Piperazine Derivatives Enhance Epithelial Cell Monolayer Permeability by Increased Cell Force Generation and Loss of Cadherin Structures
| Autor: | Katherine C. Fein, Shiyuan Zheng, Kathryn A. Whitehead, Nicholas G. Lamson, Kris Noel Dahl, Kirill Lavrenyuk |
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| Rok vydání: | 2019 |
| Předmět: |
0206 medical engineering
Biomedical Engineering 02 engineering and technology Permeability Piperazines Biomaterials chemistry.chemical_compound Myosin medicine Humans Cytoskeleton Tight junction Cadherin Epithelial Cells Permeation Cadherins 021001 nanoscience & nanotechnology 020601 biomedical engineering Epithelium Piperazine medicine.anatomical_structure Pharmaceutical Preparations chemistry Drug delivery Biophysics Caco-2 Cells 0210 nano-technology |
| Zdroj: | ACS Biomaterials Science & Engineering. 6:367-374 |
| ISSN: | 2373-9878 |
| Popis: | A major obstacle for topical and enteral drug delivery is the poor transport of macromolecular drugs through the epithelium. One potential solution is the use of permeation enhancers that alter epithelial structures. Piperazine derivatives are known permeation enhancers that modulate epithelial structures, reduce transepithelial electrical resistance, and augment the absorption of macromolecular drugs. The mechanism by which piperazine derivatives disrupt the structures of epithelial monolayers is not well understood. Here, the effects of 1-phenylpiperazine and 1-methyl-4-phenylpiperazine are modeled in the epithelial cell line NRK-52E. Live-cell imaging reveals a dose-dependent gross reorganization of monolayers at high concentrations, but reorganization differs based on the piperazine molecule. Results show that low concentrations of piperazine derivatives increase myosin force generation within the cells and do not disrupt the cytoskeletal structure. Also, cytoskeletally attached cadherin junctions are disrupted before tight junctions. In summary, piperazines appear to increase myosin-mediated contraction followed by disruption of cell-cell contacts. These results provide new mechanistic insight into how transient epithelial permeation enhancers act and will inform of the development of future generations of transepithelial delivery systems. |
| Databáze: | OpenAIRE |
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