A Dinuclear Ruthenium(II) Complex Excited by Near-Infrared Light through Two-Photon Absorption Induces Phototoxicity Deep within Hypoxic Regions of Melanoma Cancer Spheroids
A Dinuclear Ruthenium(II) Complex Excited by Near-Infrared Light through Two-Photon Absorption Induces Phototoxicity Deep within Hypoxic Regions of Melanoma Cancer Spheroids
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DOI：
10.1021/jacs.9b11313
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发表时间：
2020-03-11
影响因子：
15
通讯作者：
Haycock, John W.
中科院分区：
文献类型：
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作者：
Raza, Ahtasham;Archer, Stuart A.;Haycock, John W.
双核光氧化钌-Ⅱ配合物[{Ru-（TAP（2））}（2）（tpphz）]（+-）（TAP = 1，4，5，8-四氮杂菲，tpphz =四吡啶并[3，2-a：2 '，3'-c：3“，2”-h：2“'，3”"-j]吩嗪），1（4+），很容易被定位于线粒体和细胞核中的活细胞摄取。在这项研究中，1（4+）的双光子吸收截面进行了量化，并报告了其作为双光子吸收光疗的用途。据证实，该复合物是容易光激发使用近红外，NIR，和光通过双光子吸收，TPA。在2-D细胞培养物中，用低功率的NIR光照射导致精确聚焦的光毒性效应，其中人黑素瘤细胞在光暴露5分钟后被杀死。然后在人类癌症球体中进行类似的实验，为治疗和光治疗的发展提供了现实的肿瘤模型。使用该复合物的特征发射作为探针，研究了其进入280 μ m球状体的吸收，并证实该球状体吸收了该复合物。值得注意的是，TPA激发导致在整个球状体的深度上观察到更强的发光，尽管发射强度仍然朝向坏死核心下降。由于I（4+）可以直接光氧化DNA而不需要单线态氧或其他活性氧物质的介导，因此还研究了球状体的更深的缺氧层内的光毒性。为了量化这些光毒性作用的穿透，1（4+）通过TPA以60 mW的功率光激发，其在各个球状体的整个z轴上以10 μ m的步长逐渐聚焦。这些实验表明，在用1（4+）处理的辐照球状体中，在其整个深度（包括缺氧区域）观察到急性和快速的光诱导细胞死亡。
The dinuclear photo-oxidizing Ru-II complex [{Ru-(TAP(2))}(2)(tpphz)](+-) (TAP = 1,4,5,8- tetraazaphenanthrene, tpphz = tetrapyrido[3,2-a:2',3'-c:3 '',2 ''-h:2"',3'''-j]phenazine), 1(4+), is readily taken up by live cells localizing in mitochondria and nuclei. In this study, the two-photon absorption cross section of 1(4+) is quantified and its use as a two-photon absorbing phototherapeutic is reported. It was confirmed that the complex is readily photoexcited using near-infrared, NIR, and light through two-photon absorption, TPA. In 2-D cell cultures, irradiation with NIR light at low power results in precisely focused phototoxicity effects in which human melanoma cells were killed after 5 min of light exposure. Similar experiments were then carried out in human cancer spheroids that provide a realistic tumor model for the development of therapeutics and phototherapeutics. Using the characteristic emission of the complex as a probe, its uptake into 280 pm spheroids was investigated and confirmed that the spheroid takes up the complex. Notably TPA excitation results in more intense luminescence being observed throughout the depth of the spheroids, although emission intensity still drops off toward the necrotic core. As 1(4+) can directly photo- oxidize DNA without the mediation of singlet oxygen or other reactive oxygen species, phototoxicity within the deeper, hypoxic layers of the spheroids was also investigated. To quantify the penetration of these phototoxic effects, 1(4+) was photoexcited through TPA at a power of 60 mW, which was progressively focused in 10 mu m steps throughout the entire z-axis of individual spheroids. These experiments revealed that, in irradiated spheroids treated with 1(4+), acute and rapid photoinduced cell death was observed throughout their depth, including the hypoxic region.