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Brain‐targeted co‐delivery of β‐amyloid converting enzyme 1 shRNA and epigallocatechin‐3‐gallate by multifunctional nanocarriers for Alzheimer's disease treatment
Author(s) -
Lv Lijie,
Yang Fan,
Li He,
Yuan Jiuli
Publication year - 2020
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1002/iub.2330
Subject(s) - nanocarriers , morris water navigation task , epigallocatechin gallate , pharmacology , amyloid precursor protein , chemistry , small hairpin rna , biodistribution , presenilin , western blot , microbiology and biotechnology , alzheimer's disease , medicine , biochemistry , biology , antioxidant , gene knockdown , gene , in vitro , disease , hippocampus , drug , polyphenol
Progressive memory loss and cognitive dysfunction are hallmark clinical features of Alzheimer's disease (AD). As a possible treatment for AD, we developed an epigallocatechin‐3‐gallate (EGCG) and β‐site amyloid precursor protein (APP) cleaving enzyme 1 antisense (BACE1‐AS) shRNA‐encoded plasmid. The plasmid was loaded on to RVG29 peptide‐targeted multifunctional nanoparticles (NPs) (REGS‐PN). The polymeric NPs were characterized by flow cytometry, biocompatibility assay, pharmacokinetic analysis, Western blot analysis, and the Morris water maze (MWM) test. The differences in plasma and brain NP accumulation following intravenous administration showed a significantly longer circulation time for EGS‐PN and REGS‐PN in the blood stream. In contrast, free EGCG was rapidly eliminated from the circulation. REGS‐PM successfully travelled through the blood–brain barrier and was present at a higher concentration in the brain compared with both non‐targeted NPs and free EGCG. REGS‐PN administration to APPswe/PS1dE9 double transgenic mice (APP/PS1 mice) resulted in downregulation of the key enzyme in amyloid‐β formation (BACE1) and amyloid beta, indicating synergistic therapeutic activity. The MWM test revealed that simultaneous delivery of a therapeutic gene and EGCG (REGS‐PN) remarkably improved the spatial learning and memory capabilities of APP/PS1 mice as well as wild type mice compared with the free EGCG‐treated group. With these results, we propose that co‐delivery of a therapeutic gene (shRNA) and EGCG in a multifunctional nanocarrier could achieve higher therapeutic concentrations in the brain and could be an excellent strategy for AD treatment.