Ruthenium(II) Polypyridyl Complexes Containing COUBPY Ligands as Potent Photosensitizers for the Efficient Phototherapy of Hypoxic Tumors

Hypoxia, a hallmark of many solid tumors, is linked to increased cancer aggressiveness, metastasis, and resistance to conventional therapies, leading to poor patient outcomes. This challenges the efficiency of photodynamic therapy (PDT), which relies on the generation of cytotoxic reactive oxygen sp...

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Autores: Abad-Montero, Diego, Gandioso, Albert, Izquierdo García, Eduardo, Chumillas, Sergi, Rovira, Anna, Bosch, Manel, Jordà-Redondo, Mireia, Castaño, Davor, Bonelli, Joaquín, Novikov, Valentin, Deyà, Alba, Hernández, José Luis, Galino, Jorge, Alberto, Marta Erminia, Francés-Monerris, Antonio, Nonell, Santi, Gasser, Gilles, Marchán, Vicente
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:20.500.14342/5500
Acceso en línea:http://hdl.handle.net/20.500.14342/5500
https://doi.org/10.1021/jacs.4c15036
Access Level:acceso abierto
Palabra clave:Electromagnetic radiation
Irradiation
Ligands
Light
Oxygen
Electromagnetisme
Irradiació
Lligands (Bioquímica)
Llum
Oxigen
537
577
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spelling Ruthenium(II) Polypyridyl Complexes Containing COUBPY Ligands as Potent Photosensitizers for the Efficient Phototherapy of Hypoxic TumorsAbad-Montero, DiegoGandioso, AlbertIzquierdo García, EduardoChumillas, SergiRovira, AnnaBosch, ManelJordà-Redondo, MireiaCastaño, DavorBonelli, JoaquínNovikov, ValentinDeyà, AlbaHernández, José LuisGalino, JorgeAlberto, Marta ErminiaFrancés-Monerris, AntonioNonell, SantiGasser, GillesMarchán, VicenteElectromagnetic radiationIrradiationLigandsLightOxygenElectromagnetismeIrradiacióLligands (Bioquímica)LlumOxigen537577Hypoxia, a hallmark of many solid tumors, is linked to increased cancer aggressiveness, metastasis, and resistance to conventional therapies, leading to poor patient outcomes. This challenges the efficiency of photodynamic therapy (PDT), which relies on the generation of cytotoxic reactive oxygen species (ROS) through the irradiation of a photosensitizer (PS), a process partially dependent on oxygen levels. In this work, we introduce a novel family of potent PSs based on ruthenium(II) polypyridyl complexes with 2,2′-bipyridyl ligands derived from COUPY coumarins, termed COUBPYs. Ru-COUBPY complexes exhibit outstanding in vitro cytotoxicity against CT-26 cancer cells when irradiated with light within the phototherapeutic window, achieving nanomolar potency in both normoxic and hypoxic conditions while remaining nontoxic in the dark, leading to impressive phototoxic indices (>30,000). Their ability to generate both Type I and Type II ROS underpins their exceptional PDT efficiency. The lead compound of this study, SCV49, shows a favorable in vivo pharmacokinetic profile, excellent toxicological tolerability, and potent tumor growth inhibition in mice bearing subcutaneous CT-26 tumors at doses as low as 3 mg/kg upon irradiation with deep-red light (660 nm). These results allow us to propose SCV49 as a strong candidate for further preclinical development, particularly for treating large hypoxic solid tumors.info:eu-repo/semantics/publishedVersionAmerican Chemical SocietyUniversitat Ramon Llull. IQS2025info:eu-repo/semantics/articlep.17http://hdl.handle.net/20.500.14342/5500https://doi.org/10.1021/jacs.4c15036reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésJournal of the American Chemical Society 2025, 147 (9), 7360–7376info:eu-repo/grantAgreement/MCI/PN I+D/PID2020-117508RB-I00info:eu-repo/grantAgreement/MCIU/PN I+D/PID2023-146161OB-I00info:eu-repo/grantAgreement/MCI/PN I+D/PID2021-127554NA-I00info:eu-repo/grantAgreement/MCI/PN I+D/PID2020-115801RB-C22info:eu-repo/grantAgreement/MCIU/PN I+D/PID2023-149483NB-C22info:eu-repo/grantAgreement/MCIU/PN I+D/PID2023-146161OB-I00info:eu-repo/grantAgreement/Fundació “la Caixa”/CaixaImpulse Innovation/56000013info:eu-repo/grantAgreement/SUR del DEC/SGR/2021 SGR 01023info:eu-repo/grantAgreement/DREU/LLAVOR/2021 LLAV 00083© L'autor/aAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:20.500.14342/55002026-05-29T05:05:01Z
dc.title.none.fl_str_mv Ruthenium(II) Polypyridyl Complexes Containing COUBPY Ligands as Potent Photosensitizers for the Efficient Phototherapy of Hypoxic Tumors
title Ruthenium(II) Polypyridyl Complexes Containing COUBPY Ligands as Potent Photosensitizers for the Efficient Phototherapy of Hypoxic Tumors
spellingShingle Ruthenium(II) Polypyridyl Complexes Containing COUBPY Ligands as Potent Photosensitizers for the Efficient Phototherapy of Hypoxic Tumors
Abad-Montero, Diego
Electromagnetic radiation
Irradiation
Ligands
Light
Oxygen
Electromagnetisme
Irradiació
Lligands (Bioquímica)
Llum
Oxigen
537
577
