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Cisplatin has long been a cornerstone of anticancer therapy, yet its clinical use is limited by low selectivity, severe side effects, drug resistance, and relapse. Thus, more effective and selective therapeutic strategies are needed. In this study, we evaluated the cytotoxicity and mechanisms of action of three cisplatin derivatives (C\u2010cisplatin, D\u2010cisplatin, and Ac\u2010cisplatin) and their complexes with generation 2 polyamidoamine (PAMAM G2) dendrimers. All drug\u2013dendrimer complexes were prepared at a 10:1 molar ratio and tested on two cancer cell lines\u2014HeLa (cervical cancer) and MCF\u20107 (breast cancer)\u2014and one non\u2010cancer human microvascular endothelial cell line (HMEC\u20101). Complex formation was confirmed by zeta potential measurements. Cytotoxicity was assessed for both free and complexed drugs. To explore potential mechanisms of action, mitochondrial membrane potential and reactive oxygen species (ROS) levels were evaluated. Flow cytometry was then used to determine dominant cell\u2010death pathways. The complexes demonstrated cytotoxicity comparable to or greater than cisplatin and showed improved selectivity toward cancer cells. Among them, D\u2010cisplatin complexed with PAMAM G2 was the most promising candidate, exhibiting the highest selectivity toward HeLa cells.<\/jats:p>","DOI":"10.1002\/cmdc.202500881","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T01:30:11Z","timestamp":1765243811000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cisplatin Derivatives and Their Complexes with PAMAM Dendrimers\u2014A Way to Improve the Efficacy of Anticancer Drugs"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2189-5221","authenticated-orcid":false,"given":"Monika","family":"Marcinkowska","sequence":"first","affiliation":[{"name":"Department of General Biophysics Faculty of Biology and Environmental Protection University of Lodz  141\/143 Pomorska Street. 90\u2013236 Lodz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Antunes","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa) Faculty of Pharmacy Universidade de Lisboa  Avenue. 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Professor Gama Pinto 1649\u2013003 Lisboa Portugal"},{"name":"Instituto de Biof\u00edsica e Engenharia Biom\u00e9dica (IBEB) Faculdade de Ci\u00eancias Universidade de Lisboa  Campo Grande 1749\u2013016 Lisboa Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0599-9020","authenticated-orcid":false,"given":"Jan","family":"Kurjata","sequence":"additional","affiliation":[{"name":"Centre of Molecular and Macromolecular Studies Polish Academy of Sciences  Sienkiewicza 112 90\u2013363 Lodz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W\u0142odzimierz","family":"Sta\u0144czyk","sequence":"additional","affiliation":[{"name":"Centre of Molecular and Macromolecular Studies Polish Academy of Sciences  Sienkiewicza 112 90\u2013363 Lodz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3459-8947","authenticated-orcid":false,"given":"Barbara","family":"Klajnert\u2010Maculewicz","sequence":"additional","affiliation":[{"name":"Department of General Biophysics Faculty of Biology and Environmental Protection University of Lodz  141\/143 Pomorska Street. 90\u2013236 Lodz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"Breast cancer [Internet]. 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