Non-Invasive Brain Delivery of G4 70/30 PAMAM Dendrimers via the Intranasal Route

Effective treatment of neurological disorders remains a major clinical challenge due to the restrictive nature of the blood-brain barrier (BBB), which limits the entry of most therapeutic agents into the central nervous system (CNS). In this study, we investigated the in vivo biodistribution, safety, and CNS targeting ability of fourth generation (G4) PAMAM dendrimers, containing 70% hydroxyl and 30% amine surface groups (G4 70/30) following intranasal administration in C57BL/6J mice. Male and female mice were administered daily intranasal doses of Cy5.5-labeled G4 70/30 PAMAM dendrimers for 4 weeks, while control animals received Hank's balanced salt solution (HBSS; Gibco, Waltham, MA, USA). Whole-body fluorescence imaging was conducted weekly to assess biodistribution, followed by organ extraction and fluorescence microscopy to evaluate tissue-level accumulation. The results revealed substantial accumulation of dendrimers in the brain, with no signs of toxicity in major organs including the lungs, livers, and kidneys. Notably, male mice exhibited significantly higher fluorescent intensity in the brain compared to females. These findings support the safety and effectiveness of G4 70/30 PAMAM dendrimers for intranasal delivery and highlight their potential as carriers for CNS-targeted therapies, including drugs and nucleic acids, in the treatment of neurological disorders.