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: 8078838
• 负责人: MARK E DAVIS
• 金额: $ 31.85万
• 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/8078838
• 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; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Process; Proteins; Staging; Structure; System; Testing; Therapeutic; Tight Junctions; Time; Toxin; Virus; 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）：一种靶向 Ec-gp96 的纳米粒子递送至大脑的新方法 摘要 血脑屏障（BBB）由脑微血管内皮细胞组成，这些细胞通过紧密连接分子相互连接，从而使屏障无法渗透血液中的毒素、细菌、病毒和其他不需要的物质。 BBB 的这一特定特征与外排泵一起阻止了治疗性化合物的输送以治疗脑部疾病。 尽管已经确定了几种针对中枢神经系统进行药物递送的方法，但非特异性是这些策略的主要问题。 药物开发的关键挑战之一是将药物通过血脑屏障输送到中枢神经系统 (CNS)。 Nemani 小组使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来鉴定 BBB 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，用于结合并进入 BBB。 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 结合相容的化合物。 其中几种已被证明可有效阻止大肠杆菌的 OmpA 与 Ec-gp6 结合，从而抑制细菌对 HBMEC 的侵袭。 这首次鉴定了 Ec-gp96 的小分子配体。 此外，戴维斯小组还开发了 CDP 纳米颗粒来输送药物或其他有效负载来治疗癌症，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-gp96 靶向配体并将其与纳米颗粒缀合，以开发专门针对血脑屏障的递送系统。 公共健康相关性：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输送系统，以特异性地将药物输送到大脑中。