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

• DOI: 10.1016/j.nano.2017.06.014
• Publication Date: 2017-06-30T05:00:23Z
• Authors: Christina L. Nemeth; Gabrielle T. Drum...; Manoj K. Mishra; Fan Zhang; Patrice Carr; Maxine S. Garcia; Sydney Doman; Ali Fatemi; Michael V. Johnston; Rangaramanujam M....; Sujatha Kannan; Mary Ann Wilson
• Keywords: Dendrimers; Drug Carriers; Cerebral Palsy; Hippocampus; Antioxidants; Acetylcysteine; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Drug Delivery Systems; 0302 clinical medicine; Animals, Newborn; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Animals; Female; Tissue Distribution; Microglia

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.