title: Biomimetic ApoE-Reconstituted High Density Lipoprotein Nanocarrier for Blood-Brain Barrier Penetration and Amyloid Beta-Targeting Drug Delivery.
abstract: Amyloid beta (Aβ) and its aggregation forms in the brain have been suggested as key targets for the therapy of Alzheimer's disease (AD). Therefore, the development of nanocarriers that possess both blood-brain barrier permeability and Aβ-targeting ability is of great importance for the intervention of AD. Here we constructed a biomimetic nanocarrier named apolipoprotein E (ApoE)-reconstituted high density lipoprotein nanocarrier (ANC) from recombinant ApoE and synthetic lipids to achieve the above goals. α-Mangostin (α-M), a polyphenolic agent that can inhibit the formation of Aβ oligomers and fibrils and accelerate Aβ cellular degradation, was used as the model drug. Compared with the control liposome, ANC demonstrated about 54-fold higher cellular uptake in brain endothelial cell line in vitro in an ApoE-dependent manner and much higher brain delivery efficiency in vivo. Confocal microscopy analysis witnessed the penetration of ANC across the brain vessels and its accumulation at the surrounding of Aβ aggregates. Following the loading of α-M, the Aβ-binding affinity of the nanoformulation (ANC-α-M) was not reduced but even enhanced. The effect of ANC-α-M on facilitating the microglia-mediated uptake and degradation of Aβ1-42was enhanced by 336% and 29-fold when compared with that of the nontreated control and also much higher than that of ANC. Following intravenous administration for 2 to 4 weeks, ANC-α-M exhibited the most efficient efficacy in decreasing amyloid deposition, attenuating microgliosis, and rescuing memory defect in SAMP8 mice, an AD mouse model. Taken together, the findings of this work provided strong evidence that the ApoE-based biomimetic nanocarrier could provide a promising platform for brain drug delivery toward the treatment of AD.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Song
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Huahua
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Jialin
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Gu
authors.affiliation: Princess Margaret Cancer Centre, University Health Network , Toronto, ON M5G 2M9, Canada.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Princess Margaret Cancer Centre, University Health Network , Toronto, ON M5G 2M9, Canada.
authors.forename: Gang
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , 280 South Chongqing Road, Shanghai 200025, PR China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Gao
mesh_terms: D061605:Administration, Intravenous; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D004339:Drug Compounding; D016503:Drug Delivery Systems / Q000379:methods; D008075:Lipoproteins, HDL / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000737:chemistry; D044004:Xanthones / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D004337:Drug Carriers; D008075:Lipoproteins, HDL; D044004:Xanthones; C025121:apolipoprotein E-rich HDL; C021053:mangostin
keywords: Alzheimer’s disease; amyloid beta; biomimetic; blood−brain barrier; nanocarrier; α-mangostin