Highly Stabilized Curcumin Nanoparticles Tested in an In Vitro Blood–Brain Barrier Model and in Alzheimer’s Disease Tg2576 Mice

Abstract

The therapeutic effects of curcumin in treating Alzheimer’s disease (AD) depend on the ability to penetrate the blood–brain barrier. The latest nanoparticle technology can help to improve the bioavailability of curcumin, which is affected by the final particle size and stability. We developed a stable curcumin nanoparticle formulation to test in vitro and in AD model Tg2576 mice. Flash nanoprecipitation of curcumin, polyethylene glycol-polylactic acid co-block polymer, and polyvinylpyrrolidone in a multi-inlet vortex mixer, followed by freeze drying with β-cyclodextrin, produced dry nanocurcumin with mean particle size <80 nm. Nanocurcumin powder, unformulated curcumin, or placebo was orally administered to Tg2576 mice for 3 months. Before and after treatment, memory was measured by radial arm maze and contextual fear conditioning tests. Nanocurcumin produced significantly (p = 0.04) better cue memory in the contextual fear conditioning test than placebo and tendencies toward better working memory in the radial arm maze test than ordinary curcumin (p = 0.14) or placebo (p = 0.12). Amyloid plaque density, pharmacokinetics, and Madin–Darby canine kidney cell monolayer penetration were measured to further understand in vivo and in vitro mechanisms. Nanocurcumin produced significantly higher curcumin concentration in plasma and six times higher area under the curve and mean residence time in brain than ordinary curcumin. The P app of curcumin and tetrahydrocurcumin were 1.8 × 10−6 and 1.6 × 10−5 cm/s, respectively, for nanocurcumin. Our novel nanocurcumin formulation produced highly stabilized nanoparticles with positive treatment effects in Tg2576 mice.

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Acknowledgments

We thank Professor Robert Prud’homme, Department of Chemical and Biological Engineering, University of Princeton and Professor Christopher Macosko, Department of Chemical Engineering and Materials Science, University of Minnesota for their kind assistance in fabricating an MIVM for the present study at CUHK. We also thank Prof. William Goggins for his advice on statistical analysis of the data. This project was supported and funded by the Innovation and Technology Fund (ITS/306/09) of The Government of the Hong Kong Special Administrative Region.

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Correspondence to Larry Baum.

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Fig. S1a

ANCOVA modeling for number of reentry errors (S1a–c) and error entries (S1d–f) in radial arm maze tests (n = 13 for NC and control, and n = 10 for CUR). After-treatment error was described by a single regression equation: \( {{\left( {\mathrm{Errors}} \right)}_{{\mathrm{after}\,\mathrm{treatment}}}}=\mathrm{constant} + a\times {{\left( {\mathrm{Errors}} \right)}_{{\mathrm{before}\,\mathrm{treatment}}}}+b\times \mathrm{treatment}\,\mathrm{group} \). (GIF 15 kb)

Fig. S1b

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Fig. S1c

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Fig. S1d

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Fig. S1e

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Fig. S1f

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Fig. S2a

Four fields of a brain section, stained with ThT, of Tg2576 mice treated with a control, b NC or c CUR (GIF 123 kb)

Fig. S2b

(GIF 121 kb)

Fig. S2c

(GIF 106 kb)

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Cheng, K.K., Yeung, C.F., Ho, S.W. et al. Highly Stabilized Curcumin Nanoparticles Tested in an In Vitro Blood–Brain Barrier Model and in Alzheimer’s Disease Tg2576 Mice. AAPS J 15, 324–336 (2013). https://doi.org/10.1208/s12248-012-9444-4

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Key words

  • Alzheimer’s disease
  • behavior tests
  • nanocurcumin
  • oral route
  • pharmacokinetic