{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T02:01:09Z","timestamp":1775527269183,"version":"3.50.1"},"reference-count":47,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T00:00:00Z","timestamp":1629244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The clinical success of cisplatin, carboplatin, and oxaliplatin has sparked the interest of medicinal inorganic chemistry to synthesize and study compounds with non-platinum metal centers. Despite Ru(II)\u2013polypyridyl complexes being widely studied and well established for their antitumor properties, there are not enough in vivo studies to establish the potentiality of this type of compound. Therefore, we report to the best of our knowledge the first in vivo study of Ru(II)\u2013polypyridyl complexes against breast cancer with promising results. In order to conduct our study, we used MCF7 zebrafish xenografts and ruthenium complexes [Ru(bipy)2(C12H8N6-N,N)][CF3SO3]2Ru1 and [{Ru(bipy)2}2(\u03bc-C12H8N6-N,N)][CF3SO3]4Ru2, which were recently developed by our group. Ru1 and Ru2 reduced the tumor size by an average of 30% without causing significant signs of lethality when administered at low doses of 1.25 mg\u00b7L\u22121. Moreover, the in vitro selectivity results were confirmed in vivo against MCF7 breast cancer cells. Surprisingly, this work suggests that both the mono- and the dinuclear Ru(II)\u2013polypyridyl compounds have in vivo potential against breast cancer, since there were no significant differences between both treatments, highlighting Ru1 and Ru2 as promising chemotherapy agents in breast cancer therapy.<\/jats:p>","DOI":"10.3390\/ijms22168916","type":"journal-article","created":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T10:54:35Z","timestamp":1629284075000},"page":"8916","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Evaluation of the In Vitro and In Vivo Efficacy of Ruthenium Polypyridyl Compounds against Breast Cancer"],"prefix":"10.3390","volume":"22","author":[{"given":"Oscar","family":"Lenis-Rojas","sequence":"first","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, ITQB, Av. da Rep\u00fablica, EAN, 2780-157 Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8676-6562","authenticated-orcid":false,"given":"Catarina","family":"Roma-Rodrigues","sequence":"additional","affiliation":[{"name":"UCIBIO, Departamento Ci\u00eancias da Vida, NOVA School of Science and Technology, Universidade Nova de Lisboa, Campus Caparica, 2829-516 Caparica, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2054-4438","authenticated-orcid":false,"given":"Alexandra","family":"Fernandes","sequence":"additional","affiliation":[{"name":"UCIBIO, Departamento Ci\u00eancias da Vida, NOVA School of Science and Technology, Universidade Nova de Lisboa, Campus Caparica, 2829-516 Caparica, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal"}]},{"given":"Andreia","family":"Carvalho","sequence":"additional","affiliation":[{"name":"UCIBIO, Departamento Ci\u00eancias da Vida, NOVA School of Science and Technology, Universidade Nova de Lisboa, Campus Caparica, 2829-516 Caparica, Portugal"}]},{"given":"Sandra","family":"Cordeiro","sequence":"additional","affiliation":[{"name":"UCIBIO, Departamento Ci\u00eancias da Vida, NOVA School of Science and Technology, Universidade Nova de Lisboa, Campus Caparica, 2829-516 Caparica, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8365-7125","authenticated-orcid":false,"given":"Jorge","family":"Guerra-Varela","sequence":"additional","affiliation":[{"name":"Departamento de Zoolog\u00eda, Gen\u00e9tica y Antropolog\u00eda F\u00edsica. Facultad de Veterinaria, Universidade de Santiago de Compostela, 27002 Lugo, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7927-5303","authenticated-orcid":false,"given":"Laura","family":"S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Departamento de Zoolog\u00eda, Gen\u00e9tica y Antropolog\u00eda F\u00edsica. Facultad de Veterinaria, Universidade de Santiago de Compostela, 27002 Lugo, Spain"},{"name":"Preclinical Animal Models Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}]},{"given":"Digna","family":"V\u00e1zquez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica, Centro de Investigaciones Cient\u00edficas Avanzadas (CICA), Universidade da Coru\u00f1a, 15008 A Coru\u00f1a, Spain"}]},{"given":"Margarita","family":"L\u00f3pez-Torres","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica, Centro de Investigaciones Cient\u00edficas Avanzadas (CICA), Universidade da Coru\u00f1a, 15008 A Coru\u00f1a, Spain"}]},{"given":"Alberto","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica, Centro de Investigaciones Cient\u00edficas Avanzadas (CICA), Universidade da Coru\u00f1a, 15008 A Coru\u00f1a, Spain"}]},{"given":"Jes\u00fas","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica, Centro de Investigaciones Cient\u00edficas Avanzadas (CICA), Universidade da Coru\u00f1a, 15008 A Coru\u00f1a, Spain"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41571-020-00441-5","article-title":"COVID-19 in patients with cancer: Managing a pandemic within a pandemic","volume":"18","author":"Horn","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/s41572-019-0111-2","article-title":"Breast cancer","volume":"5","author":"Harbeck","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6175","DOI":"10.1038\/s41467-020-19933-0","article-title":"Chemotherapy induces dynamic immune responses in breast cancers that impact treatment outcome","volume":"11","author":"Park","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1634\/theoncologist.2014-0044","article-title":"Platinum-induced neurotoxicity and preventive strategies: Past, present, and future","volume":"20","author":"Avan","year":"2015","journal-title":"Oncologist"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5771","DOI":"10.1039\/C7CS00195A","article-title":"The development of anticancer ruthenium(II) complexes: From single molecule compounds to nanomaterials","volume":"46","author":"Zeng","year":"2017","journal-title":"Chem. Soc. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1021\/acs.chemrev.8b00211","article-title":"Transition metal complexes and photodynamic therapy from a tumor-centered approach: Challenges, opportunities, and highlights from the development of TLD1433","volume":"119","author":"Monro","year":"2019","journal-title":"Chem. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7317","DOI":"10.1039\/C7CS00356K","article-title":"Monomeric and dimeric coordinatively saturated and substitutionally inert Ru(ii) polypyridyl complexes as anticancer drug candidates","volume":"46","author":"Notaro","year":"2017","journal-title":"Chem. Soc. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7706","DOI":"10.1039\/C7CS00680B","article-title":"The development of ruthenium(II) polypyridyl complexes and conjugates for in vitro cellular and in vivo applications","volume":"46","author":"Poynton","year":"2017","journal-title":"Chem Soc. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Golbaghi, G., and Castonguay, A. (2020). Rationally designed ruthenium complexes for breast cancer therapy. Molecules, 25.","DOI":"10.3390\/molecules25020265"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.steroids.2010.12.009","article-title":"(Arene)Cl\u2082Ru(II) complexes with N-coordinated estrogen and androgen isonicotinates: Interaction with sex hormone binding globulin and anticancer activity","volume":"76","author":"Schobert","year":"2011","journal-title":"Steroids"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9164","DOI":"10.1021\/ic201388n","article-title":"A potent ruthenium(II) antitumor complex bearing a lipophilic levonorgestrel group","volume":"50","author":"Ruiz","year":"2011","journal-title":"Inorg. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3419","DOI":"10.1039\/C8NJ04159H","article-title":"Enhancement of therapeutic effect in breast cancer with a steroid-conjugated ruthenium complex","volume":"43","author":"Lv","year":"2019","journal-title":"New J. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1039\/C7DT03637J","article-title":"Ruthenium(ii) arene NSAID complexes: Inhibition of cyclooxygenase and antiproliferative activity against cancer cell lines","volume":"47","author":"Mandal","year":"2018","journal-title":"Dalton Trans."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10793","DOI":"10.1039\/c1dt11007a","article-title":"Targeted and multifunctional arene ruthenium chemotherapeutics","volume":"40","author":"Smith","year":"2011","journal-title":"Dalton Trans."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1039\/C5MT00122F","article-title":"Discovery of a dual-targeting organometallic ruthenium complex with high activity inducing early stage apoptosis of cancer cells","volume":"7","author":"Du","year":"2015","journal-title":"Metallomics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.jinorgbio.2013.10.017","article-title":"Multi-targeted organometallic ruthenium(II)-arene anticancer complexes bearing inhibitors of poly(ADP-ribose) polymerase-1: A strategy to improve cytotoxicity","volume":"131","author":"Wang","year":"2014","journal-title":"J. Inorg. