title: Comparison of monomeric and oligomeric transferrin as potential carrier in oral delivery of protein drugs.
abstract: Oligomeric transferrin (Tf) was used to investigate the effect that cross-linking of transferrin receptors (TfR) has on intracellular trafficking of the Tf-TfR complex and to determine whether or not the Tf-oligomer would be a better carrier than monomeric Tf for the oral delivery of protein drugs. The intracellular retention and transcytosis of the Tf-oligomer was determined by performing pulse chase studies on enterocyte-like Caco-2 cells. The intracellular retention of the Tf-oligomer was 2-fold higher than that of monomeric Tf while there was no significant difference in transcytosis. However, in vivo studies in CF-1 mice showed that the plasma concentrations of Tf from the orally administered Tf-oligomer were approximately 2-, 3- and 60-fold higher than that of orally administered monomeric Tf at 24, 48 and 72 h post-administration, respectively. In addition, the retention of the Tf-oligomer in the intestine was higher than that of monomeric Tf, which was consistent with in vitro studies. Insulin (In), when conjugated to the Tf-oligomer (Agg-Tf-S-S-In), was more effective than monomeric Tf-In conjugate (Mono-Tf-S-S-In) in reducing blood glucose levels when orally administered to streptozotocin (STZ)-induced diabetic rats. Post-oral administration of Agg-Tf-In, a delayed onset and prolonged hypoglycemic effect was observed. These results demonstrate that the cross-linking of TfR induced by the binding of the oligomeric Tf alters the intracellular trafficking and increases the intracellular retention of Tf-TfR complexes in polarized Caco-2 cells. The alteration of TfR trafficking could conceivably have caused the increase of insulin transport across the intestinal barrier when Agg-Tf-S-S-In was administered orally to STZ-induced diabetic rats. The delayed onset and prolonged effect of Agg-Tf-S-S-In in hypoglycemia strongly suggests that the Tf-oligomer can act as a sustained release carrier in the oral delivery of protein and peptide drugs.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Ching-Jou
authors.initials: CJ
authors.lastname: Lim
authors.forename: Wei-Chiang
authors.initials: WC
authors.lastname: Shen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D016764:Cell Polarity; D004337:Drug Carriers; D004355:Drug Stability; D005260:Female; D006801:Humans; D007328:Insulin / Q000008:administration & dosage* / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000378:metabolism; D014168:Transferrin / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D004337:Drug Carriers; D007328:Insulin; D011990:Receptors, Transferrin; D014168:Transferrin