In our laboratory at USC School of Pharmacy, the focus of the research is to develop delivery systems for proteins and peptides, with an emphasis on the development of oral formulations, making these compounds suitable for therapeutic applications. Currently, we are working on two major projects:

(1) Transferrin receptor-mediated transcytosis in intestinal epithelial cells

(2) Reversible lipidization of polypeptides




Transferrin receptor-mediated transcytosis in intestinal epithelial cells

For the transferrin receptor-mediated transcytosis, we have demonstrated that there are a large number of transferrin receptors on the surface of intestinal epithelial cells. Using cultured epithelial cell lines, i.e., MDCK and Caco-2, we have shown that transferrin can be used as a carrier for transepithelial transport of other proteins and peptides. We also have found that certain non-toxic agents such as Brefeldin A can further enhance this transcytotic process. Currently, we are exploiting this receptor-mediated transport mechanism for the oral delivery of insulin as transferrin conjugates for the treatment of diabetes in animal models.

Representative publications:

Wan J, Taub ME, Shah D and Shen WC: Brefeldin A enhances receptor-mediated transcytosis of transferrin in filter-grown Madin-Darby canine kidney cells. J Biol Chem 267:13446-13450, 1992.

Shah D and Shen WC: The establishment of polarity and enhanced transcytosis of transferrin receptors in enterocyte-like caco-2 cells. J Drug Targeting 2:93-99, 1994.

Shah D and Shen WC, Transepithelial delivery of an insulin-transferrin conjugate in enterocyte-like Caco-2 cells. J Pharm Sci, 85:1306-1311, 1996.

Wang J, Shen D and Shen WC: Oral delivery of an insulin-transferrin conjugate in streptozotocin-treated CF/1 mice. Pharm Res 14:(abstract in press), 1997.


Transferrin Receptor (TfR)-mediated Transcytosis

 

Reversible lipidization of polypeptides

For the lipidization of polypeptides, we have developed a novel procedure for the preparation of water soluble and biologically active fatty acid-peptide conjugates. Several polypeptides have been successfully lipidized by using this new method. Preliminary results indicated that many advantages can be achieved in these lipidized polypeptides such as enhancing epithelial absorption and prolonging plasma half-life.

Representative publications:

Ekrami HM, Kennedy AR and Shen WC: Water soluble fatty acid derivatives as acylating agents for reversible lipidization of polypeptides. FEBS Lett 371:283-286, 1995.

Honeycutt L, Wang J, Ekrami H and Shen WC, Comparison of pharmacokinetic parameters of a polypeptide, the Bowman-Birk protease inhibitor (BBI), and its plamitic acid conjugate. Pharm Res, 13:1372-1376, 1996.

Shen WC, Wang J and Shen D: Reversible lipidization of polypeptides in drug delivery. Proceed. Intern. Sym. Control. Rel. Bioact. Mater. 24: 202-203, 1997.


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