Role of serum albumin as a nanoparticulate carrier for nose-to-brain delivery of R-flurbiprofen: implications for the treatment of Alzheimer's disease

Objectives: R-flurbiprofen (R-FP) was found to offer neuroprotective effects by inhibiting mitochondrial calcium overload induced by β-amyloid peptide toxicity in Alzheimer's disease (AD). However, poor brain penetration after oral administration posed a challenge to its further development for AD treatment. In this study, we investigated the potential of serum albumin as nanoparticulate carriers for nose-to-brain delivery of R-FP to improve its brain accumulation. Methods: Mice were subjected to three treatment groups: (1) intranasal R-FP solution, (2) oral R-FP solution and (3) intranasal R-FP albumin nanoparticles. We also investigated whether the in-vivo R-FP level achieved in the brain afforded by intranasal administration of R-FP nanoparticles had any effect on mitochondrial respiratory activity in an in-vitro AD model. Key findings: Our in-vivo experiments demonstrate that the intranasal administration of serum albumin-based R-FP nanoparticles achieved higher brain-to-plasma ratio profile as compared to intranasal and oral administration of a simple R-FP solution. We observed significantly improved basal and maximal mitochondrial respiration in cells treated with R-FP albumin nanoparticles at in-vivo brain concentration. Conclusions: Serum albumin-based nanoparticles administered via the nasal route may be a viable approach in delivering therapeutic agents to the brain to alleviate mitochondrial dysfunction in AD.