(190bi) Multiscale Structural Characterization of Epithelial Cell Monolayers Associated with the Addition of Permeability Enhancers for Enhancing Drug Delivery

A major obstacle for topical and enteral drug delivery is the poor transport of macromolecular drugs through the epithelium. One potential solutions to resolve this problem is the use of permeation enhancers that alter epithelial structures. Specifically, piperazine derivatives are permeation enhancers that can modulate epithelial structures, as shown by TEER (Transepithelial electrical resistance), and augment the absorption of macromolecular drugs. We are investigating the mechanism by which the piperazine derivatives disrupt the structures of epithelial monolayers. In this project, the model cell line NRK-52E was used as the subject to measure the function and cytotoxicity of 1-phenylpiperiazine (1-ppz) and 1-Methal-4-phenylpiperiazine (1-M-4-ppz). Live cell imaging reveals a dose-dependent gross reorganization of monolayers at high concentrations, but reorganization differs based on the piperazine type. We also examine subcellular effects on NRK-52E monolayers including cytoskeletal reorganization, cell-cell connections, and force generation within cells using confocal imaging and biophysical techniques. Once the mechanisms of epithelial permeability can be quantified it will be possible to develop better delivery systems as well as new permeability enhancers.