title: Circumventing the blood-brain barrier: Local delivery of cyclosporin A stimulates stem cells in stroke-injured rat brain.
abstract: Drug delivery to the central nervous system is limited by the blood-brain barrier, which can be circumvented by local delivery. In applications of stroke therapy, for example, stimulation of endogenous neural stem/progenitor cells (NSPCs) by cyclosporin A (CsA) is promising. However, current strategies rely on high systemic drug doses to achieve small amounts of CsA in the brain tissue, resulting in systemic toxicity and undesirable global immunosuppression. Herein we describe the efficacy of local CsA delivery to the stroke-injured rat brain using an epi-cortically injected hydrogel composed of hyaluronan and methylcellulose (HAMC). CsA was encapsulated in poly(lactic-co-glycolic acid) microparticles dispersed in HAMC, allowing for its sustained release over 14days in vivo. Tissue penetration was sufficient to provide sustained CsA delivery to the sub-cortical NSPC niche. In comparison to systemic delivery using an osmotic minipump, HAMC achieved higher CsA concentrations in the brain while significantly reducing drug exposure in other organs. HAMC alone was beneficial in the stroke-injured rat brain, significantly reducing the stroke infarct volume relative to untreated stroke-injured controls. The combination of HAMC and local CsA release increased the number of proliferating cells in the lateral ventricles - the NSPC niche in the adult brain. Thus, we demonstrate a superior method of drug delivery to the rat brain that provides dual benefits of tissue protection and endogenous NSPC stimulation after stroke.
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON M5S 3G9, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors.forename: Anup
authors.initials: A
authors.lastname: Tuladhar
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON M5S 3G9, Canada; Department of Surgery, University of Toronto, 149 College Street, Toronto, ON M5S 3E1, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors.forename: Cindi M
authors.initials: CM
authors.lastname: Morshead
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON M5S 3G9, Canada; Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON M5S 3E5, Canada; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada. Electronic address: molly.shoichet@utoronto.ca.
authors.forename: Molly S
authors.initials: MS
authors.lastname: Shoichet
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D020520:Brain Infarction / Q000188:drug therapy / Q000473:pathology; D002452:Cell Count; D016572:Cyclosporine / Q000008:administration & dosage* / Q000494:pharmacology*; D004339:Drug Compounding; D016503:Drug Delivery Systems; D006820:Hyaluronic Acid; D020100:Hydrogels; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D019344:Lactic Acid; D020547:Lateral Ventricles / Q000378:metabolism; D008297:Male; D008747:Methylcellulose; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D020318:Rats, Long-Evans; D013234:Stem Cells / Q000187:drug effects*; D020521:Stroke / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology
chemical_list: D020100:Hydrogels; D007166:Immunosuppressive Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D016572:Cyclosporine; D006820:Hyaluronic Acid; D008747:Methylcellulose
keywords: Blood brain barrier; Cyclosporin A; Drug delivery; Hydrogel; Neural stem progenitor cell; Stroke