Nanotechnology Approaches to Targeting Inflammation and Excitotoxicity in a Canine Model of Hypothermic Circulatory Arrest-Induced Brain Injury

Joshua C. Grimm, J. Trent Magruder, Mary A. Wilson, Mary E. Blue, Todd C. Crawford, Juan C. Troncoso, Fan Zhang, Sujatha Kannan, Christopher M. Sciortino, Michael V. Johnston, Rangaramanujam M. Kannan, William A. Baumgartner

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalAnnals of Thoracic Surgery
DOIs
StateAccepted/In press - 2016

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Dendrimers
Nanotechnology
Brain Injuries
Canidae
Inflammation
Brain
Blood-Brain Barrier
Nanoparticles
Neurons
Drug Therapy
Penetrance
Microglia
Cardiopulmonary Bypass
Catheterization
Hippocampus
Necrosis
Apoptosis
Staining and Labeling
Wounds and Injuries

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Pulmonary and Respiratory Medicine

Cite this

@article{59fc3c69cd6a4b9b9b7e54832b49795e,
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.",
author = "Grimm, {Joshua C.} and Magruder, {J. Trent} and Wilson, {Mary A.} and Blue, {Mary E.} and Crawford, {Todd C.} and Troncoso, {Juan C.} and Fan Zhang and Sujatha Kannan and Sciortino, {Christopher M.} and Johnston, {Michael V.} and Kannan, {Rangaramanujam M.} and Baumgartner, {William A.}",
year = "2016",
doi = "10.1016/j.athoracsur.2016.02.077",
journal = "Annals of Thoracic Surgery",
issn = "0003-4975",
publisher = "Elsevier USA",

}

TY - JOUR

T1 - Nanotechnology Approaches to Targeting Inflammation and Excitotoxicity in a Canine Model of Hypothermic Circulatory Arrest-Induced Brain Injury

AU - Grimm,Joshua C.

AU - Magruder,J. Trent

AU - Wilson,Mary A.

AU - Blue,Mary E.

AU - Crawford,Todd C.

AU - Troncoso,Juan C.

AU - Zhang,Fan

AU - Kannan,Sujatha

AU - Sciortino,Christopher M.

AU - Johnston,Michael V.

AU - Kannan,Rangaramanujam M.

AU - Baumgartner,William A.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

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U2 - 10.1016/j.athoracsur.2016.02.077

DO - 10.1016/j.athoracsur.2016.02.077

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JO - Annals of Thoracic Surgery

T2 - Annals of Thoracic Surgery

JF - Annals of Thoracic Surgery

SN - 0003-4975

ER -