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Direct in vivo evidence on the mechanism by which nanoparticles facilitate the absorption of a water insoluble, P-gp substrate

Soundararajan, R; Sasaki, K; Godfrey, L; Odunze, U; Fereira, N; Schätzlein, A; Uchegbu, I; (2016) Direct in vivo evidence on the mechanism by which nanoparticles facilitate the absorption of a water insoluble, P-gp substrate. International Journal of Pharmaceutics , 514 (1) pp. 121-132. 10.1016/j.ijpharm.2016.08.013. Green open access

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Abstract

Here we examine the mechanisms by which nanoparticles enable the oral absorption of water-insoluble, P-glycoprotein efflux pump (P-gp) substrates, without recourse to P-gp inhibitors. Both 200 nm paclitaxel N-(2-phenoxyacetyl)-6-O-glycolchitosan (GCPh) nanoparticles (GCPh-PTX) and a simulated Taxol formulation, facilitate drug dissolution in biorelevant media, unlike paclitaxel nanocrystals. Verapamil (40 mg kg−1) increased the oral absorption from low dose Taxol (6 or 10 mg kg−1) by 100%, whereas the oral absorption from high dose Taxol (20 mg kg−1) or low dose GCPh-PTX (6 or 10 mg kg−1) was largely unchanged by verapamil. There was virtually no absorption from control paclitaxel nanocrystals (20 mg kg−1). Imaging of ex-vivo rat ileum samples showed that fluorescently labelled GCPh nanoparticles are mucoadhesive and are taken up by ileum epithelial cells. GCPh nanoparticles were also found to open Caco-2 cell tight junctions. In conclusion, mucoadhesive, drug solubilising GCPh nanoparticles enable the oral absorption of paclitaxel via the saturation of the P-gp pump (by high local drug concentrations) and by particle uptake and tight junction opening mechanisms.

Type: Article
Title: Direct in vivo evidence on the mechanism by which nanoparticles facilitate the absorption of a water insoluble, P-gp substrate
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ijpharm.2016.08.013
Publisher version: http://doi.org/10.1016/j.ijpharm.2016.08.013
Language: English
Additional information: © 2016 Elsevier B.V. All rights reserved. This manuscript version is made available under a Creative Commons Attribution Non-commercial Non-derivative 4.0 International license (CC BY-NC-ND 4.0). This license allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licenses are available at http://creativecommons.org/ licenses/by/4.0. Access may be initially restricted by the publisher.
Keywords: Nanoparticle; Oral; Paclitaxel; Biopharmaceutical Classification System; Chitosan amphiphile; N-(2-phenoxyacetamide)-6-O-glycolchitosan; Absorption
UCL classification: UCL
UCL > Provost and Vice Provost Offices
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 Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutics
URI: https://discovery.ucl.ac.uk/id/eprint/1529879
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