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

ACS nano (2015-10-07)
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
RESUMEN

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.

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Formaldehyde solution, ACS reagent, 37 wt. % in H2O, contains 10-15% Methanol as stabilizer (to prevent polymerization)
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Sodium dodecyl sulfate, BioReagent, suitable for electrophoresis, for molecular biology, ≥98.5% (GC)
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Formaldehyde solution, for molecular biology, 36.5-38% in H2O
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Sodium dodecyl sulfate, ACS reagent, ≥99.0%
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Sodium dodecyl sulfate, ReagentPlus®, ≥98.5% (GC)
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L-Cysteine, 97%
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Sodium dodecyl sulfate solution, BioUltra, for molecular biology, 10% in H2O
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L-Glutamine, meets USP testing specifications, suitable for cell culture, 99.0-101.0%, from non-animal source
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L-Cysteine, from non-animal source, BioReagent, suitable for cell culture, ≥98%
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Sodium dodecyl sulfate, ≥99.0% (GC), dust-free pellets
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Sodium dodecyl sulfate, BioUltra, for molecular biology, ≥99.0% (GC)
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Formaldehyde solution, for molecular biology, BioReagent, ≥36.0% in H2O (T)
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L-Glutamine, ReagentPlus®, ≥99% (HPLC)
SAFC
L-Cysteine
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Hematoxylin
SAFC
Formaldehyde solution, contains 10-15% methanol as stabilizer, 37 wt. % in H2O
Sigma-Aldrich
Sodium dodecyl sulfate solution, BioUltra, for molecular biology, 20% in H2O
SAFC
L-Glutamine
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Sodium dodecyl sulfate, BioXtra, ≥99.0% (GC)
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Sodium dodecyl sulfate, 92.5-100.5% based on total alkyl sulfate content basis
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L-Cysteine, BioUltra, ≥98.5% (RT)
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Hematoxylin, certified by the Biological Stain Commission
Supelco
Sodium dodecyl sulfate, dust-free pellets, suitable for electrophoresis, for molecular biology, ≥99.0% (GC)
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Formaldehyde solution, meets analytical specification of USP, ≥34.5 wt. %
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L-Cysteine, ≥97%, FG
Supelco
Formaldehyde solution, stabilized with methanol, ~37 wt. % in H2O, certified reference material
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Sodium dodecyl sulfate, ≥90%
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L-Glutamine, BioUltra, ≥99.5% (NT)
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Sodium dodecyl sulfate, ≥98.0% (GC)
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L-Glutamine, γ-irradiated, BioXtra, suitable for cell culture