Transport mechanism of doxorubicin loaded chitosan based nanogels across intestinal epithelium

Abstract

Chitosan/carboxymethyl chitosan nanogels (CS/CMCS-NGs) could enhance the oral bioavailability of doxorubicin hydrochloride (DOX). To identify the mechanisms that support this recent observation, different transport pathways of CS/CMCS-NGs through the small intestine were studied in this work. Transcellular mechanisms were investigated in the presence of different inhibitors of protein-mediated endocytosis. A reduction of 52.32 +/- 18% of drug transport was found when clathrin-mediated endocytosis was inhibited, which demonstrated that clathrin-mediated endocytosis played an important role in the transcellular transport of DOX:CS/CMCS-NGs. The paracellular transport results showed that CMCS in NGs could produce a transient and reversible enhancement of paracellular permeability by depriving Ca2+ from adherens junctions, whose efficacy as an absorption enhancer was about 1.7-3.3 folds higher than CS in NGs in GI tract. Finally, in vivo experiment showed that the transport capacity of DOX:CS/ CMCS-NGs was significantly inhibited by extra added Ca2+, which confirmed that the higher capacity to binding Ca2+ of CS/CMCS-NGs was beneficial for transport of DOX. (C) 2013 Elsevier B.V. All rights reserved.