Controlled release of Repifermin® from polyelectrolyte complexes stimulates endothelial cell proliferation

The therapeutic value of many growth factors is often hindered by the narrow therapeutic index and sustained concentrations required for efficacy. Controlled release approaches provide a valuable tool to achieve these goals; however, growth factor stability must be maintained. Repifermin® is a truncated form of fibroblast growth factor-10, also known as keratinocyte growth factor-2, that exhibits promise in wound healing applications; however, controlled release formulation presents a challenge for this labile protein. Taking advantage of the heparin-binding motif of this class of biopharmaceuticals, Repifermin® was effectively stabilized and packaged in polyelectrolyte complexes. In the presence of dextran sulfate, the unfolding temperature of this growth factor was increased by ∼10°C as confirmed by a variety of spectroscopic techniques. Dextran sulfate with bound Repifermin® was then complexed with several polycations (chitosan, poly-L-lysine, and polyethylenimine) resulting in the formation of ∼250 nm polyelectrolyte complexes that entrapped the protein with ∼70-80% efficiency. Release was controlled for more than 10 days and the mitogenic activity of Repifermin® on human umbilical cord vascular endothelial cells was significantly enhanced, whereas no effect was noted for free Repifermin®. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:268-280, 2009