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Even though platinum-based drugs such as cisplatin and carboplatin are effective in TNBC patients, their toxicity and development of cancer drug resistance often hamper their clinical use. Hence, novel drug entities with improved tolerability and selectivity profiles, as well as the ability to surpass resistance, are needed. The current study focuses on Pd(II) and Pt(II) trinuclear chelates with spermidine (Pd3Spd2 and Pt3Spd2) for evaluating their antineoplastic activity having been assessed towards (i) cisplatin-resistant TNBC cells (MDA-MB-231\/R), (ii) cisplatin-sensitive TNBC cells (MDA-MB-231) and (iii) non-cancerous human breast cells (MCF-12A, to assess the cancer selectivity\/selectivity index). Additionally, the complexes\u2019 ability to overcome acquired resistance (resistance index) was determined. This study revealed that Pd3Spd2 activity greatly exceeds that displayed by its Pt analog. In addition, Pd3Spd2 evidenced a similar antiproliferative activity in both sensitive and resistant TNBC cells (IC50 values 4.65\u20138.99 \u00b5M and 9.24\u201313.34 \u00b5M, respectively), with a resistance index lower than 2.3. Moreover, this Pd compound showed a promising selectivity index ratio: &gt;6.28 for MDA-MB-231 cells and &gt;4.59 for MDA-MB-231\/R cells. Altogether, the data presently gathered reveal Pd3Spd2 as a new, promising metal-based anticancer agent, which should be further explored for the treatment of TNBC and its cisplatin-resistant forms.<\/jats:p>","DOI":"10.3390\/pharmaceutics15041205","type":"journal-article","created":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T01:33:03Z","timestamp":1681176783000},"page":"1205","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Pd(II) and Pt(II) Trinuclear Chelates with Spermidine: Selective Anticancer Activity towards TNBC-Sensitive and -Resistant to Cisplatin"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9257-7020","authenticated-orcid":false,"given":"Martin","family":"Vojtek","sequence":"first","affiliation":[{"name":"LAQV\/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Clara B.","family":"Martins","sequence":"additional","affiliation":[{"name":"Molecular Physical-Chemistry R & D Unit, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5324-8826","authenticated-orcid":false,"given":"Raquel","family":"Ramos","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Sara Gomes","family":"Duarte","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8424-1431","authenticated-orcid":false,"given":"Isabel M. P. L. V. O.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laboratory of Bromatology and Hydrology, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1280-3321","authenticated-orcid":false,"given":"Ana L. M.","family":"Batista de Carvalho","sequence":"additional","affiliation":[{"name":"Molecular Physical-Chemistry R & D Unit, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8391-0055","authenticated-orcid":false,"given":"M. Paula M.","family":"Marques","sequence":"additional","affiliation":[{"name":"Molecular Physical-Chemistry R & D Unit, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"},{"name":"Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3000-456 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4668-9360","authenticated-orcid":false,"given":"Carmen","family":"Diniz","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1021\/acs.chemrev.0c00383","article-title":"Challenges and Opportunities in Cancer Drug Resistance","volume":"121","author":"Ward","year":"2021","journal-title":"Chem. 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