title: A hydrogel composite system for sustained epi-cortical delivery of Cyclosporin A to the brain for treatment of stroke.
abstract: Stimulation of endogenous neural stem/progenitor cells (NSPCs) with therapeutic factors holds potential for the treatment of stroke. Cyclosporin A (CsA) is a particularly promising candidate molecule because it has been shown to act as a survival factor for these cells over a period of weeks both in vitro and in vivo; however, systemically-delivered CsA compromises the entire immune system, necessitating sustained localized delivery. Herein we describe a local delivery strategy for CsA using an epi-cortical hydrogel of hyaluronan-methylcellulose (HAMC) as the drug reservoir. Three methods of incorporating the drug into the hydrogel (solubilized, particulate, and poly(lactic-co-glycolic) acid (PLGA) microsphere-encapsulated) resulted in tunable release, spanning a period of hours to weeks. Importantly, PLGA-encapsulated CsA released from the hydrogel had equivalent bioactivity to fresh drug as measured by the neurosphere assay. Moreover, when CsA was released from the PLGA/HAMC composite that was injected on the cortex of adult mice, CsA was detected in the NSPC niche at a constant concentration for at least 24days post-implant. Thus this hydrogel composite system may be promising for the treatment of stroke.
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON, Canada M5S 3E5.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Caicco
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cooke
authors.forename: Yuanfei
authors.initials: Y
authors.lastname: Wang
authors.forename: Anup
authors.initials: A
authors.lastname: Tuladhar
authors.forename: Cindi M
authors.initials: CM
authors.lastname: Morshead
authors.forename: Molly S
authors.initials: MS
authors.lastname: Shoichet
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D002853:Chromatography, Liquid; D016572:Cyclosporine / Q000008:administration & dosage* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems / Q000379:methods*; D006820:Hyaluronic Acid / Q000737:chemistry; D020100:Hydrogels / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry; D008747:Methylcellulose / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D008954:Models, Biological; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects*; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012995:Solubility; D020521:Stroke / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D013499:Surface Properties; D053719:Tandem Mass Spectrometry; D013997:Time Factors
chemical_list: D003692:Delayed-Action Preparations; D020100:Hydrogels; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D016572:Cyclosporine; D006820:Hyaluronic Acid; D008747:Methylcellulose