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Dual-drug loaded nanoparticles of Epigallocatechin-3-gallate (EGCG)/Ascorbic acid enhance therapeutic efficacy of EGCG in a APPswe/PS1dE9 Alzheimer's disease mice model.

Abstract
Epigallocatechin-3-gallate (EGCG) is a candidate for treatment of Alzheimer's disease (AD) but its inherent instability limits bioavailability and effectiveness. We found that EGCG displayed increased stability when formulated as dual-drug loaded PEGylated PLGA nanoparticles (EGCG/AA NPs). Oral administration of EGCG/AA NPs in mice resulted in EGCG accumulation in all major organs, including the brain. Pharmacokinetic comparison of plasma and brain accumulation following oral administration of free or EGCG/AA NPs showed that, whilst in both cases initial EGCG concentrations were similar, long-term (5-25 h) concentrations were ca. 5 fold higher with EGCG/AA NPs. No evidence was found that EGCG/AA NPs utilised a specific pathway across the blood-brain barrier (BBB). However, EGCG, empty NPs and EGCG/AA NPs all induced tight junction disruption and opened the BBB in vitro and ex vivo. Oral treatment of APPswe/PS1dE9 (APP/PS1) mice, a familial model of AD, with EGCG/AA NPs resulted in a marked increase in synapses, as judged by synaptophysin (SYP) expression, and reduction of neuroinflammation as well as amyloid β (Aβ) plaque burden and cortical levels of soluble and insoluble Aβ(1-42) peptide. These morphological changes were accompanied by significantly enhanced spatial learning and memory. Mechanistically, we propose that stabilisation of EGCG in NPs complexes and a destabilized BBB led to higher therapeutic EGCG concentrations in the brain. Thus EGCG/AA NPs have the potential to be developed as a safe and strategy for the treatment of AD.
AuthorsAmanda Cano, Miren Ettcheto, Jui-Hsien Chang, Emma Barroso, Marta Espina, Britta A Kühne, Marta Barenys, Carmen Auladell, Jaume Folch, Eliana B Souto, Antoni Camins, Patric Turowski, Maria Luisa García
JournalJournal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 301 Pg. 62-75 (05 10 2019) ISSN: 1873-4995 [Electronic] Netherlands
PMID30876953 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
Chemical References
  • Amyloid beta-Peptides
  • Antioxidants
  • Drug Carriers
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyethylene Glycols
  • Catechin
  • epigallocatechin gallate
  • Ascorbic Acid
Topics
  • Alzheimer Disease (drug therapy, metabolism)
  • Amyloid beta-Peptides (metabolism)
  • Animals
  • Antioxidants (administration & dosage, chemistry, pharmacokinetics)
  • Ascorbic Acid (administration & dosage, chemistry, pharmacokinetics)
  • Brain (metabolism)
  • Catechin (administration & dosage, analogs & derivatives, chemistry, pharmacokinetics)
  • Disease Models, Animal
  • Drug Carriers (administration & dosage, chemistry, pharmacokinetics)
  • Drug Liberation
  • Endothelial Cells (metabolism)
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nanoparticles (administration & dosage, chemistry)
  • Polyethylene Glycols (administration & dosage, chemistry, pharmacokinetics)
  • Polylactic Acid-Polyglycolic Acid Copolymer (administration & dosage, chemistry, pharmacokinetics)
  • Rats

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