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.
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Cano, A., Ettcheto, M., Chang, J. H., Barroso, E., Espina, M., Kühne, B. A., Barenys, M., Auladell, C., Folch, J., Souto, E. B., Camins, A., Turowski, P., & García, M. L. (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 : official journal of the Controlled Release Society, 301, 62–75. https://doi.org/10.1016/j.jconrel.2019.03.010
This article has received the Jorge Heller Award from the Controlled Release Society
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Keywords: Epigallocatechin gallate, EGCG, Polymeric nanoparticles, PLGA-PEG, Alzheimer’s disease, APP/PS1 mice, Neuroinflammation, Amyloid β (Aβ) plaque burden, Pharmacokinetics, Bioavailability, #Nanoparticles, #Phytochemicals, #Alzheimers.
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