Abad-Montero Diego, Gandioso Albert, Izquierdo-García Eduardo, Chumillas Sergi, Rovira Anna, Bosch Manel, Jordà-Redondo Mireia, Castaño Davor, Bonelli Joaquín, Novikov Valentin V, Deyà Alba, Hernández José Luis, Galino Jorge, Alberto Marta E, Francés-Monerris Antonio, Nonell Santi, Gasser Gilles, Marchán Vicente
Departament de Química Inorgànica i Orgànica, Secció de Química Orgànica, Universitat de Barcelona (UB), and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Martí i Franquès 1-11, E-08028 Barcelona, Spain.
Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, F-75005 Paris, France.
J Am Chem Soc. 2025 Mar 5;147(9):7360-7376. doi: 10.1021/jacs.4c15036. Epub 2025 Feb 15.
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 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, , shows a favorable 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 as a strong candidate for further preclinical development, particularly for treating large hypoxic solid tumors.
缺氧是许多实体瘤的一个标志，与癌症侵袭性增加、转移以及对传统疗法的耐药性有关，导致患者预后不良。这对光动力疗法（PDT）的效率提出了挑战，光动力疗法依赖于通过照射光敏剂（PS）产生细胞毒性活性氧（ROS），这一过程部分取决于氧气水平。在这项工作中，我们引入了一类新型的强效光敏剂，基于钌（II）多吡啶配合物，其具有源自香豆素类COUPY的2,2'-联吡啶配体，称为COUBPYs。当在光疗窗口内用光照射时，Ru-COUBPY配合物对CT-26癌细胞表现出出色的细胞毒性，在常氧和缺氧条件下均达到纳摩尔效力，同时在黑暗中保持无毒，从而产生令人印象深刻的光毒性指数（>30,000）。它们产生I型和II型ROS的能力支撑了其卓越的光动力疗法效率。本研究的先导化合物在以低至3 mg/kg的剂量用深红色光（660 nm）照射时，在携带皮下CT-26肿瘤的小鼠中显示出良好的药代动力学特征、出色的毒理学耐受性和有效的肿瘤生长抑制作用。这些结果使我们能够提出将其作为进一步临床前开发的有力候选物，特别是用于治疗大型缺氧实体瘤。
