RATIONAL DELIVERY STRATEGIES FOR THE DESIGN OF PEPTIDES WITH ENHANCED ORAL DELIVERY

One of the most significant biological barriers to delivery of peptides and peptide mimetics is the intestinal mucosa, which is a cell monolayer with tight intercellular junctions representing both an anatomical and an enzymatic barrier to the permeability of most polar molecules. In order to properly evaluate strategies for enhancing membrane permeability of peptides and peptide mimetics, our laboratory has developed an in. vitro model of the intestinal mucosa, which consists of human adenocarcinoma cells (Caco-2) grown onto microporous membranes. This cell culture system, as well as an in. situ intestinal perfusion model, has been employed in our laboratory to evaluate strategies for enhancing membrane permeability of peptides. The strategies that will be discussed in this article include: (1) designing conjugates of peptide mimetics targeted to endogenous transporter systems (e.g., bile acid) so as to enhance their intestinal permeability by a carrier-mediated pathway; and (2) optimizing the lipophilicity, hydrogen-bonding potential and conformation of peptide mimetics so as to enhance their intestinal permeability by passive diffusion.