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.
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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 > 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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