Release rate controls biological activity of nerve growth factor released from fibrin matrices containing affinity-based delivery systems.
Previously, combinatorial techniques were used to identify peptide sequences exhibiting high, medium, and low affinity for heparin. Bidomain peptides were synthesized containing a transglutaminase sequence for one domain and one of the heparin-affinity sequences for the other domain. A delivery system was made consisting of bi-domain peptides, heparin, and nerve growth factor (NGF), which binds to heparin with moderate affinity. The goal of this research was to determine whether peptide affinity for heparin and the molar ratio of peptide to heparin affected the release rate of NGF from the delivery system and the biological activity of NGF released. This study also explored whether peptide affinity modulated biological activity independent of release rate. Mathematically modeling the delivery system confirmed that release could be controlled by both peptide affinity and molar ratio of peptide to heparin. Experimentally, the rate of NGF release from the delivery system was found to be affected by peptide affinity and molar ratio. The delivery system presented biologically active NGF as assayed by embryonic chick dorsal root ganglia (DRGs) neurite extension, where extension was similar to or increased for DRGs grown in fibrin matrices containing the delivery system compared to DRGs grown with NGF in the culture media. Furthermore, by modulating the molar ratio of peptide to heparin in the delivery system, similar release rates of NGF were obtained for different affinity peptides and these conditions promoted similar levels of neurite extension, demonstrating that release rate appears to be the main mechanism controlling the biological activity of released NGF.
Wood
Matthew D
MD
Department of Biomedical Engineering, Washington University, St. Louis, Missouri 63130, USA.
Sakiyama-Elbert
Shelly E
SE
D000818:Animals; D002642:Chick Embryo; D003692:Delayed-Action Preparations; D004058:Diffusion; D016503:Drug Delivery Systems; D005079:Excipients; D005337:Fibrin / Q000737:chemistry*; D005343:Fibrinolytic Agents / Q000737:chemistry; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006493:Heparin / Q000737:chemistry; D007700:Kinetics; D015233:Models, Statistical; D020932:Nerve Growth Factor / Q000008:administration & dosage* / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis
D003692:Delayed-Action Preparations; D005079:Excipients; D005343:Fibrinolytic Agents; D010455:Peptides; D005337:Fibrin; D006493:Heparin; D020932:Nerve Growth Factor