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However, its use also leads to serious side effects, such as nephrotoxicity, ototoxicity, and cardiotoxicity, which limit the dose that can be safely administered to patients. To minimize these problems, dendrimers may be used as carriers for cisplatin through the coordination of their terminal functional groups to platinum. Here, cisplatin was conjugated to half-generation anionic PAMAM dendrimers in mono- and bidentate forms, and their biological effects were assessed in vitro. After preparation and characterization of the metallodendrimers, their cytotoxicity was evaluated against several cancer cell lines (A2780, A2780cisR, MCF-7, and CACO-2 cells) and a non-cancer cell line (BJ cells). The results showed that all the metallodendrimers were cytotoxic and that the cytotoxicity level depended on the cell line and the type of coordination mode (mono- or bidentate). Although, in this study, a correlation between dendrimer generation (number of carried metallic fragments) and cytotoxicity could not be completely established, the monodentate coordination form of cisplatin resulted in lower IC50 values, thus revealing a more accessible cisplatin release from the dendritic scaffold. Moreover, most of the metallodendrimers were more potent than the cisplatin, especially for the A2780 and A2780cisR cell lines, which showed higher selectivity than for non-cancer cells (BJ cells). The monodentate G0.5COO(Pt(NH3)2Cl)8 and G2.5COO(Pt(NH3)2Cl)32 metallodendrimers, as well as the bidentate G2.5COO(Pt(NH3)2)16 metallodendrimer, were even more active towards the cisplatin-resistant cell line (A2780cisR cells) than the correspondent cisplatin-sensitive one (A2780 cells). Finally, the effect of the metallodendrimers on the hemolysis of human erythrocytes was neglectable, and metallodendrimers\u2019 interaction with calf thymus DNA seemed to be stronger than that of free cisplatin.<\/jats:p>","DOI":"10.3390\/pharmaceutics15020689","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T05:27:01Z","timestamp":1676870821000},"page":"689","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Biological Effects in Cancer Cells of Mono- and Bidentate Conjugation of Cisplatin on PAMAM Dendrimers: A Comparative Study"],"prefix":"10.3390","volume":"15","author":[{"given":"Cl\u00e1udia","family":"Camacho","sequence":"first","affiliation":[{"name":"CQM\u2013Centro de Qu\u00edmica da Madeira, Molecular Materials Research Group (MMRG), Campus da Penteada, Universidade da Madeira, 9000-390 Funchal, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8684-6100","authenticated-orcid":false,"given":"Dina","family":"Maciel","sequence":"additional","affiliation":[{"name":"CQM\u2013Centro de Qu\u00edmica da Madeira, Molecular Materials Research Group (MMRG), Campus da Penteada, Universidade da Madeira, 9000-390 Funchal, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7856-2041","authenticated-orcid":false,"given":"Helena","family":"Tom\u00e1s","sequence":"additional","affiliation":[{"name":"CQM\u2013Centro de Qu\u00edmica da Madeira, Molecular Materials Research Group (MMRG), Campus da Penteada, Universidade da Madeira, 9000-390 Funchal, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4552-1953","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"CQM\u2013Centro de Qu\u00edmica da Madeira, Molecular Materials Research Group (MMRG), Campus da Penteada, Universidade da Madeira, 9000-390 Funchal, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41568-020-00308-y","article-title":"The rediscovery of platinum-based cancer therapy","volume":"21","author":"Rottenberg","year":"2020","journal-title":"Nat. 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