N-alkylation of highly quaternized chitosan derivatives affects the paracellular permeation enhancement in bronchial epithelia in vitro.

• Published in: European Journal of Pharmaceutics and Biopharmaceutics
• Main Authors: Benediktsdóttir, Berglind Eva, Gudjónsson, Thórarinn, Baldursson, Ólafur, Másson, Már
• Format: Article in Journal/Newspaper
• Language: English
• Published: Elsevier Science BV 2014
• Subjects: Lyfjagjöf; Dose-Response Relationship; Drug; Chitosan/analogs & derivatives*; Tight Junctions/metabolism; Molecular Weight; Permeability; Alkylation; Bronchi/cytology; Bronchi/metabolism*; Cell Line; Cell Survival/drug effects; Chitosan/chemistry; Chitosan/pharmacokinetics; Drug Carriers*/chemistry; Drug Carriers*/pharmacokinetics; Epithelial Cells/metabolism*; Epithelial Cells/ultrastructure; Humans; Quaternary Ammonium Compounds*/chemistry; Quaternary Ammonium Compounds*/pharmacokinetics; Structure-Activity Relationship; Tight Junctions/drug effects; Reykjavík; Iceland
• Online Access: http://hdl.handle.net/2336/332604; https://doi.org/10.1016/j.ejpb.2013.04.002

To access publisher's full text version of this article click on the hyperlink at the bottom of the page This study describes the structure-activity relationship for carefully characterized N-alkyl-N-quaternary chitosan derivatives as permeation enhancers for drugs that are mainly absorbed through the paracellular pathway, such as macromolecular drugs and hydrophilic drugs, in a well defined bronchial epithelial cell line. The O-methyl free derivatives used in the study were fully trimethylated (100%) N,N,N-trimethyl chitosan (TMC) and N-propyl-(QuatPropyl), N-butyl-(QuatButyl) and N-hexyl (QuatHexyl)-N,N-dimethyl chitosan, with 85-91% degree of quaternization. The fully trimethylated TMC, from 0.25mg/ml, decreased transepithelial electrical resistance (TER) in a reversible manner and enhanced the permeation of the macromolecule FITC-dextran 4kDa (FD4) 2-5 fold. TMC did not cause any alterations in the tight junction (TJ) protein claudin-4 or in F-actin architecture. QuatHexyl was the most effective polymer to produce enhanced permeation and decreased TER from 0.016mg/ml. Nevertheless, this enhanced permeation was accompanied by reduced viability and dissociation of F-actin and claudin-4 proteins. The structure-activity relationship suggests that more lipophilic derivatives show more permeation enhancement, TJ disassembly, and less viability in the order of hexyl≈butyl>propyl>methyl and demonstrates that the permeation effect is not only mediated by permanent positive charge but also by the extent of N-alkylation. These results are relevant to elucidate the structural factors contributing to the permeation enhancement of chitosan derivatives and for potential use in pulmonary applications. Eimskip Fund of University of Iceland Landspitali University Hospital Science