Circumventing the blood-brain barrier: Local delivery of cyclosporin A stimulates stem cells in stroke-injured rat brain

J Control Release. 2015 Oct 10;215:1-11. doi: 10.1016/j.jconrel.2015.07.023. Epub 2015 Jul 27.

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.

Keywords: Blood brain barrier; Cyclosporin A; Drug delivery; Hydrogel; Neural stem progenitor cell; Stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects*
  • Brain Infarction / drug therapy
  • Brain Infarction / pathology
  • Cell Count
  • Cyclosporine / administration & dosage*
  • Cyclosporine / pharmacology*
  • Drug Compounding
  • Drug Delivery Systems
  • Hyaluronic Acid
  • Hydrogels
  • Immunosuppressive Agents / administration & dosage*
  • Immunosuppressive Agents / pharmacology*
  • Lactic Acid
  • Lateral Ventricles / metabolism
  • Male
  • Methylcellulose
  • Polyglycolic Acid
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Rats
  • Rats, Long-Evans
  • Stem Cells / drug effects*
  • Stroke / chemically induced
  • Stroke / drug therapy*
  • Stroke / pathology

Substances

  • Hydrogels
  • Immunosuppressive Agents
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid
  • Cyclosporine
  • Hyaluronic Acid
  • Methylcellulose