Maintenance of vascular endothelial growth factor and potentially other therapeutic proteins bioactivity during a photo-initiated free radical cross-linking reaction forming biodegradable elastomers.
Previously, we prepared a biodegradable elastomeric device that can release different therapeutic proteins at a nearly constant rate in nanomolar concentrations with high bioactivity. The elastomer device was fabricated using a photo-initiated free radical cross-linking reaction of acrylated star(epsilon-caprolactone-co-D,L-lactide) in organic solvent in the presence of solid protein particles. The objective of this study was to examine the effect of various parameters used for fabricating the photo-cross-linked elastomeric device on the stability of a therapeutic protein, vascular endothelial growth factor (VEGF), to determine which factor plays the dominant role in protecting VEGF. VEGF was lyophilized with or without bovine serum albumin (BSA) and then suspended in solid state in a macromer (acrylated star-poly(epsilon-caprolactone-co-D,L-lactide)) solution containing different concentrations of a free radical initiator, 2,2-dimethoxy-2-phenylacetophenone (DMPA). The protein suspension was then UV-irradiated at different intensities. UV irradiation with the generation of free radicals was detrimental to VEGF stability. BSA preserved the VEGF bioactivity during UV irradiation but provided little protection in the presence of the photo-initiator DMPA. The acrylated macromer acted as a free radical scavenger and effectively preserved VEGF and BSA stability during UV-initiated photo-polymerization. The detrimental effect of UV radiation with free radical generation on VEGF stability during device manufacture can be eliminated by choosing the proper bulking agents coupled with an efficient photo-polymerization reaction.
Gu
Frank
F
Department of Chemical Engineering, Queen's University, Kingston, Ontario, Canada.
Neufeld
Ronald
R
Amsden
Brian
B
D020003:1-Octanol / Q000737:chemistry; D000327:Adsorption; D000814:Aniline Compounds / Q000737:chemistry; D001672:Biocompatible Materials / Q000737:chemistry*; D002208:Caproates / Q000737:chemistry / Q000494:pharmacology; D002850:Chromatography, Gel; D003432:Cross-Linking Reagents / Q000737:chemistry; D004355:Drug Stability; D020724:Elastomers / Q000737:chemistry*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology; D005609:Free Radicals / Q000737:chemistry*; D005612:Freeze Drying / Q000379:methods; D005663:Furans / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D046911:Macromolecular Substances / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology / Q000528:radiation effects; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000494:pharmacology; D014466:Ultraviolet Rays; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology
D000814:Aniline Compounds; D001672:Biocompatible Materials; D002208:Caproates; D003432:Cross-Linking Reagents; D020724:Elastomers; D016166:Free Radical Scavengers; D005609:Free Radicals; D005663:Furans; D007783:Lactones; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D012710:Serum Albumin, Bovine; C018674:tetrahydrofuran; C121056:caprolactone; C050795:N,N-dimethyl-4-anisidine; D020003:1-Octanol