A Novel Method of Nanoparticle Delivery to Brain by Targeting Ec-gp96

一种靶向EC-gp96的纳米粒子脑内给药新方法 摘要 血脑屏障(BBB)由脑微血管内皮细胞组成 细胞之间通过紧密连接的分子相互连接，从而使 不透毒素、细菌、病毒和其他有害物质的屏障 从鲜血中。血脑屏障的这一特殊特征伴随着外排 泵阻止了治疗脑部疾病的治疗化合物的输送。 尽管，已经确定了几种针对中枢神经的方法 对于药物输送系统，非特异性是这些策略的一个主要问题。 药物开发中的关键挑战之一是将药物输送到 穿过血脑屏障的中枢神经系统(CNS)。Nemani小组对E.Coli的研究， 使用两种体外人脑微血管内皮细胞模型 细胞和新生的小鼠，已经被用来鉴定一种BBB特异性受体， Ec-gp96与引起脑膜炎的大肠杆菌K1结合并进入 大脑。这种相互作用发生在大肠杆菌外膜蛋白A和 EC-gp96用于绑定和进入血脑屏障。计算机模拟技术的研究 Goddard小组的OmpA-EC-gp96相互作用预测了几种化合物 与EC-gp96的绑定兼容。其中有几个已经被证明是 有效地阻止大肠杆菌OmpA与EC-GP6的结合，从而 抑制细菌对HBMEC的侵袭。这是第一次确定 时间为EC-gp96的小分子配体。此外，戴维斯集团还拥有 开发的CDP纳米颗粒用于运送治疗癌症的药物或其他有效载荷 其中一些方法正在进行第一阶段和第二阶段的临床试验。 这些令人兴奋的实验结果为这一提议奠定了基础，它将 设计EC-gp96靶向配体并将其偶联到纳米粒上开发 一种专门针对血脑屏障的递送系统。

A Novel Method of Nanoparticle Delivery to Brain by Targeting Ec-gp96 ABSTRACT The blood brain barrier (BBB) is composed of brain microvascular endothelial cells connected each other with tight junction molecules thereby, making the barrier impermeable to toxins, bacteria, viruses, and other unwanted substance from blood. This specific characteristic feature of the BBB along with efflux pumps prevents the delivery of therapeutic compound to treat brain diseases. Although, several methods have been identified to target the central nervous system for drug delivery, non-specificity is a major problem with these strategies. One of the critical challenges in drug development is the delivery of drugs to the central nervous system (CNS) across the BBB. E. coli studies by Nemani group, performed using both an in vitro model of human brain microvascular endothelial cells and in newborn mice, have been used to identified a BBB specific receptor, Ec-gp96 to which E. coli K1, a meningitis causing bacterium binds and enters the brain. This interaction occurs between outer membrane protein A of E. coli and Ec-gp96 for binding to and entry of the BBB. The computer modeling studies of OmpA-Ec-gp96 interaction by Goddard group have predicted several compounds compatible with the binding to Ec-gp96. Of these several have been shown to be effective in preventing the binding of OmpA of E. coli with Ec-gp6 and thus inhibiting the invasion of the bacteria in HBMEC. This has identified for the first time small molecule ligands for Ec-gp96. Furthermore, Davis group has developed CDP nanoparticles to deliver drugs or other payloads to treat cancers and some of the methods are being tested in Phase I and Phase II clinical trials. These exciting experimental results set the stage for this proposal which will design Ec-gp96 targeting ligands and conjugate them to nanoparticles to develop a delivery system specifically targeting the blood-brain barrier.