Poster Presentation 12th Australian Peptide Conference 2017

Improvement of oral delivery of EGFR-targeted hybrid peptide by combination with bile acid (#148)

Arong Gaowa 1 2 , Tomohisa Horibe 2 , Masayuki Kohno 2 , Koji Kawakami 2
  1. Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University, Tsu, Japan
  2. Department of Pharmacoepidemiology, Kyoto University, Kyoto, Japan

We previously reported that epidermal growth factor receptor (EGFR)-targeted hybrid type lytic peptide has highly potent and selective pharmacological activities toward KRAS-mutated EGFR-positive cancer cells. Although the oral route is the most preferred for all drugs, oral delivery of peptide drugs faces many hurdles such as poor absorption, poor permeability and rapid degradation. In this study, in order to improve the in vitro cell permeability and in vivo intestinal absorption of this hybrid peptide, we prepared an oral formulation of this peptide with bile acid as an absorption enhancer. The oral formulation of peptide was formed through the electrostatic interaction between the cationic peptide and anionic bile acid. In vitro permeability study was performed using Caco-2 cell monolayers cultured on Transwell cell culture inserts. Peptide and peptide-bile acid complex were labelled with fluorescein isothiocyanate (FITC) for quantitative detection by spectrofluorimetry in permeability studies. In Caco-2 cells, the absorption permeability of peptide from the peptide-bile acid complex was increased 5-fold compared with that of free peptide. The in vitro dissolution test was carried out under various pH conditions in the range of 1.5 to 9.0. Stability investigations showed that the peptide-bile acid complex were reasonably stable at gastric acid pH (< 3.5), but were relatively fast release at intestinal fluid pH. In vivo antitumor activities of peptide and peptide-bile acid complex were performed using the xenograft mouse model of gastric cancer. In animal experiments, the antitumor activity of peptide-bile acid complex was much higher to that of peptide alone. These results indicate that the bile acid was an effective absorption enhancer for improving the oral absorption and therapeutic efficacy of EGFR-targeted hybrid peptide.