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

摘要血脑屏障（BBB）是由脑微血管内皮细胞通过紧密连接的分子相互连接而成，从而使屏障无法渗透到血液中的毒素、细菌、病毒和其他有害物质。血脑屏障的这种特殊特征以及外排泵阻止了治疗性化合物的输送，以治疗脑部疾病。虽然已经确定了几种针对中枢神经系统的药物递送方法，但这些策略的主要问题是非特异性。药物开发的关键挑战之一是药物通过血脑屏障传递到中枢神经系统（CNS）。Nemani小组利用人脑微血管内皮细胞体外模型和新生小鼠进行的大肠杆菌研究，已被用于鉴定血脑屏障特异性受体Ec-gp96，大肠杆菌K1（一种引起脑膜炎的细菌）与该受体结合并进入大脑。这种相互作用发生在大肠杆菌的外膜蛋白A和Ec-gp96之间，以结合和进入血脑屏障。Goddard小组对OmpA-Ec-gp96相互作用的计算机模拟研究预测了几种与Ec-gp96结合的相容化合物。其中几种已被证明有效地阻止大肠杆菌的OmpA与Ec-gp6的结合，从而抑制HBMEC中细菌的入侵。这是首次鉴定出Ec-gp96的小分子配体。此外，戴维斯集团已经开发出CDP纳米颗粒来运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该提案奠定了基础，该提案将设计Ec-gp96靶向配体并将其结合到纳米颗粒上，以开发专门针对血脑屏障的递送系统。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This proposal is aimed at designing ligands targeting a protein only found in the cells lining the blood-brain barrier, that will be used to make a drug-delivery system based on nanoparticles to specifically deliver drugs into the brain.