title: Endogenous Polysialic Acid Based Micelles for Calmodulin Antagonist Delivery against Vascular Dementia.
abstract: Clinical treatment for vascular dementia still remains a challenge mainly due to the 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 first 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 behavior over a period of 72 h with a 3.6% (w/w) drug content and a 107.0 ± 4.0 nm size was then fabricated. The PSA-ODA micelle could cross the BBB mainly via active endocytosis by brain endothelial cells followed by transcytosis. In a water maze test for spatial learning, calmodulin antagonist loaded PSA-ODA micelle significantly reduced the 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 the same context was also observed. Overall, the PSA-ODA micelle developed from the endogenous material might promote the development of therapeutic approaches for improving the efficacy of brain-targeted drug delivery and have great potential for vascular dementia treatment.
authors.forename: Xiao-Juan
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: School of Medicine, Zhejiang University City College , Hangzhou 310058, China.
authors.forename: Yin-Ping
authors.initials: YP
authors.lastname: Gao
authors.forename: Nan-Nan
authors.initials: NN
authors.lastname: Lu
authors.forename: Wei-Shuo
authors.initials: WS
authors.lastname: Li
authors.forename: Ji-Fang
authors.initials: JF
authors.lastname: Xu
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Ying
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Liao
authors.forename: Chao
authors.initials: C
authors.lastname: Tan
authors.forename: Ling-Xiao
authors.initials: LX
authors.lastname: Shao
authors.affiliation: School of Medicine, Zhejiang University City College , Hangzhou 310058, China.
authors.forename: Ying-Mei
authors.initials: YM
authors.lastname: Lu
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University , Sendai 980-8574, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Feng
authors.initials: F
authors.lastname: Han
authors.forename: Yong-Zhong
authors.initials: YZ
authors.lastname: Du
mesh_terms: D000818:Animals; D002147:Calmodulin; D015140:Dementia, Vascular; D004337:Drug Carriers; D016503:Drug Delivery Systems; D051379:Mice; D008823:Micelles; D011108:Polymers; D012794:Sialic Acids / Q000737:chemistry*
chemical_list: D002147:Calmodulin; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D012794:Sialic Acids; C021319:polysialic acid
keywords: blood−brain barrier; calmodulin antagonist; drug-delivery system; polymeric micelle; polysialic acid; vascular dementia