|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|
|Pagination||121 - 132|
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.
|Short Title||International Journal of Pharmaceutics|