title: Poly(ethylene glycol) modification enhances penetration of fibroblast growth factor 2 to injured spinal cord tissue from an intrathecal delivery system.
abstract: There is no effective treatment for spinal cord injury and clinical drug delivery techniques are limited by the blood-spinal cord barrier. Our lab has developed an injectable drug delivery system consisting of a biopolymer blend of hyaluronan and methylcellulose (HAMC) that can sustain drug release for up to 24h in the intrathecal space. Fibroblast growth factor 2 (FGF2) has great potential for treatment of spinal cord injury due to its angiogenic and trophic effects, but previous studies showed no penetration into spinal cord tissue when delivered locally. Conjugation to poly(ethylene glycol) (PEG) is known to improve penetration of proteins into tissue by reducing clearance and providing immunogenic shielding. We investigated conjugation of PEG to FGF2 and compared its distribution relative to unmodified FGF2 in injured spinal cord tissue when delivered intrathecally from HAMC. Importantly, PEG conjugation nearly doubled the concentration of FGF2 in the injured spinal cord when delivered locally and, contrary to previous reports, we show that some FGF2 penetrated into the injured spinal cord using a more sensitive detection technique. Our results suggest that PEGylation of FGF2 enhanced tissue penetration by reducing its rate of elimination.
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON, Canada.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Kang
authors.forename: Charles H
authors.initials: CH
authors.lastname: Tator
authors.forename: Molly S
authors.initials: MS
authors.lastname: Shoichet
mesh_terms: D000818:Animals; D004333:Drug Administration Routes; D016503:Drug Delivery Systems; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000627:therapeutic use; D006820:Hyaluronic Acid / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D007278:Injections, Spinal; D008747:Methylcellulose / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D011092:Polyethylene Glycols / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D016222:Fibroblast Growth Factor 2; D011092:Polyethylene Glycols; D006820:Hyaluronic Acid; D008747:Methylcellulose