Chitosan functionalized nanocochleates for enhanced oral absorption of cyclosporine A.

It remains a significant challenge to overcome the poor permeability of cyclosporine A and enhance its oral absorption. In this study, we have identified a positively charged chitosan that is able to induce coiling up of anionic lipids to form nanocochleates with an average size of 114.2 ± 0.8 nm, without the need for calcium ions. These functional chitosan-induced nanocochleates enhanced gastrointestinal absorption of cyclosporine A, up to a 3-fold increase in oral bioavailability. A fluorescence-labeling study confirmed that absorption mainly occurred in the duodenum and jejunum. Transport studies indicated that uptake of chitosan-induced nanocochleates by Caco-2 cells was by clathrin- and caveolae-mediated endocytosis, but not by macropinocytosis. Furthermore, three cellular tight junction proteins, ZO-1, F-actin and claudin-4, were significantly down-regulated, suggesting that chitobiose-induced nanocochleates are able to reconstruct and open tight junctions in intestinal epithelial cells to enhance drug absorption. In summary, these novel bifunctional chitosan-induced nanocochleates appear to have potential to facilitate oral delivery of cyclosporine A.