A hydrogel composite system for sustained epi-cortical delivery of Cyclosporin A to the brain for treatment of stroke

J Control Release. 2013 Mar 28;166(3):197-202. doi: 10.1016/j.jconrel.2013.01.002. Epub 2013 Jan 8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / cytology
  • Brain / metabolism*
  • Brain / pathology
  • Chromatography, Liquid
  • Cyclosporine / administration & dosage*
  • Cyclosporine / cerebrospinal fluid
  • Cyclosporine / pharmacokinetics
  • Cyclosporine / therapeutic use
  • Delayed-Action Preparations
  • Drug Delivery Systems / methods*
  • Hyaluronic Acid / chemistry
  • Hydrogels / chemistry
  • Lactic Acid / chemistry
  • Methylcellulose / chemistry
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Electron, Scanning
  • Microspheres
  • Models, Biological
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects*
  • Particle Size
  • Polyglycolic Acid / chemistry
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Solubility
  • Stroke / cerebrospinal fluid
  • Stroke / drug therapy
  • Stroke / pathology
  • Stroke / therapy*
  • Surface Properties
  • Tandem Mass Spectrometry
  • Time Factors


  • Delayed-Action Preparations
  • Hydrogels
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid
  • Cyclosporine
  • Hyaluronic Acid
  • Methylcellulose