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Pracharova, J., Novohradsky, V., Kostrhunova, H., Starha, P., Travnicek, Z., Kasparkova, J., and Brabec, V. (2018). Half-sandwich Os(II) and Ru(II) bathophenanthroline complexes: Anticancer drug candidates with unusual potency and cellular activity profile in highly invasive triple-negative breast cancer cells. Dalton Trans.","DOI":"10.1039\/C8DT02236D"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.phrs.2016.03.032","article-title":"The water soluble ruthenium(II) organometallic compound [Ru(p-cymene)(bis(3,5 dimethylpyrazol-1-yl)methane)Cl]Cl suppresses triple negative breast cancer growth by inhibiting tumor infiltration of regulatory T cells","volume":"107","author":"Montani","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9995","DOI":"10.1021\/jm5012337","article-title":"In vitro and in vivo evaluation of water-soluble iminophosphorane ruthenium(II) compounds. A potential chemotherapeutic agent for triple negative breast cancer","volume":"57","author":"Frik","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Colina-Vegas, L., Oliveira, K., Cunha, B., Cominetti, M., Navarro, M., and Azevedo Batista, A. (2018). Anti-proliferative and anti-migration activity of Arene\u2013ruthenium(II) complexes with azole therapeutic agents. Inorganics, 6.","DOI":"10.3390\/inorganics6040132"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5805","DOI":"10.1021\/acs.jmedchem.7b01689","article-title":"Ru(II) compounds: Next-generation anticancer metallotherapeutics?","volume":"61","author":"Thota","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"112030","DOI":"10.1016\/j.ejmech.2019.112030","article-title":"Synthesis and biological assessment of a ruthenium(II) cyclopentadienyl complex in breast cancer cells and on the development of zebrafish embryos","volume":"188","author":"Golbaghi","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9135","DOI":"10.1021\/acs.inorgchem.9b00735","article-title":"Ruthenium-cyclopentadienyl bipyridine-biotin based compounds: Synthesis and biological effect","volume":"58","author":"Karas","year":"2019","journal-title":"Inorg. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/j.ejmech.2018.12.022","article-title":"Unprecedented inhibition of P-gp activity by a novel ruthenium-cyclopentadienyl compound bearing a bipyridine-biotin ligand","volume":"163","author":"Karas","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jinorgbio.2012.04.014","article-title":"Synthesis of organometallic ruthenium(II) complexes with strong activity against several human cancer cell lines","volume":"114","author":"Morais","year":"2012","journal-title":"J. Inorg. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5265","DOI":"10.1038\/s41467-020-18954-z","article-title":"Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells","volume":"11","author":"Valle","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.trecan.2020.03.012","article-title":"Zebrafish xenografts for drug discovery and personalized medicine","volume":"6","author":"Xiao","year":"2020","journal-title":"Trends Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Cabezas-S\u00e1inz, P., Pensado-L\u00f3pez, A., S\u00e1inz, B., and S\u00e1nchez, L. (2020). Modeling cancer using zebrafish xenografts: Drawbacks for mimicking the human microenvironment. Cells, 9.","DOI":"10.3390\/cells9091978"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"83071","DOI":"10.18632\/oncotarget.13068","article-title":"Marine guanidine alkaloids crambescidins inhibit tumor growth and activate intrinsic apoptotic signaling inducing tumor regression in a colorectal carcinoma zebrafish xenograft model","volume":"7","author":"Roel","year":"2016","journal-title":"Oncotarget"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"19127","DOI":"10.1039\/C6DT03591D","article-title":"Heteroleptic mononuclear compounds of ruthenium(II): Synthesis, structural analyses, in vitro antitumor activity and in vivo toxicity on zebrafish embryos","volume":"45","author":"Fernandes","year":"2016","journal-title":"Dalton Trans."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7127","DOI":"10.1021\/acs.inorgchem.7b00790","article-title":"Dinuclear RuII(bipy)2 Derivatives: Structural, biological, and in vivo zebrafish toxicity evaluation","volume":"56","author":"Fernandes","year":"2017","journal-title":"Inorg. