Breaking the barrier: an osmium photosensitizer with unprecedented hypoxic phototoxicity for real world photodynamic therapy.
Breaking the barrier: an osmium photosensitizer with unprecedented hypoxic phototoxicity for real world photodynamic therapy.
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DOI：
10.1039/d0sc03008b
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发表时间：
2020-09-28
期刊：
影响因子：
8.4
通讯作者：
McFarland SA
中科院分区：
文献类型：
--
作者：
Roque JA 3rd;Barrett PC;Cole HD;Lifshits LM;Shi G;Monro S;von Dohlen D;Kim S;Russo N;Deep G;Cameron CG;Alberto ME;McFarland SA
一种无毒的Os（ii）低聚噻吩络合物Os-4 T是一种非常有效的光响应抗癌剂，可以在缺氧和近红外光下活化。低氧在癌症治疗中提出了双重挑战，因为低氧条件诱导生物学变化，使恶性组织同时更具侵袭性且对标准化疗不敏感。本文报道了第一种接近光疗剂理想性能的金属基光敏剂。将Os（phen）2基支架与一系列IP-nT配体组合，其中phen = 1，10-菲咯啉，IP-nT =咪唑并[4，5-f][1，10]菲咯啉，其连接到n = 0-4个噻吩环。Os-4 T（n = 4）成为该系列中最有前途的复合物，具有皮摩尔活性，在常氧下的光疗指数（PI）超过106。该光敏剂在低氧（1%O2）条件下，可见光和绿色光下PI > 90（EC 50 = 0.651 μM），红光下PI > 70。Os-4 T在常氧条件下对733 nm近红外光也有活性（EC 50 = 0.803 μM，PI = 77）。计算和光谱研究都证实了在n = 3时，最低三重激发态的性质从三重金属-配体电荷转移（3 MLCT）到配体内电荷转移（3 ILCT）的切换，其中n = 4时具有较低的能量和较长的寿命。该系列中的所有化合物在黑暗中相对无毒，但随着噻吩的增加，其光毒性逐渐增加。这些常氧和缺氧活动是迄今为止报道的最大的，证明了锇在光疗应用中的实用性。此外，Os-4 T在小鼠中具有>200 mg kg-1的最大耐受剂量（MTD），这使该光敏剂成为体内应用的优秀候选物。
A nontoxic Os(ii) oligothienyl complex Os-4T is an extremely potent light-responsive anticancer agent that can be activated in hypoxia and with NIR light. 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.
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DOI：
10.3322/caac.20114
发表时间：
2011-07
期刊：
CA: a cancer journal for clinicians
影响因子：
--
作者：
Agostinis P;Berg K;Cengel KA;Foster TH;Girotti AW;Gollnick SO;Hahn SM;Hamblin MR;Juzeniene A;Kessel D;Korbelik M;Moan J;Mroz P;Nowis D;Piette J;Wilson BC;Golab J
通讯作者：
Golab J
影响因子：
10.3
作者：
Chen, Kevin G.;Leapman, Richard D.;Gottesman, Michael M.
通讯作者：
Gottesman, Michael M.
影响因子：
4.4
作者：
Cossi, M;Barone, V
通讯作者：
Barone, V
DOI：
10.1007/bf01114537
发表时间：
1990-04-01
期刊：
THEORETICA CHIMICA ACTA
影响因子：
--
作者：
ANDRAE, D;HAUSSERMANN, U;PREUSS, H
通讯作者：
PREUSS, H
影响因子：
4.3
作者：
Alberto, Marta Erminia;Adamo, Carlo
通讯作者：
Adamo, Carlo