title: Intranasal delivery of growth differentiation factor 5 to the central nervous system.
abstract: BACKGROUND
  Growth differentiation factor 5 (GDF5), in addition to its role in bone and joint development, protects dopaminergic (DA) neurons from degeneration, and is a potential therapeutic agent for Parkinson's disease. Its large size and insolubility at physiologic pH are obstacles for drug administration to the central nervous system (CNS) in humans.
  
  
  OBJECTIVE
  In this study, formulations to deliver GDF5 to the brain using intranasal (IN) administration were developed.
  
  
  METHODS
  IN administration of GDF5 in acidic buffer, 20 mM sodium acetate (NaAc) at pH 4.25, was performed in rats. Also, a lipid microemulsion (LME) comprised of olive oil and phosphatidylserine (PS) was used to formulate GDF5 at neutral pH for IN administration. Tissue concentrations of GDF5 were determined by both gamma counting and enzyme-linked immunosorbent assay (ELISA).
  
  
  RESULTS
  IN administration of GDF5 in acidic buffers bypassed the blood-brain barrier (BBB), resulting in delivery to the brain with limited systemic exposure. IN administration of GDF5-LME increased drug targeting to the midbrain eightfold when compared to IN administration of GDF5 in acidic buffer.
  
  
  CONCLUSIONS
  This study is the first to show that GDF5 can be formulated at neutral pH and can be directly delivered to the CNS via IN administration, with biologically relevant concentrations in the midbrain where it may be used to treat Parkinson's disease.
authors.affiliation: Alzheimer's Research Center, Regions Hospital, HealthPartners Research Foundation, Saint Paul, MN 55105, USA. Leah.R.Hanson@HealthPartners.com
authors.forename: Leah R
authors.initials: LR
authors.lastname: Hanson
authors.forename: Jared M
authors.initials: JM
authors.lastname: Fine
authors.forename: John D
authors.initials: JD
authors.lastname: Hoekman
authors.forename: Thuhien M
authors.initials: TM
authors.lastname: Nguyen
authors.forename: Rachel B
authors.initials: RB
authors.lastname: Burns
authors.forename: Paula M
authors.initials: PM
authors.lastname: Martinez
authors.forename: Jens
authors.initials: J
authors.lastname: Pohl
authors.forename: William H
authors.initials: WH
authors.lastname: Frey
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods; D055428:Growth Differentiation Factor 5 / Q000008:administration & dosage* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C525893:GDF5 protein, human; D055428:Growth Differentiation Factor 5