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

一种靶向Ec-gp 96的纳米粒脑内给药新方法 摘要 血脑屏障（blood brain barrier，BBB）是由脑微血管内皮细胞（brain microvascular endothelial endothelial cells，brain 细胞通过紧密连接分子相互连接，从而使 不渗透毒素、细菌、病毒和其他有害物质的屏障 从血液中。血脑屏障沿着流出的这一特定特征 泵阻止输送治疗脑部疾病的治疗化合物。 虽然，已经确定了几种方法来靶向中枢神经系统， 对于药物递送系统，非特异性是这些策略的主要问题。 药物开发中的关键挑战之一是将药物递送到患者体内。 中枢神经系统（CNS）穿过BBB。E. Nemani小组的大肠杆菌研究， 使用人脑微血管内皮细胞的体外模型和 细胞和新生小鼠中，已用于鉴定BBB特异性受体， Ec-gp 96的E.大肠杆菌K1，一种引起脑膜炎的细菌结合并进入 个脑袋这种相互作用发生在E.杆菌和 Ec-gp 96用于结合和进入BBB。的计算机模拟研究 戈达德小组利用OmpA-Ec-gp 96相互作用预测了几个化合物 与结合至Ec-gp 96相容。其中有几个已经被证明是 有效地阻止了E.大肠杆菌与Ec-gp 6，因此 抑制细菌在HBMEC中的侵袭。这是第一个 时间小分子配体Ec-gp 96。此外，戴维斯集团还 开发了CDP纳米颗粒，用于输送药物或其他有效载荷来治疗癌症 其中一些方法正在进行I期和II期临床试验。 这些令人兴奋的实验结果为这项提案奠定了基础， 设计Ec-gp 96靶向配体，并将其与纳米颗粒偶联， 一种专门针对血脑屏障的输送系统。

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.