Cano, A;
Ettcheto, M;
Chang, J-H;
Barroso, E;
Espina, M;
Kühne, BA;
Barenys, M;
... García, ML; + view all
(2019)
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.
Journal of Controlled Release
, 301
pp. 62-75.
10.1016/j.jconrel.2019.03.010.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | 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 |
| Location: | Netherlands |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jconrel.2019.03.010 |
| Publisher version: | https://doi.org/10.1016/j.jconrel.2019.03.010 |
| Language: | English |
| Additional information: | Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/). |
| Keywords: | Epigallocatechin gallate, EGCG, Polymeric nanoparticles, PLGA-PEG, Alzheimer's disease, APP/PS1 mice |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10071026 |
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