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J Control Release. 2015 Sep 28;214:112-20. doi: 10.1016/j.jconrel.2015.07.009. Epub 2015 Jul 13.

Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury.

Author information

1
Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States; Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD21205, United States.
2
Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD 21205, United States.
3
Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD21205, United States; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, United States.
4
Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD21205, United States; Ophthalmology, Wilmer Eye Institute at Johns Hopkins School of Medicine, 21205, United States.
5
Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD 21205, United States; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States.
6
Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD21205, United States; Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD 21205, United States; Ophthalmology, Wilmer Eye Institute at Johns Hopkins School of Medicine, 21205, United States.
7
Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States; Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD21205, United States; Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD 21205, United States. Electronic address: skannan3@jhmi.edu.

Abstract

Extreme prematurity is a major risk factor for perinatal and neonatal brain injury, and can lead to white matter injury that is a precursor for a number of neurological diseases, including cerebral palsy (CP) and autism. Neuroinflammation, mediated by activated microglia and astrocytes, is implicated in the pathogenesis of neonatal brain injury. Therefore, targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes in models of perinatal white matter injury. In this work, we use a mouse model of ischemia-induced neonatal white matter injury to study the biodistribution of generation 4, hydroxyl-functionalized polyamidoamine dendrimers. Following systemic administration of the Cy5-labeled dendrimer (D-Cy5), we demonstrate dendrimer uptake in cells involved in ischemic injury, and in ongoing inflammation, leading to secondary injury. The sub-acute response to injury is driven by astrocytes. Within five days of injury, microglial proliferation and migration occurs, along with limited differentiation of oligodendrocytes and oligodendrocyte death. From one day to five days after injury, a shift in dendrimer co-localization occurred. Initially, dendrimer predominantly co-localized with astrocytes, with a subsequent shift towards microglia. Co-localization with oligodendrocytes reduced over the same time period, demonstrating a region-specific uptake based on the progression of the injury. We further show that systemic administration of a single dose of dendrimer-N-acetyl cysteine conjugate (D-NAC) at either sub-acute or delayed time points after injury results in sustained attenuation of the 'detrimental' pro-inflammatory response up to 9days after injury, while not impacting the 'favorable' anti-inflammatory response. The D-NAC therapy also led to improvement in myelination, suggesting reduced white matter injury. Demonstration of treatment efficacy at later time points in the postnatal period provides a greater understanding of how microglial activation and chronic inflammation can be targeted to treat neonatal brain injury. Importantly, it may also provide a longer therapeutic window.

KEYWORDS:

Dendrimer; Ischemia; Microglia; Neonatal; Neuroinflammation; Targeted delivery

PMID:
26184052
PMCID:
PMC4732874
DOI:
10.1016/j.jconrel.2015.07.009
[Indexed for MEDLINE]
Free PMC Article

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