Nicholas A Peppas, ScD
Fletcher Stuckey Pratt Chair in Engineering
Professor of Biomedical Engineering, Chemical Engineering and Pharmacy
Chairman, Biomedical Engineering Department
The University of Texas at Austin
Transport mechanisms of therapeutic proteins across the epithelial cell layer are discussed in view of recent molecular/cellular studies. We have successfully developed strategies to overcome the inherent challenges to transmucosal protein delivery and the narrow absorption window in the small intestine (with tight junctions between cells permitting only the transport of molecules with radii less than 11 Ǻ) by protein incorporation into molecularly designed macromolecular networks. Protein/polymer dynamics become important under these conditions. We demonstrate that complexation networks function interactively with cells through macromolecular tethers that interpenetrate and adhere to the cells with adhesive forces of approximately 130 x 10-3 mJ. While our research addresses design strategies to improve epithelial transport by paracellular protein transport, we address also transcellular transport results. We have been able to successfully synthesize and characterize protein-transporter conjugates which utilize the specific targeting mechanisms of ligand-receptor interactions for use with complexation hydrogels to ultimately deliver a significant amount of protein to the bloodstream through the transcellular route. The addition of the transporter transferrin to the therapeutic protein allows for specific targeting of the bioconjugate entity as well as potentially increased transport. The transferrin receptor is expressed on human intestinal epithelial cells. The cellular model used for evaluation of insulin-transferrin bioconjugates is a co-culture consisting of both absorptive enterocyte-like Caco-2 cells and mucus-producing HT29-MTX goblet cells. Cellular studies performed in the presence of microparticles give insight into the effect of complexation hydrogels on the transport processes of the epithelial cell monolayer. Conclusions are drawn regarding the effect of protein-transporter conjugation and the presence of complexation hydrogels on epithelial transport of insulin, calcitonin, interferon-beta and other therapeutic proteins.