Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model.
Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model.
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DOI：
10.1016/j.jconrel.2017.01.032
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发表时间：
2017-03-10
期刊：
影响因子：
--
通讯作者：
Kannan RM
中科院分区：
文献类型：
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作者：
Zhang F;Trent Magruder J;Lin YA;Crawford TC;Grimm JC;Sciortino CM;Wilson MA;Blue ME;Kannan S;Johnston MV;Baumgartner WA;Kannan RM
低温停循环（HCA）在心脏手术期间提供神经保护，但需要缺血期，可导致兴奋性毒性、神经炎症和随后的神经损伤。羟基聚酰胺胺（PAMAM）树枝状聚合物靶向受损大脑中的活化小胶质细胞和受损神经元，并在小型和大型动物模型中提供治疗。我们研究了树枝状聚合物大小对脑摄取的影响，并在HCA诱导的脑损伤的临床相关犬模型中探索了药代动力学。与第4代树枝状聚合物（G4，~ 4.3nm）相比，第6代（G6，~ 6.7nm）树枝状聚合物显示出延长的血液循环时间和增加的损伤脑中的积累，其在最终施用后48小时在脑中不可检测。在受伤动物的脑脊液（CSF）中发现了高水平的G6树枝状聚合物，峰值时CSF/血清比约为20%，高于临床使用的许多神经药物治疗的比例。G6树枝状聚合物的脑渗透（通过药物CSF/血清水平测量）与观察到的神经炎症的严重程度相关。与G4树枝状聚合物相比，G6树枝状聚合物还显示出降低的肾清除率，略微增加的肝脏和脾脏摄取。这些结果，在一个大型动物模型中，可以提供深入了解潜在的临床翻译的树枝状聚合物。
Hypothermic circulatory arrest (HCA) provides neuroprotection during cardiac surgery but entails an ischemic period that can lead to excitotoxicity, neuroinflammation, and subsequent neurologic injury. Hydroxyl polyamidoamine (PAMAM) dendrimers target activated microglia and damaged neurons in the injured brain, and deliver therapeutics in small and large animal models. We investigated the effect of dendrimer size on brain uptake and explored the pharmacokinetics in a clinically-relevant canine model of HCA-induced brain injury. Generation 6 (G6, ~6.7 nm) dendrimers showed extended blood circulation times and increased accumulation in the injured brain compared to generation 4 dendrimers (G4, ~4.3 nm), which were undetectable in the brain by 48 hrs after final administration. High levels of G6 dendrimers were found in cerebrospinal fluid (CSF) of injured animals with a CSF/serum ratio of ~20% at peak, a ratio higher than that of many neurologic pharmacotherapies already in clinical use. brain penetration (measured by drug CSF/serum level) of G6 dendrimers correlated with the severity of neuroinflammation observed. G6 dendrimers also showed decreased renal clearance rate, slightly increased liver and spleen uptake compared to G4 dendrimers. These results, in a large animal model, may offer insights into the potential clinical translation of dendrimers.