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NIR-Absorbing Ru^II Complexes Containing α-Oligothiophenes for Applications in Photodynamic Therapy.