Enhanced Drug Delivery of Platinum(II) Complexes Using Acetamide‐Functionalized PAMAM Dendrimers: Synthesis, Characterization, and Anticancer Activity Against A549 Lung Cancer Cells

Abstract Since the discovery of cisplatin, extensive research has been conducted on platinum‐based complexes aimed at reducing toxicity and improving selectivity. Drug delivery systems such as poly(amidoamine) (PAMAM) dendrimers have emerged as promising carriers due to their biocompatibility, tunable surface chemistry, and potential to overcome issues such as low solubility and poor selectivity. In this study, Generation 4 (G4) and Generation 5 (G5) PAMAM dendrimers, along with acetamide‐functionalized counterparts (Gn‐Ac), were synthesized and characterized. Additionally, a series of platinum(II) complexes incorporating N,N ‐di(alkyl)‐ N '‐acylthiourea and 1,10‐phenanthroline (phen) derivatives (PtL1, PtL2, and PtL3) were prepared. Host–guest interactions between the dendrimers and the platinum complexes were studied using 1 H NMR, DOSY NMR, and viscosity measurements, revealing notable chemical shift changes, significant decreases in diffusion coefficients, and increases in viscosity upon encapsulation. Cytotoxicity screening against the A549 lung cancer cell line showed that dendrimer‐platinum aggregates involving acetamide‐functionalized dendrimers exhibited reduced toxicity compared to non‐functionalized dendrimers. Furthermore, dendrimer cavity size influenced interaction strength, with the G5‐Ac dendrimer displaying stronger interactions with PtL3, as confirmed by NOE cross‐peaks between the complex protons and the internal dendrimer protons. Lastly, the known anticancer agent 5‐fluorouracil (5‐FU) was successfully encapsulated in G5 dendrimers and used as a positive control in anticancer in vitro screening.