Constructing Brain Aβ-Targeting Nanoparticles Loaded with EGCG for Treating Alzheimer’s Disease in Mice

YANG Peng, GUO Qian, XU Shu-ting, SHENG Dong-yu, ZHANG Qi-zhi

Abstract

To construct a nanodelivery system surface-modified with RD2 peptide (polypeptide sequence PTLHTHNRRRRR) for brain tissue penetration and β-amyloid (Aβ) binding. Epigallocatechin-3-gallate (EGCG) was selected for encapsulation in the targeted delivery system and its therapeutic potential for Alzheimer’s disease (AD) was investigated.  Methods  EGCG-load nanoparticles (NP/EGCG), NP/EGCG with RD2 peptide surface modification (RD2-NP/EGCG), as well as RD2 peptide-modified blank nanoparticles (RD2-NP) were prepared and characterized. Thioflavin T assay was done to assess the ability of RD2-NP to bind with Aβ and ex vivo imaging was conducted to evaluate the distribution of RD2-NP in brain lesion sites. The AD mice model was established by injecting oligomeric Aβ42 in the bilateral hippocampi of ICR mice. Then AD mice were administered intravenously through the tail vein with normal saline, EGCG solution, NP/EGCG or RD2-NP/EGCG for 28 d, respectively, and the Morris water maze tests were performed to assess the spatial memory of mice. Subsequently, RT-PCR method was used to determine the mRNA levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the hippocampus of the mice, and the morphological changes of hippocampal neurons were observed with Nissl staining. Additionally, the pathological changes of heart, liver, spleen, lung, and kidney were characterized by hematoxylin-eosin (HE) staining.  Results  The particle diameter of the prepared RD2-NP/EGCG was (204.83±2.80) nm and the zeta potential was −23.88 mV. The encapsulation efficiency and drug loading capacity were 94.39% and 5.90%, respectively. The RD2 peptide modification has no significant effect on the physiochemical properties of the nanoparticles. RD2-NP had good Aβ binding ability, and it could be concentrated in hippocampus and cerebral cortex, the most common Aβ deposition sites. The four-week RD2-NP/EGCG treatment significantly decreased the expression of the pro-inflammatory cytokine TNF-α and IL-1β, restored neuronal losses and hippocampal damage, and ameliorated spatial memory impairment in AD model mice. Moreover, treatment with the RD2-NP/EGCG did not present organ toxicity.  Conclusion  Surface modified RD2 peptide nanodelivery system can efficiently deliver drugs to AD lesions and improve the therapeutic effect of EGCG on AD.

 

Keywords: Brain targeting, β-amyloid binding ability, RD2 peptide, Nanodelivery system, Alzheimer’s disease, Epigallocatechin-3-gallate

 

Full Text:

PDF


References


PLASSMAN B L， LANGA K M， FISHER G G， et al. Prevalence of dementia in the United States: The aging, demographics, and memory study. Neuroepidemiology，2007，29(1/2): 125–132.

FRISONI G B， BOCCARDI M， BARKHOF F， et al. Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol，2017，16(8): 661–676.

WONG K H， RIAZ M K， XIE Y， et al. Review of current strategies for delivering Alzheimer's disease drugs across the blood-brain barrier. Int J Mol Sci，2019，20(2): 381–406.

YANG P， SHENG D， GUO Q， et al. Neuronal mitochondria-targeted micelles relieving oxidative stress for delayed progression of Alzheimer's disease. Biomaterials，2020，238: 1–12.

GUO Q， ZHENG X， YANG P， et al. Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer’s disease. Acta Pharm Sin B，2019，9(3): 590–603.

CARTER M D， SIMMS G A， WEAVER D F. The development of new therapeutics for Alzheimer’s disease. Clin Pharmacol Ther，2010，88(4): 475–486.

VAN GROEN T， SCHEMMERT S， BRENER O， et al. The Abeta oligomer eliminating D-enantiomeric peptide RD2 improves cognition without changing plaque pathology. Sci Rep，2017，7(1): 16275.

GRANJA A， FRIAS I， NEVES A R， et al. Therapeutic potential of Epigallocatechin Gallate nanodelivery systems. Biomed Res Int，2017，17: 1–15.

ZHANG C， WAN X， ZHENG X Y， et al. Dual-functional nanoparticles targeting amyloid plaques in the brains of Alzheimer’s disease mice. Biomaterials，2014，35: 456–465.

SINGH N A， BHARDWAJ V， RAVI C， et al. EGCG nanoparticles attenuate aluminum chloride induced neurobehavioral deficits, beta amyloid and tau pathology in a rat model of Alzheimer’s disease. Front Aging Neurosci，2018，10: 244[2021-03-01]. https://doi.org/10.3389/fnagi.2018.00244.

ZHANG C， ZHENG X Y， WAN X， et al. The potential use of H102 peptide-loaded dual-functional nanoparticles in the treatment of Alzheimer’s disease. J Control Release，2014，192: 317–324.

GUO Q， XU S， YANG P， et al. A dual-ligand fusion peptide improves the brain-neuron targeting of nanocarriers in Alzheimer’s disease mice. J Control Release，2020，320: 347–362.

KAUR T， PATHAK C M， PANDHI P， et al. Effects of green tea extract on learning, memory, behavior and acetylcholinesterase activity in young and old male rats. Brain Cogn，2008，67(1): 25–30.

LEVITES Y， WEINREB O， MAOR G， et al. Green tea polyphenol (−)-Epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration. J Neurochem，2010，78(5): 1073–1082.

CANO A， ETTCHETO M， ESPINA M， et al. Epigallocatechin-3-gallate loaded PEGylated-PLGA nanoparticles: A new anti-seizure strategy for temporal lobe epilepsy. Nanomedicine，2018，14(4): 1073–1085.

KRUPKOVA O， FERGUSON S J， WUERTZ-KOZAK K. Stability of (−)-epigallocatechin gallate and its activity in liquid formulations and delivery systems. J Nutr Biochem，2016，37: 1–12.


Refbacks

  • There are currently no refbacks.