Endogenous Polysialic Acid Based Micelles for Calmodulin Antagonist Delivery against Vascular Dementia

Xiao Juan Wang, Yin Ping Gao, Nan Nan Lu, Wei Shuo Li, Ji Fang Xu, Xiao Ying Ying, Gang Wu, Mei Hua Liao, Chao Tan, Ling Xiao Shao, Ying Mei Lu, Chen Zhang, Kohji Fukunaga, Feng Han, Yong Zhong Du

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)35045-35058
Number of pages14
JournalACS Applied Materials and Interfaces
Volume8
Issue number51
DOIs
Publication statusPublished - 2016 Dec 28

Keywords

  • blood−brain barrier
  • calmodulin antagonist
  • drug-delivery system
  • polymeric micelle
  • polysialic acid
  • vascular dementia

ASJC Scopus subject areas

  • Materials Science(all)

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