期刊
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
卷 155, 期 -, 页码 77-87出版社
ELSEVIER
DOI: 10.1016/j.ejpb.2020.08.001
关键词
Epithelial permeation; Insulin; Octaarginine; Cell-penetrating peptide; Simulated intestinal fluid; Microfold cell
资金
- Research Foundation for Pharmaceutical Sciences
- Kobe Gakuin University
- JSPS KAKENHI [16K08211]
- Grants-in-Aid for Scientific Research [16K08211] Funding Source: KAKEN
We previously reported that oral and intestinal absorption of insulin in rats and mice is significantly enhanced in vivo by coadministration with cell-penetrating peptides (CPPs). To evaluate the clinical use of CPPs as absorption enhancers, it is imperative to clarify the mechanisms associated with the permeation-stimulatory effect of CPPs in vitro. The confirmation experiment revealed a discrepancy between in vivo and in vitro effects of CPPs, such as D-octaarginine (D-R8) and L-penetratin, on epithelial permeation of insulin. The present study was designed to determine the factors that work in vivo but are deficient in an in vitro system consisting of Caco-2 cells. The effects of D-R8 and L-penetratin on permeation of insulin through the Caco-2 cell monolayer were partially boosted in fasted-state simulated intestinal fluid (FaSSIF). Contrary to expectation, the effects of CPPs on cellular uptake of insulin and the binding ratio of CPPs to insulin analyzed by surface plasmon resonance in normal buffer and FaSSIF were similar. Also, the effects of CPPs, especially D-R8, on cellular uptake of insulin, were stronger in Caco-2 cell monolayers with microfold cell (M cell)-like properties. These results suggested a key role of intestinal lipids and M cells in the stimulatory effect of CPPs on net epithelial permeation of insulin in vivo.
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