title: Chitosan functionalized nanocochleates for enhanced oral absorption of cyclosporine A.
abstract: 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.
authors.affiliation: Department of Pharmacy, Songjiang Hospital Affiliated Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.|Urology Department, First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, Songjiang Hospital Affiliated Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.|Jiangxi Province Tumor Hospital, Nanchang, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Department of Pharmacy, Songjiang Hospital Affiliated Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000199:Actins / Q000378:metabolism; D000284:Administration, Oral; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D048271:Chitosan / Q000737:chemistry*; D062506:Claudin-4 / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D004187:Disaccharides / Q000737:chemistry; D065546:Drug Liberation; D006801:Humans; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D014018:Tissue Distribution / Q000187:drug effects; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D000199:Actins; D062506:Claudin-4; D004187:Disaccharides; D062826:Zonula Occludens-1 Protein; C032438:chitobiose; D016572:Cyclosporine; D048271:Chitosan