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In this study, the two-photon absorption cross section of 14+ 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 \u03bcm 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 14+ 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, 14+ was photoexcited through TPA at a power of 60 mW, which was progressively focused in 10 \u03bcm steps throughout the entire z-axis of individual spheroids. These experiments revealed that, in irradiated spheroids treated with 14+, acute and rapid photoinduced cell death was observed throughout their depth, including the hypoxic region.<\/jats:p>","DOI":"10.1021\/jacs.9b11313","type":"journal-article","created":{"date-parts":[[2020,2,17]],"date-time":"2020-02-17T11:32:46Z","timestamp":1581939166000},"page":"4639-4647","source":"Crossref","is-referenced-by-count":126,"title":["A Dinuclear\nRuthenium(II) Complex Excited by Near-Infrared\nLight through Two-Photon Absorption Induces Phototoxicity Deep within\nHypoxic Regions of Melanoma Cancer Spheroids"],"prefix":"10.1021","volume":"142","author":[{"given":"Ahtasham","family":"Raza","sequence":"first","affiliation":[{"name":"University of Sheffield , , Mappin St , ,","place":["Sheffield, U.K., S1 3JD"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart A.","family":"Archer","sequence":"additional","affiliation":[{"name":"University of Sheffield , , Brook Hill , , ,","place":["Sheffield, U.K., S3 7HF"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon D.","family":"Fairbanks","sequence":"additional","affiliation":[{"name":"University of Sheffield , , Brook Hill , , ,","place":["Sheffield, U.K., S3 7HF"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsty L.","family":"Smitten","sequence":"additional","affiliation":[{"name":"University of Sheffield , , Brook Hill , , ,","place":["Sheffield, U.K., S3 7HF"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley W.","family":"Botchway","sequence":"additional","affiliation":[{"name":"STFC Rutherford Appleton Laboratory , , ,","place":["Oxfordshire, U.K., OX11 0QX"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8662-7917","authenticated-orcid":true,"given":"James A.","family":"Thomas","sequence":"additional","affiliation":[{"name":"University of Sheffield , , Brook Hill , , ,","place":["Sheffield, U.K., S3 7HF"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila","family":"MacNeil","sequence":"additional","affiliation":[{"name":"University of Sheffield , , Mappin St , ,","place":["Sheffield, U.K., S1 3JD"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Haycock","sequence":"additional","affiliation":[{"name":"University of Sheffield , , Mappin St , ,","place":["Sheffield, U.K., S1 3JD"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,2,17]]},"reference":[{"issue":"5","key":"2026090313480712400_cit1","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1111\/j.1445-2197.1991.tb00230.x","article-title":"A History of Photodynamic\nTherapy","volume":"61","author":"Daniell","year":"1991","journal-title":"Aust N Z. 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