Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury.
Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury.
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DOI：
10.1016/j.jconrel.2015.07.009
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发表时间：
2015-09-28
期刊：
影响因子：
--
通讯作者：
Kannan S
中科院分区：
文献类型：
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作者：
Nance E;Porambo M;Zhang F;Mishra MK;Buelow M;Getzenberg R;Johnston M;Kannan RM;Fatemi A;Kannan S
极早产是围产期和新生儿脑损伤的主要危险因素，并可导致白色物质损伤，这是许多神经系统疾病的前兆，包括脑瘫（CP）和自闭症。由活化的小胶质细胞和星形胶质细胞介导的神经炎症与新生儿脑损伤的发病机制有关。因此，靶向给药以减轻神经炎症可能会大大改善围产期白色物质损伤模型的治疗结果。在这项工作中，我们使用缺血诱导的新生儿白色物质损伤的小鼠模型来研究第4代羟基官能化聚酰胺-胺树枝状聚合物的生物分布。在全身施用Cy 5标记的树枝状聚合物（D-Cy 5）后，我们证明了参与缺血性损伤和正在进行的炎症的细胞中的树枝状聚合物摄取，导致继发性损伤。对损伤的亚急性反应由星形胶质细胞驱动。在损伤后5天内，发生小胶质细胞增殖和迁移，沿着少突胶质细胞的有限分化和少突胶质细胞死亡。损伤后1天至5天，树枝状聚合物共定位发生了变化。最初，树枝状聚合物主要与星形胶质细胞共定位，随后转向小胶质细胞。与少突胶质细胞的共定位在同一时间段内减少，表明基于损伤进展的区域特异性摄取。我们进一步表明，在损伤后的亚急性或延迟时间点全身施用单剂量的树枝状聚合物-N-乙酰半胱氨酸缀合物（D-NAC）导致损伤后长达9天的“有害的”促炎反应的持续减弱，同时不影响“有利的”抗炎反应。D-NAC治疗还导致髓鞘形成的改善，表明减少了白色物质损伤。在出生后后期时间点的治疗效果的证明提供了对小胶质细胞活化和慢性炎症如何靶向治疗新生儿脑损伤的更好理解。重要的是，它还可以提供更长的治疗窗口。
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 9 days 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.