Uptake of dendrimer-drug by different cell types in the hippocampus after hypoxic–ischemic insult in neonatal mice: Effects of injury, microglial activation and hypothermia

Christina L. Nemeth, Gabrielle T. Drummond, Manoj K. Mishra, Fan Zhang, Patrice Carr, Maxine S. Garcia, Sydney Doman, Ali Fatemi, Michael V. Johnston, Rangaramanujam M. Kannan, Sujatha Kannan, Mary Ann Wilson

Research output: Contribution to journalArticlepeer-review

Abstract

Perinatal hypoxic–ischemic encephalopathy (HIE) can result in neurodevelopmental disability, including cerebral palsy. The only treatment, hypothermia, provides incomplete neuroprotection. Hydroxyl polyamidoamine (PAMAM) dendrimers are being explored for targeted delivery of therapy for HIE. Understanding the biodistribution of dendrimer-conjugated drugs into microglia, neurons and astrocytes after brain injury is essential for optimizing drug delivery. We conjugated N-acetyl-L-cysteine to Cy5-labeled PAMAM dendrimer (Cy5-D-NAC) and used a mouse model of perinatal HIE to study effects of timing of administration, hypothermia, brain injury, and microglial activation on uptake. Dendrimer conjugation delivered therapy most effectively to activated microglia but also targeted some astrocytes and injured neurons. Cy5-D-NAC uptake was correlated with brain injury in all cell types and with activated morphology in microglia. Uptake was not inhibited by hypothermia, except in CD68+ microglia. Thus, dendrimer-conjugated drug delivery can target microglia, astrocytes and neurons and can be used in combination with hypothermia for treatment of HIE.

Original languageEnglish (US)
Pages (from-to)2359-2369
Number of pages11
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume13
Issue number7
DOIs
StatePublished - Oct 2017

Keywords

  • Cerebral palsy
  • Dendrimer nanoparticles
  • Hypothermia
  • Hypoxia-ischemia
  • Microglia
  • Neuroinflammation

ASJC Scopus subject areas

  • Bioengineering
  • Medicine (miscellaneous)
  • Molecular Medicine
  • Biomedical Engineering
  • Materials Science(all)
  • Pharmaceutical Science

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