title: VEGF-induced angiogenesis following localized delivery via injectable, low viscosity poly(trimethylene carbonate).
abstract: The purpose of this study was to examine the potential of low molecular weight poly(trimethylene carbonate) for localized vascular endothelial growth factor (VEGF) delivery. Poly(trimethylene carbonate) of various molecular weights was prepared by ring-opening polymerization initiated by 1-octanol. The resultant polymers were liquid at room temperature with low glass transition temperatures and viscosities at 37 degrees C that permitted their injection through an 18 (1/2) G 1.5'' needle. Particles consisting of VEGF co-lyophilized with trehalose were mixed into the polymers and the rate of release of VEGF was assessed in vitro. With a 1% particle loading, VEGF was released from the polymer at a rate of 20 ng/day over a period of 3 weeks. This release behavior was independent of the molecular weight of polymer used. Increasing the VEGF content in the lyophilized particles did not increase the VEGF release rate, an effect attributed to the solubility limit of VEGF in the solution formed upon dissolution of the particles. The VEGF released retained its bioactivity at greater than 95% of that of as-lyophilized VEGF, as assessed using a human aortic endothelial cell proliferation assay. This high bioactivity was supported by in vivo release experiments, wherein VEGF containing polymer implants induced the generation of significantly greater numbers of blood vessels towards the polymer implant than controls. The blood vessels did not remain stable and were reduced in number by three weeks, due to the unsustained and low concentration of VEGF released. This formulation approach, of using a low viscosity polymer delivery vehicle, is potentially useful for localized delivery of acid-sensitive proteins, such as VEGF.
authors.affiliation: Department of Chemical Engineering, Queen's University, Kingston, Ontario, Canada K7L 3N6. brian.amsden@chee.queensu.ca
authors.forename: Brian G
authors.initials: BG
authors.lastname: Amsden
authors.forename: Laurianne
authors.initials: L
authors.lastname: Timbart
authors.forename: Dale
authors.initials: D
authors.lastname: Marecak
authors.forename: Rafi
authors.initials: R
authors.lastname: Chapanian
authors.forename: M Yat
authors.initials: MY
authors.lastname: Tse
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pang
mesh_terms: D020003:1-Octanol; D000818:Animals; D001011:Aorta / Q000166:cytology; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004146:Dioxanes / Q000138:chemical synthesis / Q000737:chemistry*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005612:Freeze Drying; D006801:Humans; D007267:Injections; D008297:Male; D008970:Molecular Weight; D018919:Neovascularization, Physiologic / Q000502:physiology; D058105:Polymerization; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D012709:Serum Albumin / Q000737:chemistry / Q000235:genetics; D012995:Solubility; D014199:Trehalose; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D042442:Vascular Endothelial Growth Factors / Q000008:administration & dosage / Q000737:chemistry; D014783:Viscosity
chemical_list: D004146:Dioxanes; D011108:Polymers; D011994:Recombinant Proteins; D012709:Serum Albumin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C443643:trimethylene carbonate; D014199:Trehalose; D020003:1-Octanol