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 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 <i>in vitro</i> 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, <b>SCV49</b>, shows a favorable <i>in vivo</i> 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 <b>SCV49</b> as a strong candidate for further preclinical development, particularly for treating large hypoxic solid tumors.
Authors
- Joaquín Bonelli (ORCID: https://orcid.org/0000-0003-4958-373X)
- Manel Bosch (ORCID: https://orcid.org/0000-0001-5870-6346)
- E. Izquierdo (ORCID: https://orcid.org/0000-0002-7253-6934)
- Vicente Marchán (ORCID: https://orcid.org/0000-0002-1905-2156)
- Albert Gandioso (ORCID: https://orcid.org/0000-0002-5114-8502)
- Antonio Francés‐Monerris (ORCID: https://orcid.org/0000-0001-8232-4989)
- Santi Nonell (ORCID: https://orcid.org/0000-0002-8900-5291)
- Mireia Jordà‐Redondo (ORCID: https://orcid.org/0000-0003-0024-3638)
- Marta E. Alberto (ORCID: https://orcid.org/0000-0001-9925-7233)
- Gilles Gasser (ORCID: https://orcid.org/0000-0002-4244-5097)
- Sergi Chumillas (ORCID: https://orcid.org/0000-0002-0173-6031)
- Diego Abad-Montero (ORCID: https://orcid.org/0000-0003-4138-7785)
- Valentin V. Novikov (ORCID: https://orcid.org/0000-0002-0225-0594)
- José Luís Hernández (ORCID: https://orcid.org/0000-0002-9172-6004)
- Jorge Galino
- Alba Deyà
- Anna Rovira
- Davor Castaño
Institutions
- Centre National de la Recherche Scientifique (FR)
- Chimie ParisTech - PSL (FR)
- Universitat de València (ES)
- Université Paris Sciences et Lettres (FR)
- Leitat Technological Center (ES)
- Institut Químic de Sarrià (ES)
- Institut de Biomedicina de la Universitat de Barcelona
- University of Calabria (IT)
- Universitat Ramon Llull (ES)
- Chiesi (France) (FR)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2025-02-15
- DOI
- https://doi.org/10.1021/jacs.4c15036
- Citations
- 42
- Primary Topic
- Nanoplatforms for cancer theranostics
- Type
- article
- Field-Weighted Citation Impact
- 28.31
Funders
- “la Caixa” Foundation
- Ministerio de Ciencia, Innovación y Universidades
- Institució Catalana de Recerca i Estudis Avançats
- Fondation ARC pour la Recherche sur le Cancer
- Universitat de Barcelona
- Fundació Bosch i Gimpera
- European Research Council
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- European Regional Development Fund
- Agencia Estatal de Investigación