Nose-to-brain delivery of an amyloid beta blocking peptide using polylactic acid-poloxamer 188 nanocarriers

BACKGROUND: Alzheimer's disease, characterized by a progressive cognitive decline, represents a major global health challenge. A novel blocking peptide (seq: KRKKSRYKSWSVYVG) which binds with high affinity for toxic amyloid beta oligomers implicated in the early stages of the disease pathogenesis, has shown promising therapeutic potential. To overcome the challenges of brain drug delivery, nanoparticles combined with a nose-to-brain delivery approach were used to enhance brain biodistribution and drug delivery efficiency. In this study, we evaluated the feasibility of using these nanoparticles to deliver the blocking peptide to the brain. RESULTS: Nanoparticles composed of polylactic acid and poloxamer P188 were synthesized and successfully functionalised with surface-adsorbed blocking peptide, exhibiting physicochemical characteristics suitable for nose-to-brain delivery. The nanoparticles preserved the blocking peptide therapeutic activity against amyloid beta aggregation and, in addition, protected it from enzymatic degradation. Functional cellular evaluation showed biocompatibility of the nanoparticle-blocking peptide compound and potential internalization by neuronal cells. Importantly, in vivo experiments demonstrated the successful delivery of the nanoparticles from the nasal cavity to the brain, representing a significant step forward in targeted brain delivery. CONCLUSION: Nanoparticles functionalised with an anti-amyloid beta aggregation peptide successfully reached the brain following intranasal administration, suggesting their potential as a therapeutic strategy against the Alzheimer's disease.