Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest.
Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest.
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DOI：
10.1021/nn404872e
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发表时间：
2014-03-25
期刊：
影响因子：
17.1
通讯作者：
Kannan, Rangaramanujam M.
中科院分区：
文献类型：
--
作者：
Mishra, Manoj K.;Beaty, Claude A.;Lesniak, Wojciech G.;Kambhampati, Siva R.;Zhang, Fan;Wilson, Mary A.;Blue, Mary E.;Troncoso, Juan C.;Kannan, Sujatha;Johnston, Michael V.;Baumgartner, William A.;Kannan, Rangaramanujam M.
关键词：
循环停止后脑损伤的治疗是一个具有挑战性的健康问题，没有可行的治疗方案。基于在低温停循环（HCA）诱导的脑损伤的临床相关的大型动物（犬）模型中的研究，神经炎症和兴奋性毒性已被确定为介导HCA后的脑损伤的关键参与者。大剂量丙戊酸（VPA）治疗显示出一定的神经保护作用，但与不良副作用有关。在大型动物模型中，我们首次探索了全身施用的聚酰胺胺（PAMAM）树枝状聚合物是否可以有效地到达大脑中的靶细胞并提供治疗。我们表明，在全身给药后，羟基封端的PAMAM树枝状聚合物在受伤动物的大脑中被吸收，并选择性地定位在大脑中受伤的神经元和小胶质细胞中。其他主要器官中的生物分布与小动物模型中观察到的相似。我们研究了两种临床批准的药物，N-乙酰半胱氨酸（NAC）（减弱神经炎症）和丙戊酸（减弱兴奋性毒性）的全身性树枝状聚合物-药物联合治疗，建立在围产期脑损伤的兔模型的积极成果。我们制备并表征了多克量的树枝状聚合物-NAC（D-NAC）和树枝状聚合物-VPA（D-VPA）缀合物。一种谷胱甘肽敏感性接头，可实现快速细胞内释放。在初步疗效研究中，D-NAC和D-VPA的联合治疗在该大型动物模型中显示出前景，产生与VPA和NAC或游离VPA的高剂量联合治疗相当的24小时神经功能缺损评分改善，但剂量为十分之一，同时显著降低了不良副作用。由于药物的不良副作用在HCA中被夸大，树枝状聚合物缀合物的副作用减少和神经保护的建议为这些纳米级药物递送系统提供了希望。
Treatment of brain injury following circulatory arrest is a challenging health issue with no viable therapeutic options. Based on studies in a clinically relevant large animal (canine) model of hypothermic circulatory arrest (HCA)-induced brain injury, neuroinflammation and excitotoxicity have been identified as key players in mediating the brain injury after HCA. Therapy with large doses of valproic acid (VPA) showed some neuroprotection but was associated with adverse side effects. For the first time in a large animal model, we explored whether systemically administered polyamidoamine (PAMAM) dendrimers could be effective in reaching target cells in the brain and deliver therapeutics. We showed that, upon systemic administration, hydroxyl-terminated PAMAM dendrimers are taken up in the brain of injured animals and selectively localize in the injured neurons and microglia in the brain. The biodistribution in other major organs was similar to that seen in small animal models. We studied systemic dendrimer–drug combination therapy with two clinically approved drugs, N-acetyl cysteine (NAC) (attenuating neuroinflammation) and valproic acid (attenuating excitotoxicity), building on positive outcomes in a rabbit model of perinatal brain injury. We prepared and characterized dendrimer-NAC (D-NAC) and dendrimer-VPA (D-VPA) conjugates in multigram quantities. A glutathione-sensitive linker to enable for fast intracellular release. In preliminary efficacy studies, combination therapy with D-NAC and D-VPA showed promise in this large animal model, producing 24 h neurological deficit score improvements comparable to high dose combination therapy with VPA and NAC, or free VPA, but at one-tenth the dose, while significantly reducing the adverse side effects. Since adverse side effects of drugs are exaggerated in HCA, the reduced side effects with dendrimer conjugates and suggestions of neuroprotection offer promise for these nanoscale drug delivery systems.
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