title: GM1-Modified Lipoprotein-like Nanoparticle: Multifunctional Nanoplatform for the Combination Therapy of Alzheimer's Disease.
abstract: Alzheimer's disease (AD) exerts a heavy health burden for modern society and has a complicated pathological background. The accumulation of extracellular β-amyloid (Aβ) is crucial in AD pathogenesis, and Aβ-initiated secondary pathological processes could independently lead to neuronal degeneration and pathogenesis in AD. Thus, the development of combination therapeutics that can not only accelerate Aβ clearance but also simultaneously protect neurons or inhibit other subsequent pathological cascade represents a promising strategy for AD intervention. Here, we designed a nanostructure, monosialotetrahexosylganglioside (GM1)-modified reconstituted high density lipoprotein (GM1-rHDL), that possesses antibody-like high binding affinity to Aβ, facilitates Aβ degradation by microglia, and Aβ efflux across the blood-brain barrier (BBB), displays high brain biodistribution efficiency following intranasal administration, and simultaneously allows the efficient loading of a neuroprotective peptide, NAP, as a nanoparticulate drug delivery system for the combination therapy of AD. The resulting multifunctional nanostructure, αNAP-GM1-rHDL, was found to be able to protect neurons from Aβ(1-42) oligomer/glutamic acid-induced cell toxicity better than GM1-rHDL in vitro and reduced Aβ deposition, ameliorated neurologic changes, and rescued memory loss more efficiently than both αNAP solution and GM1-rHDL in AD model mice following intranasal administration with no observable cytotoxicity noted. Taken together, this work presents direct experimental evidence of the rational design of a biomimetic nanostructure to serve as a safe and efficient multifunctional nanoplatform for the combination therapy of AD.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , 280 South Chongqing Road, Shanghai, 200025, People's Republic of China.
authors.forename: Meng
authors.initials: M
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, People's Republic of 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, People's Republic of 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, People's Republic of 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, People's Republic of 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, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , 280 South Chongqing Road, Shanghai, 200025, People's Republic of China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Kang
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
authors.forename: Xingye
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai 201203, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Medical Biophysics and Ontario Cancer Institute, University of Toronto , Toronto, Ontario M5G 1L7, 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, People's Republic of 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, People's Republic of China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Gao
mesh_terms: D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000150:complications / Q000473:pathology / Q000628:therapy*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004705:Endocytosis / Q000187:drug effects; D005677:G(M1) Ganglioside / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D005971:Glutamates / Q000633:toxicity; D008075:Lipoproteins, HDL / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D008569:Memory Disorders / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D008813:Mice, Inbred ICR; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D000066829:Neuroprotection / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D010316:Particle Size; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D055672:Static Electricity; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D005971:Glutamates; D008075:Lipoproteins, HDL; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010455:Peptides; C075222:amyloid beta-protein (1-42); D005677:G(M1) Ganglioside
keywords: Alzheimer’s disease; GM1 ganglioside; amyloid-β; combination therapy; intranasal administration; nanoplatform; reconstituted high-density lipoprotein