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A dipyridophenazine Ni(II) dithiolene complex as a dual-acting cancer phototherapy agent activatable within the phototherapeutic window

Sarkar, T and Sahoo, S and Neekhra, S and Paul, M and Biswas, S and Babu, BN and Srivastava, R and Hussain, A (2023) A dipyridophenazine Ni(II) dithiolene complex as a dual-acting cancer phototherapy agent activatable within the phototherapeutic window. In: European Journal of Medicinal Chemistry, 261 .

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A combination of photodynamic therapy (PDT) and photothermal therapy (PTT) within the phototherapeutic window (600�900 nm) can lead to significantly enhanced therapeutic outcomes, surpassing the efficacy observed with PDT or PTT alone in cancer phototherapy. Herein, we report a novel small-molecule mixed-ligand Ni(II)-dithiolene complex (Ni-TDD) with a dipyridophenazine ligand, demonstrating potent red-light PDT and significant near-infrared (NIR) light mild-temperature PTT activity against cancer cells and 3D multicellular tumour spheroids (MCTSs). The four-coordinate square planar complex exhibited a moderately intense absorption band (ε � 3700 M�1cm�1) centered around 900 nm and demonstrated excellent dark and photostability in an aqueous phase. Ni-TDD induced a potent red-light (600�720 nm) PDT effect on HeLa cancer cells (IC50 = 1.8 μM, photo irritation factor = 44), triggering apoptotic cell death through efficient singlet oxygen generation. Ni-TDD showed a significant intercalative binding affinity towards double-helical calf thymus DNA, resulting in a binding constant (Kb) � 106 M�1. The complex induced mild hyperthermia and exerted a significant mild-temperature PTT effect on MDA-MB-231 cancer cells upon irradiation with 808 nm NIR light. Simultaneous irradiation of Ni-TDD-treated HeLa MCTSs with red and NIR light led to a remarkable synergistic inhibition of growth, exceeding the effects of individual irradiation, through the generation of singlet oxygen and mild hyperthermia. Ni-TDD displayed minimal toxicity towards non-cancerous HPL1D and L929 cells, even at high micromolar concentrations. This is the first report of a Ni(II) complex demonstrating red-light PDT activity and the first example of a first-row transition metal complex exhibiting combined PDT and PTT effects within the clinically relevant phototherapeutic window. Our findings pave the way for designing and developing metal-dithiolene complexes as dual-acting cancer phototherapy agents using long wavelength light for treating solid tumors. © 2023 Elsevier Masson SAS

Item Type: Journal Article
Publication: European Journal of Medicinal Chemistry
Publisher: European Journal of Medicinal Chemistry
Additional Information: The copyright for this article belongs to the Elsevier Masson s.r.l.
Department/Centre: Division of Chemical Sciences > Inorganic & Physical Chemistry
Date Deposited: 24 Nov 2023 11:03
Last Modified: 24 Nov 2023 11:03
URI: https://eprints.iisc.ac.in/id/eprint/83294

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