Cisplatin Derivatives and Their Complexes with PAMAM Dendrimers-A Way to Improve the Efficacy of Anticancer Drugs.

Female cancers, primarily breast, cervical, and ovarian cancers, remain a major public health challenge, with rising incidence and high mortality. 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-cisplatin, D-cisplatin, and Ac-cisplatin) and their complexes with generation 2 polyamidoamine (PAMAM G2) dendrimers. All drug-dendrimer complexes were prepared at a 10:1 molar ratio and tested on two cancer cell lines-HeLa (cervical cancer) and MCF-7 (breast cancer)-and one non-cancer human microvascular endothelial cell line (HMEC-1). 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-death pathways. The complexes demonstrated cytotoxicity comparable to or greater than cisplatin and showed improved selectivity toward cancer cells. Among them, D-cisplatin complexed with PAMAM G2 was the most promising candidate, exhibiting the highest selectivity toward HeLa cells.