π-Extended Ru–COUBPY Photosensitizers for In Vivo Anticancer Phototherapy Using One-Photon 780 nm Near-Infrared Light Diego Abad-Montero, Eduardo Izquierdo-García, Pierre Mesdom, Albert Gandioso, Elena de la Torre-Rubio, Manel Bosch, Juan Sanz-Villafruela, Alba Deyà, Marta Redrado, Valentin V. Novikov, José Luis Hernández, Jorge Galino, Marta E. Alberto, Antonio Francés-Monerris, Gilles Gasser, Vicente Marchán Journal of the American Chemical Society, 2025 High Resolution Image Download MS PowerPoint Slide Photodynamic therapy (PDT) is a promising cancer treatment modality, offering precise spatial and temporal control of drug activation using light. However, clinical translation of current photosensitizers (PSs) is limited by inefficient activation at wavelengths within the phototherapeutic window, especially in the deep-red and near-infrared (NIR) region. NIR light provides advantages such as reduced absorption by endogenous chromophores, minimized tissue photodamage, and improved tissue penetration, highlighting the need for PSs to be activatable in this range. Herein, we report a novel series of ruthenium(II) polypyridyl complexes ( Ru4–7 ) featuring π-extended COUBPY ligands, designed via a vinylogation strategy and synthesized through an innovative postcoordination ligand assembly approach. This structural modification enhances molar absorptivity and red-shifts the absorption bands well into the NIR region without substantially compromising photostability. Complexes Ru4–7 efficiently generate both Type I and Type II reactive oxygen species, and their photodynamic activity, combined with preferential mitochondrial accumulation, leads to potent nanomolar phototoxicity against CT-26 colorectal cancer cells under deep-red and NIR irradiation, even under hypoxia. Notably, the lead complex Ru6 demonstrated strong in vivo phototoxicity in mice bearing subcutaneous CT-26 tumors, achieving significant tumor growth inhibition upon irradiation with 660 and 780 nm light. Ru6 thus represents one of the first Ru(II) polypyridyl complexes to exhibit robust in vivo PDT antitumor activity under one-photon NIR activation. Its broad wavelength activation profile further underscores its potential versatility for treating tumors of varying size and anatomical location depending on specific light penetration requirements. These findings mark a promising step toward next-generation PSs for treating deep-seated and hypoxic tumors.
Exploring the Impact of Phenanthroline-Based Glycoconjugated Ru(II) Polypyridyl Photosensitizers on Metastasis-Related Processes Elena de la Torre‐Rubio, María‐Selma Arias‐Pérez, Lourdes Gude, Tomás Cuenca, Cristina García‐Iriepa, Eva Royo Chemistry A European Journal, 2025 Novel water‐soluble, phosphorescent ruthenium(II) polypyridyl‐glycoconjugates of general formula [Ru{N‐(1,10‐phenanthroline)}2{N‐(1,10‐phenanthrolin‐5‐yl)‐β‐glycopyranosylamine}][Cl]2 (glycopyranosyl = D‐glucopyranosyl (1), D‐mannopyranosyl (2), L‐rhamnopyranosyl (3), L‐xylopyranosyl (4), and 2,3,4‐tri‐O‐acetyl‐L‐xylopyranosyl (5)) and corresponding aglycone [Ru{N‐(1,10‐phenanthroline)}2{N‐(1,10‐phenanthrolin‐5‐amine)}][Cl]2 (6) have been synthesized and fully characterized. Their stability and behavior in physiological media have been assessed using ultraviolet visible spectroscopy (UV‐Vis) and 1H nuclear magnetic resonance (¹H‐NMR), revealing minor N‐glycosidic cleavage and high photostability. The photocytotoxicity of the complexes has been evaluated in two different cancer (PC‐3 and MCF‐7) and one nontumorigenic (HFF‐1) cell lines. While exhibiting no toxicity in the dark, some glycoconjugates achieve photoselectivity indexes of up to 40 upon blue‐light irradiation. Remarkably, complexes 1–6 potently affect the metastatic phenotype of PC‐3 cells, evidenced by the inhibition of migration in the wound healing assay and the increased resistance to trypsin detachment following photoactivation.