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nrm3904","article-title":"Remodelling the extracellular matrix in development and disease","volume":"15","author":"Bonnans","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_34","first-page":"179486","article-title":"Exosome in tumour microenvironment: Overview of the crosstalk between normal and cancer cells","volume":"2014","author":"Fernandes","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1002\/asia.201301331","article-title":"Cobalt complexes with pyrazole ligands as catalyst precursors for the peroxidative oxidation of cyclohexane: X-ray absorption spectroscopy studies and biological applications","volume":"9","author":"Silva","year":"2014","journal-title":"Chem. Asian J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.jconrel.2016.11.021","article-title":"Multifunctional gold-nanoparticles: A nanovectorization tool for the targeted delivery of novel chemotherapeutic agents","volume":"245","author":"Fernandes","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1039\/C5MB00791G","article-title":"In vitro and in vivo biological characterization of the anti-proliferative potential of a cyclic trinuclear organotin(iv) complex","volume":"12","author":"Martins","year":"2016","journal-title":"Mol. Biosyst."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1007\/s00775-014-1110-0","article-title":"Insights into the mechanisms underlying the antiproliferative potential of a Co(II) coordination compound bearing 1,10-phenanthroline-5,6-dione: DNA and protein interaction studies","volume":"19","author":"Silva","year":"2014","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1039\/c0mt00101e","article-title":"Cellular uptake and subcellular distribution of ruthenium-based metallodrugs under clinical investigation versus cisplatin","volume":"3","author":"Groessl","year":"2011","journal-title":"Metallomics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jinorgbio.2018.01.018","article-title":"Synthesis, characterisation and DNA intercalation studies of regioisomers of ruthenium (II) polypyridyl complexes","volume":"182","author":"Perdisatt","year":"2018","journal-title":"J. Inorg. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7038","DOI":"10.1039\/C8CC03786H","article-title":"An estrogen receptor targeted ruthenium complex as a two-photon photodynamic therapy agent for breast cancer cells","volume":"54","author":"Zhao","year":"2018","journal-title":"Chem. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9454","DOI":"10.1039\/D0DT01040E","article-title":"Bifunctional ruthenium(II) polypyridyl complexes of curcumin as potential anticancer agents","volume":"49","author":"Li","year":"2020","journal-title":"Dalton Trans."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/nature12111","article-title":"The zebrafish reference genome sequence and its relationship to the human genome","volume":"496","author":"Howe","year":"2013","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.vascn.2008.05.006","article-title":"Zebrafish assays as early safety pharmacology screens: Paradigm shift or red herring?","volume":"58","author":"Redfern","year":"2008","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1515\/dmdi-2013-0015","article-title":"Biological characterization of the antiproliferative potential of Co(II) and Sn(IV) coordination compounds in human cancer cell lines: A comparative proteomic approach","volume":"28","author":"Silva","year":"2013","journal-title":"Drug Metab. Drug Interact."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"12888","DOI":"10.1039\/c2dt11577h","article-title":"Cobalt complexes bearing scorpionate ligands: Synthesis, characterization, cytotoxicity and DNA cleavage","volume":"41","author":"Silva","year":"2012","journal-title":"Dalton Trans."},{"key":"ref_47","unstructured":"Stirling, D., and Tomlinson, G. (2017). Quantifish\u2014A Zebrafish Fluorescence Analyser, Zenodo."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8916\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:46:50Z","timestamp":1760165210000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8916"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,18]]},"references-count":47,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22168916"],"URL":"https:\/\/doi.org\/10.3390\/ijms22168916","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,18]]}}}