Intranasal delivery of pApoE2 via penetratin-mannose multi-functionalized chitosan polymeric micelles to the brain: Reduced total tau and phosphorylated tau burden in transgenic Alzheimer's mouse model.

The phosphorylated tau accumulation is a classical pathological hallmark of future cognitive decline and a cause of neuronal death in Alzheimer's disease (AD). In this study, we developed multi-functionalized chitosan (CS) based polymeric micelles to effectively deliver pApoE2 via intranasal administration to the brain. The CS was modified with caproic acid (CA), cell-penetrating peptide penetratin (PEN), and GLUT-1 transporter ligand mannose (MAN) for selective and enhanced delivery to the brain. The multi-functionalized Cap-g-CS-PEN-MAN polymeric micelles were ≤200 nm in size, cationic in charge, and uniformly distributed (PDI ≤ 0.3). The multi-functionalized polymeric micelles did not exhibit toxicity against bEnd.3 cells and erythrocytes up to polymer concentrations of 500 μg/mL. The Cap-g-CS-PEN-MAN /pDNA polyplex was stable against a DNase rich environment. The Cap-g-CS-PEN-MAN/pAPoE2 polyplex demonstrated elevated expression of ApoE in primary astrocytes and neurons, 9.47 ± 2.13 and 5.67 ± 2.69 ng/mg of protein, respectively. The therapeutic efficacy of the Cap-g-CS-PEN-MAN/pApoE2 polyplex was analyzed against the PS19 tauopathy mice model. Total tau burden was significantly (p ≤ 0.05) reduced by 4.09 ± 1.4 ng/mg of protein in Cap-g-CS-PEN-MAN/pApoE2 polyplex administered mice over the other groups. Phosphorylated tau pT181 level was also significantly (p ≤ 0.05) reduced in Cap-g-CS-PEN-MAN/pApoE2 polyplex administered mice over saline, pApoE2 and Cap-g-CS/pApoE2 treated groups.