title: Sustained delivery of bioactive neurotrophin-3 to the injured spinal cord.
abstract: Spinal cord injury is a debilitating condition that currently lacks effective clinical treatment. Neurotrophin-3 (NT-3) has been demonstrated in experimental animal models to induce axonal regeneration and functional improvements, yet its local delivery remains challenging. For ultimate clinical translation, a drug delivery system is required for localized, sustained, and minimally invasive release. Here, an injectable composite drug delivery system (DDS) composed of biodegradable polymeric nanoparticles dispersed in a hyaluronan/methyl cellulose hydrogel was injected into the intrathecal space to achieve acute local delivery to the spinal cord after a thoracic clip compression injury. NT-3 was encapsulated in the DDS and released in vitro for up to 50 d. With a single injection of the DDS into the intrathecal space of the injured spinal cord, NT-3 diffused ventrally through the cord and was detectable in the spinal cord for at least 28 d therein. Delivery of NT-3 resulted in significant axon growth with no effect on the astroglial response to injury in comparison with vehicle and injury controls. NT-3 treatment promoted functional improvements at 21 d according to the Basso Beattie Bresnahan locomotor scale in comparison with the DDS alone. The sustained delivery of bioactive NT-3 to the injured spinal cord achieved in this study demonstrates the promise of this DDS for central nervous system repair.
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON, Canada M5S 3E5. molly.shoichet@utoronto.ca.
authors.forename: Irja
authors.initials: I
authors.lastname: Elliott Donaghue
authors.forename: Charles H
authors.initials: CH
authors.lastname: Tator
authors.forename: Molly S
authors.initials: MS
authors.lastname: Shoichet
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D020100:Hydrogels / Q000008:administration & dosage / Q000737:chemistry; D007278:Injections, Spinal / Q000379:methods*; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D020933:Neurotrophin 3 / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D013116:Spinal Cord / Q000737:chemistry / Q000187:drug effects*; D013119:Spinal Cord Injuries / Q000188:drug therapy*
chemical_list: D003692:Delayed-Action Preparations; D020100:Hydrogels; D020933:Neurotrophin 3; D011108:Polymers