Hypoxia presents a two-fold challenge in the treatment of cancer, as low oxygen conditions induce biological changes that make malignant tissues simultaneously more aggressive and less susceptible to standard chemotherapy. This paper reports the first metal-based photosensitizer that approaches the ideal properties for a phototherapy agent. The Os(phen)₂-based scaffold was combined with a series of IP-nT ligands, where phen = 1,10-phenanthroline and IP-nT = imidazo[4,5-f][1,10]phenanthroline tethered to n = 0–4 thiophene rings. Os-4T (n = 4) emerged as the most promising complex in the series, with picomolar activity and a phototherapeutic index (PI) exceeding 10⁶ in normoxia. The photosensitizer exhibited an unprecedented PI > 90 (EC₅₀ = 0.651 μM) in hypoxia (1% O₂) with visible and green light, and a PI > 70 with red light. Os-4T was also active with 733 nm near-infrared light (EC₅₀ = 0.803 μM, PI = 77) under normoxia. Both computation and spectroscopic studies confirmed a switch in the nature of the lowest-lying triplet excited state from triplet metal-to-ligand charge transfer (³MLCT) to intraligand charge transfer (³ILCT) at n = 3, with a lower energy and longer lifetime for n = 4. All compounds in the series were relatively nontoxic in the dark but became increasingly phototoxic with additional thiophenes. These normoxic and hypoxic activities are the largest reported to date, demonstrating the utility of osmium for phototherapy applications. Moreover, Os-4T had a maximum tolerated dose (MTD) in mice that was >200 mg kg⁻¹, which positions this photosensitizer as an excellent candidate for in vivo applications.

中文翻译：

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突破障碍：一种具有光化学毒性的unprecedented光敏剂，可用于现实世界的光动力疗法

低氧对癌症的治疗提出了两方面的挑战，因为低氧条件会诱发生物学变化，使恶性组织同时更具侵略性，并且对标准化学疗法的敏感性降低。本文报道了第一种接近光疗剂理想性能的金属基光敏剂。基于Os（phen）₂的支架与一系列IP- n T配体结合，其中phen = 1,10-菲咯啉，IP- n T =咪唑并[4,5- f ] [1,10]菲咯啉至n = 0–4噻吩环。Os-4T（n= 4）成为该系列中最有前途的复合物，在常氧状态下具有皮摩尔活性和光疗指数（PI）超过10 ⁶。该光敏剂在可见光和绿光下的缺氧（1％O ₂）表现出前所未有的PI> 90（EC ₅₀ = 0.651μM），PI在70以上的红光。在常氧下，Os-4T在733 nm近红外光下（EC ₅₀ = 0.803μM，PI = 77）也具有活性。两个计算和光谱研究证实在最低地势三重激发态的性质的开关从三重态的金属-配体电荷转移（³ MLCT）至intraligand电荷转移（³在ILCT）ñ= 3，n = 4时具有较低的能量和更长的寿命。该系列中的所有化合物在黑暗中相对无毒，但与其他噻吩一起变得越来越光毒性。这些常氧和低氧活动是迄今为止报道的最大量，证明了在光疗应用中的效用。此外，Os-4T在小鼠中的最大耐受剂量（MTD）> 200 mg kg ^-1，这使该光敏剂成为体内应用的极佳候选者。