title: A new paradigm for local and sustained release of therapeutic molecules to the injured spinal cord for neuroprotection and tissue repair.
abstract: After spinal cord injury (SCI), a complex cascade of events leads to tissue degeneration and a penumbra of cell death. Neuroprotective molecules to limit tissue loss are promising; however, intravenous delivery is limited by the blood-spinal cord barrier and short systemic half-life. Current local delivery strategies are flawed: bolus injection results in drug dispersion throughout the intrathecal (IT) space, and catheters/pumps are invasive and open to infection. Our laboratory previously developed a hydrogel of hyaluronan (HA) and methylcellulose (MC) (HAMC) that, when injected into the IT space, was safe and, remarkably, had some therapeutic benefit on its own. In order to test this new paradigm of local and sustained delivery, relative to conventional delivery strategies, we tested, for the first time, the in vivo efficacy of HAMC as an IT drug delivery system by delivering a known neuroprotective molecule, erythropoietin (EPO). In vitro studies showed that EPO was released from HAMC within 16 h, with 80% bioactivity maintained. When the material alone was injected in vivo, individual fluorescent labels on HA and MC showed that HA dissolved from the gel within 24 h, whereas the hydrophobically associated MC persisted in the IT space for 4-7 days. Using a clip compression injury model of moderate severity, HAMC with EPO was injected in the IT space and, in order to better understand the potential of this delivery system, compared to the therapeutic effect of both common delivery strategies-IT EPO and intraperitoneal EPO-and a control of IT HAMC alone. IT HAMC delivery of EPO resulted in both reduced cavitation after SCI and a greater number of neurons relative to the other delivery strategies. These data suggest that the localized and sustained release of EPO at the tissue site by HAMC delivery enhances neuroprotection. This new system of IT delivery holds great promise for the safe, efficacious, and local delivery of therapeutic molecules directly to the spinal cord.
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Kang
authors.forename: Peter C
authors.initials: PC
authors.lastname: Poon
authors.forename: Charles H
authors.initials: CH
authors.lastname: Tator
authors.forename: Molly S
authors.initials: MS
authors.lastname: Shoichet
mesh_terms: D000818:Animals; D002452:Cell Count; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D004921:Erythropoietin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D006820:Hyaluronic Acid / Q000378:metabolism; D008747:Methylcellulose / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D003692:Delayed-Action Preparations; D018696:Neuroprotective Agents; D004921:Erythropoietin; D006820:Hyaluronic Acid; D008747:Methylcellulose