TY - JOUR
T1 - Uptake of dendrimer-drug by different cell types in the hippocampus after hypoxic–ischemic insult in neonatal mice
T2 - Effects of injury, microglial activation and hypothermia
AU - Nemeth, Christina L.
AU - Drummond, Gabrielle T.
AU - Mishra, Manoj K.
AU - Zhang, Fan
AU - Carr, Patrice
AU - Garcia, Maxine S.
AU - Doman, Sydney
AU - Fatemi, Ali
AU - Johnston, Michael V.
AU - Kannan, Rangaramanujam M.
AU - Kannan, Sujatha
AU - Wilson, Mary Ann
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/10
Y1 - 2017/10
N2 - 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.
AB - 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.
KW - Cerebral palsy
KW - Dendrimer nanoparticles
KW - Hypothermia
KW - Hypoxia-ischemia
KW - Microglia
KW - Neuroinflammation
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UR - http://www.scopus.com/inward/citedby.url?scp=85027862236&partnerID=8YFLogxK
U2 - 10.1016/j.nano.2017.06.014
DO - 10.1016/j.nano.2017.06.014
M3 - Article
C2 - 28669854
AN - SCOPUS:85027862236
SN - 1549-9634
VL - 13
SP - 2359
EP - 2369
JO - Nanomedicine: Nanotechnology, Biology, and Medicine
JF - Nanomedicine: Nanotechnology, Biology, and Medicine
IS - 7
ER -