title: Sustained dual drug delivery of anti-inhibitory molecules for treatment of spinal cord injury.
abstract: Myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs) are major contributors to axon growth inhibition following spinal cord injury and limit functional recovery. The NEP1-40 peptide competitively binds the Nogo receptor and partially blocks inhibition from MAIs, while chondroitinase ABC (ChABC) enzymatically digests CSPGs, which are upregulated at the site of injury. In vitro studies showed that the combination of ChABC and NEP1-40 increased neurite extension compared to either treatment alone when dissociated embryonic dorsal root ganglia were seeded onto inhibitory substrates containing both MAIs and CSPGs. Furthermore, the ability to provide sustained delivery of biologically active ChABC and NEP1-40 from biomaterial scaffolds was achieved by loading ChABC into lipid microtubes and NEP1-40 into poly (lactic-co-glycolic acid) (PLGA) microspheres, obviating the need for invasive intrathecal pumps or catheters. Fibrin scaffolds embedded with the drug delivery systems (PLGA microspheres and lipid microtubes) were capable of releasing active ChABC for up to one week and active NEP1-40 for over two weeks in vitro. In addition, the loaded drug delivery systems in fibrin scaffolds decreased CSPG deposition and development of a glial scar, while also increasing axon growth after spinal cord injury in vivo. Therefore, the sustained, local delivery of ChABC and NEP1-40 within the injured spinal cord may block both myelin and CSPG-associated inhibition and allow for improved axon growth.
authors.affiliation: Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, United States.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Wilems
authors.affiliation: Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, United States. Electronic address: sakiyama@wustl.edu.
authors.forename: Shelly E
authors.initials: SE
authors.lastname: Sakiyama-Elbert
mesh_terms: D000818:Animals; D002645:Chickens; D019765:Chondroitin ABC Lyase / Q000008:administration & dosage* / Q000627:therapeutic use; D003692:Delayed-Action Preparations / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005337:Fibrin / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry; D009185:Myelin Proteins / Q000008:administration & dosage* / Q000627:therapeutic use; D055495:Neurogenesis / Q000187:drug effects; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000627:therapeutic use; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D020318:Rats, Long-Evans; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D003692:Delayed-Action Preparations; D009185:Myelin Proteins; C509624:NEP1-40 protein, human; D010446:Peptide Fragments; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D005337:Fibrin; D019765:Chondroitin ABC Lyase
keywords: Chondroitinase ABC; Controlled release; Lipid microtubes; NEP1-40; PLGA microspheres