Endogenous polysialic acid based micelles for calmodulin antagonist delivery against vascular dementia.

Clinical treatment for vascular dementia still remains a challenge mainly due to Blood-Brain Barrier (BBB). Here, a micelle based on polysialic acid (PSA) which is a hydrophilic and endogenous carbohydrate polymer, was designed to deliver calmodulin antagonist for therapy of vascular dementia. PSA was firstly chemically conjugated with octadecylamine (ODA), and the obtained PSA-ODA copolymer could self-assemble into micelle in aqueous solution with a 120.0 μg/mL critical micelle concentration. The calmodulin antagonist loaded PSA-ODA micelle, featuring sustained drug release behaviour over a period of 72 h with 3.6 % (w/w) drug content and 107.0 ± 4.0 nm size was then fabricated. The PSA-ODA micelle could cross BBB mainly via active endocytosis by brain endothelial cells followed by transcytosis. In water maze test for spatial learning, calmodulin antagonist loaded PSA-ODA micelle significantly reduced escape latencies of right unilateral common carotid arteries occlusion (rUCCAO) mice with dosage significantly reduced versus free drug. The decrease of hippocampal phospho-CaMKII (Thr286/287) and phospho-synapsin I (Ser603) was partially restored in rUCCAO mice following calmodulin antagonist loaded PSA-ODA micelle treatment. Consistent with the restored CaMKII phosphorylation, the elevation of BrdU/NeuN double-positive cells in same context was also observed. Overall, the PSA-ODA micelle developed from the endogenous material might promote the development of therapeutic approaches for improving efficacy of brain-targeted drug delivery and have a great potential for vascular dementia treatment.