title: Nanotechnology Approaches to Targeting Inflammation and Excitotoxicity in a Canine Model of Hypothermic Circulatory Arrest-Induced Brain Injury.
abstract: BACKGROUND
  Neurocognitive dysfunction and injury remain problematic after cardiac procedures requiring hypothermic circulatory arrest (HCA). Due to poor blood-brain barrier penetrance and toxicities associated with systemic drug therapies, clinical success has been elusive. Accordingly, we explored targeted dendrimer (a nanoparticle) drug therapies in our well-established canine model of HCA to characterize the biodistribution and cellular localization of these nanoparticles in areas of known neuronal apoptosis and necrosis.
  
  
  METHODS
  Class A, 27- to 30-kg male hounds were administered an initial intravenous bolus (10% of the total dose [200 mg]) of generation-six polyamidoamine dendrimer (6.7 nm) labeled with cyanine 5, and cardiopulmonary bypass with peripheral cannulation was initiated. After 90 minutes of HCA, 70% of the total dose was infused over a 6-hour period. The final 20% of the total dose was given 24 hours post-HCA. The brain was harvested 48 hours later (72 hours post-HCA) and analyzed for dendrimer 6-cyanine 5 biodistribution.
  
  
  RESULTS
  The dorsal hippocampus demonstrated the highest brain accumulation of dendrimer 6-cyanine 5, which closely corresponds to the distribution of apoptotic neurons evident with histologic staining and on confocal imaging. In injured brain regions, dendrimer traversed the blood-brain barrier and localized within the target cells (injured neurons and microglia).
  
  
  CONCLUSIONS
  These findings have exciting implications for the future development of novel therapeutics to mitigate neurocognitive deficits in this group of patients.
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins Medical Institution, Baltimore, Maryland.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Grimm
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins Medical Institution, Baltimore, Maryland.
authors.forename: J Trent
authors.initials: JT
authors.lastname: Magruder
authors.affiliation: Kennedy Krieger Institute, The Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Wilson
authors.affiliation: Kennedy Krieger Institute, The Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Blue
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins Medical Institution, Baltimore, Maryland.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Crawford
authors.affiliation: Department of Pathology and Neurology, The Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: Center for Nanomedicine, Department of Ophthalmology, The Johns Hopkins Medical Institution, Baltimore, Maryland.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Center for Nanomedicine, Department of Ophthalmology, The Johns Hopkins Medical Institution, Baltimore, Maryland.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Kannan
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins Medical Institution, Baltimore, Maryland.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Sciortino
authors.affiliation: Kennedy Krieger Institute, The Johns Hopkins Hospital, Baltimore, Maryland.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Johnston
authors.affiliation: Center for Nanomedicine, Department of Ophthalmology, The Johns Hopkins Medical Institution, Baltimore, Maryland.
authors.forename: Rangaramanujam M
authors.initials: RM
authors.lastname: Kannan
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins Medical Institution, Baltimore, Maryland. Electronic address: wbaumgar@jhmi.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Baumgartner
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001930:Brain Injuries / Q000628:therapy*; D050792:Circulatory Arrest, Deep Hypothermia Induced / Q000009:adverse effects*; D003072:Cognition Disorders / Q000628:therapy*; D050091:Dendrimers / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004285:Dogs; D007249:Inflammation / Q000628:therapy*; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage*
chemical_list: D050091:Dendrimers