期刊
ACS NANO
卷 9, 期 11, 页码 10801-10816出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.5b03124
关键词
reconstituted high-density lipoprotein; nanoplatform; Alzheimer's disease; amyloid-beta; combination therapy; GM1 ganglioside; intranasal administration
类别
资金
- National Natural Science Foundation of China [81373351, 81573382]
- Shanghai Science and Technology Committee [12NM0502000, 14ZR1423700]
- Shanghai Talent Development Fund, National Science and Technology Major Project [2012ZX09303001-001]
- SJTU [YG2014MS75]
Alzheimer's disease (AD) exerts a heavy health burden for modern society and has a complicated pathological background. The accumulation of extracellular beta-amyloid (A beta) is crucial in AD pathogenesis, and A beta-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 A beta 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 A beta, facilitates A beta degradation by microglia, and A beta 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, alpha NAP-GM1-rHDL, was found to be able to protect neurons from A beta(1-42) oligomer/glutamic acid-induced cell toxicity better than GM1-rHDL in vitro and reduced A beta deposition, ameliorated neurologic changes, and rescued memory loss more efficiently than both alpha NAP 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.
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