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: 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
• Journal: The Annals of thoracic surgery (Ann Thorac Surg) Vol. 102 Issue 3 Pg. 743-750 (Sep 2016) ISSN: 1552-6259 [Electronic] Netherlands
• PMID: 27154161 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Chemical References

• Dendrimers

Topics

• Animals
• Blood-Brain Barrier
• Brain Injuries (therapy)
• Circulatory Arrest, Deep Hypothermia Induced (adverse effects)
• Cognition Disorders (therapy)
• Dendrimers (administration & dosage)
• Disease Models, Animal
• Dogs
• Inflammation (therapy)
• Male
• Nanoparticles (administration & dosage)