title: B6 peptide-modified PEG-PLA nanoparticles for enhanced brain delivery of neuroprotective peptide.
abstract: The blood-brain barrier (BBB), which is formed by the brain capillary wall, greatly hinders the development of new drugs for the brain. Over the past decades, among the various receptor-mediated endogenous BBB transport systems, the strategy of using transferrin or anti-transferrin receptor antibodies to facilitate brain drug delivery system is of particular interest. However, the application of large proteins still suffers from the drawbacks including synthesis procedure, stability, and immunological response. Here, we explored a B6 peptide discovered by phase display as a substitute for transferrin, and conjugated it to PEG-PLA nanoparticles (NP) with the aim of enhancing the delivery of neuroprotective drug across the BBB for the treatment of Alzheimer's disease. B6-modified NP (B6-NP) exhibited significantly higher accumulation in brain capillary endothelial cells via lipid raft-mediated and clathrin-mediated endocytosis. In vivo, fluorescently labeled B6-NP exhibited much higher brain accumulation when compared with NP. Administration of B6-NP encapsulated neuroprotective peptide-NAPVSIPQ (NAP)-to Alzheimer's disease mouse models showed excellent amelioration in learning impairments, cholinergic disruption, and loss of hippocampal neurons even at lower dose. These findings together suggested that B6-NP might serve as a promising DDS for facilitating the brain delivery of neuropeptides.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
authors.forename: Zhongyang
authors.initials: Z
authors.lastname: Liu
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Gao
authors.forename: Ting
authors.initials: T
authors.lastname: Kang
authors.forename: Mengyin
authors.initials: M
authors.lastname: Jiang
authors.forename: Deyu
authors.initials: D
authors.lastname: Miao
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Gu
authors.forename: Quanyin
authors.initials: Q
authors.lastname: Hu
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Song
authors.forename: Lei
authors.initials: L
authors.lastname: Yao
authors.forename: Yifan
authors.initials: Y
authors.lastname: Tu
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
authors.forename: Xinguo
authors.initials: X
authors.lastname: Jiang
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001921:Brain / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D014018:Tissue Distribution; D025101:Vitamin B 6 / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D018696:Neuroprotective Agents; D009842:Oligopeptides; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols; D025101:Vitamin B 6