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

一种靶向 Ec-gp96 的纳米粒子递送至大脑的新方法

• 批准号: 7949884
• 负责人: MARK E DAVIS
• 金额: $ 33.32万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7949884
• 关键词: Affect; Affinity; Agonist; Animal Model; Animals; Antibodies; Bacteria; Binding; Binding Sites; Blood; Blood - brain barrier anatomy; Brain; Brain Diseases; Carrier Proteins; Cell Line; Central Nervous System Agents; Characteristics; Computer Simulation; Coupled; Disease; Drug Delivery Systems; Endothelial Cells; Escherichia coli; Extravasation; Fluorescent Dyes; Gold; Human; In Vitro; Ligands; Liposomes; Location; Malignant Neoplasms; Membrane Proteins; Meningitis; Metabolism; Methods; Monitor; Motivation; Mus; Neuraxis; Newborn Infant; Organ; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Process; Proteins; Specificity; Staging; Structure; System; Testing; Therapeutic; Tight Junctions; Time; Toxin; Virus; abstracting; base; brain tissue; design; drug development; efflux pump; firewall; in vitro Model; in vivo; monolayer; nanoparticle; novel; particle; prevent; public health relevance; receptor; receptor expression; small molecule; uptake; vector

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.

描述（由申请人提供）：通过靶向Ec-gp 96将纳米颗粒递送至脑的新方法摘要血脑屏障（BBB）由通过紧密连接分子彼此连接的脑微血管内皮细胞组成，从而使屏障对毒素、细菌、病毒和来自血液的其它不需要的物质不可渗透。 BBB的这种特定特征沿着外排泵阻止治疗化合物的递送以治疗脑疾病。 尽管已经确定了几种靶向中枢神经系统的药物递送方法，但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通过BBB将药物递送至中枢神经系统（CNS）。 E. 利用人脑微血管内皮细胞的体外模型和新生小鼠进行的Nemani组的大肠杆菌研究已经用于鉴定BBB特异性受体Ec-gp 96，E. 大肠杆菌K1，一种引起脑膜炎的细菌结合并进入大脑。 这种相互作用发生在E. coli和Ec-gp 96用于结合并进入BBB。 戈达德小组对OmpA-Ec-gp 96相互作用的计算机模拟研究预测了几种与Ec-gp 96结合相容的化合物。 其中有几种已被证明能有效地阻止大肠杆菌OmpA的结合。 大肠杆菌与Ec-gp 6共转染HBMEC，从而抑制细菌的侵袭。 这是第一次鉴定Ec-gp 96的小分子配体。 此外，戴维斯集团已经开发出CDP纳米颗粒来输送药物或其他有效载荷来治疗癌症，其中一些方法正在I期和II期临床试验中进行测试。 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-gp 96靶向配体并将其与纳米颗粒结合，以开发特异性靶向血脑屏障的递送系统。 公共卫生关系：该提案旨在设计针对仅在血脑屏障内衬细胞中发现的蛋白质的配体，该配体将用于制造基于纳米颗粒的药物递送系统，以将药物特异性递送到大脑中。