Title | Direct in vivo evidence on the mechanism by which nanoparticles facilitate the absorption of a water insoluble, P-gp substrate. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Soundararajan R, Sasaki K, Godfrey L, Odunze U, Fereira N, Schatzlein A, Uchegbu I |
Journal | International Journal of Pharmaceutics |
Volume | 514 |
Issue | 1 |
Pagination | 121 - 132 |
Date Published | 2016/11/30 |
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 200nm 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 (40mgkg(-1)) increased the oral absorption from low dose Taxol (6 or 10mgkg(-1)) by 100%, whereas the oral absorption from high dose Taxol (20mgkg(-1)) or low dose GCPh-PTX (6 or 10mgkg(-1)) was largely unchanged by verapamil. There was virtually no absorption from control paclitaxel nanocrystals (20mgkg(-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. |
URL | http://linkinghub.elsevier.com/retrieve/pii/S0378517316307426 |
Short Title | International Journal of Pharmaceutics |