Os(II) Oligothienyl Complexes as a Hypoxia-Active Photosensitizer Class for Photodynamic Therapy
| Autor: | S.D. Kim, Evan Bradner, Colin G. Cameron, Marta E. Alberto, Patrick C. Barrett, Gagan Deep, John Roque, Ge Shi, Nino Russo, Sherri A. McFarland, David von Dohlen, Houston D. Cole, Liubov M. Lifshits |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Cell Survival
medicine.medical_treatment Photodynamic therapy Tumor cells Antineoplastic Agents Thiophenes 010402 general chemistry 01 natural sciences Article Inorganic Chemistry Coordination Complexes medicine Tumor Cells Cultured Humans Photosensitizer Physical and Theoretical Chemistry Density Functional Theory Cell Proliferation Photosensitizing Agents 010405 organic chemistry Chemistry Hypoxia (medical) Osmium Cell Hypoxia 0104 chemical sciences Photochemotherapy Cancer research medicine.symptom Drug Screening Assays Antitumor |
| Zdroj: | Inorg Chem |
| ISSN: | 1520-510X |
| Popis: | Hypoxia presents a challenge to anticancer therapy, reducing the efficacy of many available treatments. Photodynamic therapy (PDT) is particularly susceptible to hypoxia given that its mechanism relies on oxygen. Herein, we introduce two new osmium-based polypyridyl photosensitizers that are active in hypoxia. The lead compounds emerged from a systematic study of two Os(II) polypyridyl families derived from 2,2′-bipyridine (bpy) or 4,4′-dimethyl-2,2′-bipyridine (dmb) as coligands combined with imidazo[4,5-f][1,10]phenanthroline ligands tethered to n=0–4 thiophenes (IP-nT). The compounds were characterized and investigated for their spectroscopic and (photo)biological activities. The two hypoxia-active Os(II) photosensitizers had n=4 thiophenes, with the bpy analog 1–4T being the most potent. In normoxia, 1–4T had low nanomolar activity (EC(50)=1–13 nM) with phototherapeutic indices (PI) ranging from 5,500 to 55,000 with red and visible light, respectively. Submicromolar potency was maintained even in hypoxia (1% O(2)), with light EC(50) and PI values of 732–812 nM and 68–76, respectively — among the largest PIs to date for hypoxic photoactivity. This high degree of activity coincided with a low-energy, long-lived (0.98–3.6 μs) mixed-character intraligand-charge-transfer ((3)ILCT)/ligand-to-ligand charge transfer ((3)LLCT) state only accessible in quaterthiophene complexes 1–4T and 2–4T. The coligand identity strongly influenced the photophysical and photobiological results in this study, whereby the bpy coligand led to longer lifetimes (3.6 μs) and more potent photocytotoxicity relative to dmb. The unactivated compounds were relatively nontoxic both in vitro and in vivo. The maximum tolerated dose (MTD) for 1–4T and 2–4T in mice was ≥ 200 mg kg(−1), an excellent starting point for future in vivo validation. |
| Databáze: | OpenAIRE |
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