title_short Ruthenium(II) Polypyridyl Complexes Containing COUBPY Ligands as Potent Photosensitizers for the Efficient Phototherapy of Hypoxic Tumors
title_full Ruthenium(II) Polypyridyl Complexes Containing COUBPY Ligands as Potent Photosensitizers for the Efficient Phototherapy of Hypoxic Tumors
title_fullStr Ruthenium(II) Polypyridyl Complexes Containing COUBPY Ligands as Potent Photosensitizers for the Efficient Phototherapy of Hypoxic Tumors
title_full_unstemmed Ruthenium(II) Polypyridyl Complexes Containing COUBPY Ligands as Potent Photosensitizers for the Efficient Phototherapy of Hypoxic Tumors
title_sort Ruthenium(II) Polypyridyl Complexes Containing COUBPY Ligands as Potent Photosensitizers for the Efficient Phototherapy of Hypoxic Tumors
dc.creator.none.fl_str_mv Abad-Montero, Diego
Gandioso, Albert
Izquierdo García, Eduardo
Chumillas, Sergi
Rovira, Anna
Bosch, Manel
Jordà-Redondo, Mireia
Castaño, Davor
Bonelli, Joaquín
Novikov, Valentin
Deyà, Alba
Hernández, José Luis
Galino, Jorge
Alberto, Marta Erminia
Francés-Monerris, Antonio
Nonell, Santi
Gasser, Gilles
Marchán, Vicente
author Abad-Montero, Diego
author_facet Abad-Montero, Diego
Gandioso, Albert
Izquierdo García, Eduardo
Chumillas, Sergi
Rovira, Anna
Bosch, Manel
Jordà-Redondo, Mireia
Castaño, Davor
Bonelli, Joaquín
Novikov, Valentin
Deyà, Alba
Hernández, José Luis
Galino, Jorge
Alberto, Marta Erminia
Francés-Monerris, Antonio
Nonell, Santi
Gasser, Gilles
Marchán, Vicente
author_role author
author2 Gandioso, Albert
Izquierdo García, Eduardo
Chumillas, Sergi
Rovira, Anna
Bosch, Manel
Jordà-Redondo, Mireia
Castaño, Davor
Bonelli, Joaquín
Novikov, Valentin
Deyà, Alba
Hernández, José Luis
Galino, Jorge
Alberto, Marta Erminia
Francés-Monerris, Antonio
Nonell, Santi
Gasser, Gilles
Marchán, Vicente
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Ramon Llull. IQS
dc.subject.none.fl_str_mv Electromagnetic radiation
Irradiation
Ligands
Light
Oxygen
Electromagnetisme
Irradiació
Lligands (Bioquímica)
Llum
Oxigen
537
577
topic Electromagnetic radiation
Irradiation
Ligands
Light
Oxygen
Electromagnetisme
Irradiació
Lligands (Bioquímica)
Llum
Oxigen
537
577
description Hypoxia, a hallmark of many solid tumors, is linked to increased cancer aggressiveness, metastasis, and resistance to conventional therapies, leading to poor patient outcomes. This challenges the efficiency of photodynamic therapy (PDT), which relies on the generation of cytotoxic reactive oxygen species (ROS) through the irradiation of a photosensitizer (PS), a process partially dependent on oxygen levels. In this work, we introduce a novel family of potent PSs based on ruthenium(II) polypyridyl complexes with 2,2′-bipyridyl ligands derived from COUPY coumarins, termed COUBPYs. Ru-COUBPY complexes exhibit outstanding in vitro cytotoxicity against CT-26 cancer cells when irradiated with light within the phototherapeutic window, achieving nanomolar potency in both normoxic and hypoxic conditions while remaining nontoxic in the dark, leading to impressive phototoxic indices (>30,000). Their ability to generate both Type I and Type II ROS underpins their exceptional PDT efficiency. The lead compound of this study, SCV49, shows a favorable in vivo pharmacokinetic profile, excellent toxicological tolerability, and potent tumor growth inhibition in mice bearing subcutaneous CT-26 tumors at doses as low as 3 mg/kg upon irradiation with deep-red light (660 nm). These results allow us to propose SCV49 as a strong candidate for further preclinical development, particularly for treating large hypoxic solid tumors.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.14342/5500
https://doi.org/10.1021/jacs.4c15036
url http://hdl.handle.net/20.500.14342/5500
https://doi.org/10.1021/jacs.4c15036
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Journal of the American Chemical Society 2025, 147 (9), 7360–7376
info:eu-repo/grantAgreement/MCI/PN I+D/PID2020-117508RB-I00
info:eu-repo/grantAgreement/MCIU/PN I+D/PID2023-146161OB-I00
info:eu-repo/grantAgreement/MCI/PN I+D/PID2021-127554NA-I00
info:eu-repo/grantAgreement/MCI/PN I+D/PID2020-115801RB-C22
info:eu-repo/grantAgreement/MCIU/PN I+D/PID2023-149483NB-C22
info:eu-repo/grantAgreement/MCIU/PN I+D/PID2023-146161OB-I00
info:eu-repo/grantAgreement/Fundació “la Caixa”/CaixaImpulse Innovation/56000013
info:eu-repo/grantAgreement/SUR del DEC/SGR/2021 SGR 01023
info:eu-repo/grantAgreement/DREU/LLAVOR/2021 LLAV 00083
dc.rights.none.fl_str_mv © L'autor/a
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv © L'autor/a
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv p.17
dc.publisher.none.fl_str_mv American Chemical Society
publisher.none.fl_str_mv American Chemical Society
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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