Fluorescent Vitamin B12–Platinum(II) Derivatives as Potential Metallotheranostic Agents for the Treatment and Imaging of Tumors Rozan Mehder, Elena de la Torre-Rubio, Isabel de la Cueva-Alique, Ciaran O’Malley, Adrián Pérez-Redondo, Lourdes Gude, Eva Royo, Luca Ronconi Inorganics, 2024 Vitamin B12 (cyanocobalamin) is an essential nutrient with very low bioavailability. Compared with normal cells, tumor cells show an increased demand for vitamin B12 to support their abnormal proliferation, which is a feature that can be exploited for the tumor-specific delivery of therapeutic and/or diagnostic agents by functionalizing vitamin B12 with suitable metallodrugs and/or luminescent probes. In this context, we report on the design of fluorescent vitamin B12–metal conjugates of the type [FLUO–B12–{M}] in which cyanocobalamin is functionalized at the 5′-site of the ribose unit with a fluorophore (FLUO: rhodamine 6G), whereas the Co(III)–cyano moiety is N-coordinated to a metal-based anticancer scaffold ({M}: Pt(II) substrate bearing enantiopure phenylamino-oxime ligands derived from R- or S-limonene). Two novel fluorescent cyanocobalamin–platinum(II) derivatives and their corresponding non-fluorescent counterparts were successfully generated and fully characterized, including the evaluation of their lipophilicity and luminescent properties. Although they exhibit low antiproliferative activity (IC50 = 40–70 μM), both fluorescent vitamin B12–platinum(II) conjugates showed an enhanced capability to inhibit cell viability compared with the inactive metal precursors and the non-fluorescent vitamin B12–platinum(II) analogues, confirming the beneficial effect of functionalization with the rhodamine 6G scaffold not only for imaging purposes but also with the aim of improving their biological activity.
Carbohydrate effect of novel arene Ru(II) phenanthroline-glycoconjugates on metastatic biological processes Elena de la Torre-Rubio, Laura Muñoz-Moreno, Ana M. Bajo, Maria-Selma Arias-Pérez, Tomás Cuenca, Lourdes Gude, Eva Royo Journal of Inorganic Biochemistry, 2023 Novel water-soluble half-sandwich ruthenium(II) polypyridyl-glycoconjugates [Ru(p-cymene)Cl{N-(1,10-phenanthroline-5-yl)-β-glycopyranosylamine}][Cl] (glycopyranosyl = d-glucopyranosyl (1), D-mannopyranosyl (2), L-rhamnopyranosyl (3) and l-xylopyranosyl (4)) have been synthesized and fully characterized. Their behaviour in water under physiological conditions has been studied by nuclear magnetic resonance spectroscopy, revealing their hydrolytic stability. Interactions of the novel compounds with duplex-deoxiribonucleic acid (dsDNA) were investigated by different techniques and the results indicate that, under physiological pH and saline conditions, the metal glycoconjugates bind DNA in the minor groove and/or through external, electrostatic interactions, and by a non-classical, partial intercalation mechanism in non-saline phosphate buffered solution. Effects of compounds 1–4 on cell viability have been assessed in vitro against two human cell lines (androgen-independent prostate cancer PC-3 and non-tumorigenic prostate RWPE-1), showing moderate cytotoxicities, with IC50 values higher than those found for free ligands [N-(1,10-phenanthroline-5-yl)-β-glycopyranosylamine] (glycopyranosyl = d-glucopyranosyl (a), D-mannopyranosyl (b), L-rhamnopyranosyl (c) and l-xylopyranosyl (d)) or corresponding metal-aglycone. Cell viability was assayed in the presence and absence of the glucose transporters (GLUTs) inhibitor [N4-{1-(4-cyanobenzyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-7-fluoroquinoline-2,4-dicarboxamide] (BAY-876), and the results point to a negligible impact of the inhibition of GLUTs on the cytotoxicity caused by Ru(II) compounds 1–4. Remarkably, glycoconjugates 1–4 potently affect the migration pattern of PC-3 cells, and the wound healing assay evidence that the presence of the carbohydrate and the Ru(II) center is a requisite for the anti-migratory activity observed in these novel derivatives. In addition, derivatives 1–4 strongly affect the matrix metalloproteinase MMP-9 activities of PC-3 cells, while proMMP-2 and especially proMMP-9 were influenced to a much lesser extent.
