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J Control Release. 2019 May 10;301:62-75. doi: 10.1016/j.jconrel.2019.03.010. Epub 2019 Mar 13.

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.

Author information

1
Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain; Institute of Nanoscience and Nanotechnology (IN2UB), Barcelona, Spain; Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain; UCL Institute of Ophthalmology, University College of London, United Kingdom.
2
Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain; Unit of Biochemistry and Pharmacology, Faculty of Medicine and Health Sciences, University of Rovira i Virgili, Reus, Tarragona, Spain.
3
UCL Institute of Ophthalmology, University College of London, United Kingdom.
4
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain; Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Health Institute Carlos III, Barcelona, Spain; Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.
5
Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain; Institute of Nanoscience and Nanotechnology (IN2UB), Barcelona, Spain.
6
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain.
7
Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Spain.
8
Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Unit of Biochemistry and Pharmacology, Faculty of Medicine and Health Sciences, University of Rovira i Virgili, Reus, Tarragona, Spain.
9
Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
10
Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain.
11
UCL Institute of Ophthalmology, University College of London, United Kingdom.. Electronic address: p.turowski@ucl.ac.uk.
12
Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Spain; Institute of Nanoscience and Nanotechnology (IN2UB), Barcelona, Spain. Electronic address: marisagarcia@ub.edu.

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.

KEYWORDS:

APP/PS1 mice; Alzheimer's disease; EGCG; Epigallocatechin gallate; PLGA-PEG; Polymeric nanoparticles

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