Corelease of Bioactive VEGF and HGF from Viscous Liquid Poly(5-ethylene ketal ε-caprolactone-co-d,l-lactide)

Abstract

The potential of a viscous liquid injectable delivery system composed of poly(5-ethylene ketal ε-caprolactone-co-D,L-lactide) (PEKCDLLA) to release bioactive vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) using an osmotic pressure release mechanism for the purpose of treating critical limb ischemia was investigated. VEGF and HGF were lyophilized separately with trehalose and bovine serum albumin (BSA) and incorporated into the polymer by simple mixing. VEGF and HGF were released by convective flow through superhydrated regions formed within the polymer as a result of the osmotic activity generated upon dissolution of the particles, along with the contributions of polymer degradation at later time points. A sustained release of highly bioactive VEGF and HGF for over 40 days with minimal burst was achieved under conditions of multidirectional delivery. The solubility of the growth factors in the concentrated trehalose solution formed upon dissolution of the particle within the polymer was determined to be a key parameter governing the rate and extent of growth factor release. This formulation approach, of using a low viscosity polymer delivery vehicle, is potentially useful for localized delivery of acid and temperature sensitive proteins, such as VEGF and HGF. This system may also serve as a platform for controlled and predictable delivery patterns for other therapeutic proteins in other clinical settings.