GM1-Modified Lipoprotein-like Nanoparticle: Multifunctional Nanoplatform for the Combination Therapy of Alzheimer鈥檚 Disease

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• 作者：Meng Huang ; Meng Hu ; Qingxiang Song ; Huahua Song ; Jialin Huang ; Xiao Gu ; Xiaolin Wang ; Jun Chen ; Ting Kang ; Xingye Feng ; Di Jiang ; Gang Zheng ; Hongzhuan Chen ; Xiaoling Gao
• 刊名：ACS Nano
• 出版年：2015
• 出版时间：November 24, 2015
• 年：2015
• 卷：9
• 期：11
• 页码：10801-10816
• 全文大小：1259K
• ISSN：1936-086X

文摘

Alzheimer鈥檚 disease (AD) exerts a heavy health burden for modern society and has a complicated pathological background. The accumulation of extracellular 尾-amyloid (A尾) is crucial in AD pathogenesis, and A尾-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尾 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尾, facilitates A尾 degradation by microglia, and A尾 efflux across the blood鈥揵rain 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, 伪NAP-GM1-rHDL, was found to be able to protect neurons from A尾_1鈥?2 oligomer/glutamic acid-induced cell toxicity better than GM1-rHDL in vitro and reduced A尾 deposition, ameliorated neurologic changes, and rescued memory loss more efficiently than both 伪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.