Engineering PAMAM dendrimers for optimized drug delivery

Dendrimers, first introduced by Fritz Vögtle in 1978, have emerged as promising nanocarriers for drug delivery due to their unique branched architecture, large internal cavities, and numerous surface amine groups. These dendrimers efficiently load various drugs through electrostatic interactions, covalent bonding, or encapsulation, owing to their high density of terminal amine groups. However, the inherent cationic nature of PAMAM dendrimers can lead to cytotoxicity and limited systemic circulation due to interactions with negatively charged biomolecules. To address these limitations, surface modification strategies have been developed to enhance targeting, trigger controlled drug release, and decrease cytotoxicity. This review critically examines recent advancements in engineering PAMAM dendrimers for improved drug delivery, focusing on strategies to increase drug loading capacity, achieve tissue-specific targeting, reduce toxicity, and enable stimuli-responsive release. Furthermore, this review evaluates the challenges and future prospects of engineered PAMAM dendrimer-based drug delivery systems to provide a comprehensive roadmap for advancing these platforms in nanomedicine and targeted therapeutics.