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Ultrasound Contrast Agents for Inflammation and Angiogenesis

用于炎症和血管生成的超声造影剂

基本信息

批准号：
7404351
负责人：
Joshua J. Rychak
金额：
$ 9.97万
依托单位：
TARGESON, LLC
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7404351
关键词：
Adhesions Amides Animal Model Antibodies Avidin Binding Biological Assay Biological Markers Biotin Blood flow Caliber Chemistry Class Clinical Condition Contrast Media Coupling Development Disease Drug Formulations E-Selectin Encapsulated Endothelium Exercise Exhibits Family Flow Cytometry Fluorescence Spectroscopy Fluorescent Antibody Technique Gases Goals Image In Vitro Inflammation Inflammatory Kinetics Knowledge Label Ligand Binding Ligands Liquid substance Localized Maleimides Marketing Mediating Methods Microbubbles Molecular Target Mus Object Attachment Oligosaccharides P-Selectin Process Selectins Severities Site Sulfhydryl Compounds Surface System Testing Therapeutic Time Toxic effect Translations Ultrasonography Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors angiogenesis base density drug discovery fluorophore functional group imaging probe immunogenic immunogenicity molecular imaging particle pre-clinical pre-clinical research receptor receptor binding shear stress size thioether user-friendly

项目摘要

DESCRIPTION (provided by applicant): We propose to develop molecular imaging probes for imaging angiogenesis and inflammation using contrast-enhanced ultrasound. These probes are gas-encapsulated microbubbles that can be coated with ligands specific for molecular markers of disease using robust covalent coupling chemistries. The agents proposed here will be used to image the severity and spatial extent of disease in preclinical animal models, and have strong potential for clinical translation. We propose to develop microbubbles bearing versatile covalent ligand-coupling chemistries, which will allow preclinical users to couple their own ligands. Additionally, we will develop two pre-targeted agents bearing covalently bound ligands specific for biomarkers of inflammation and angiogenesis. Although site-targeted microbubble contrast agents are currently commercially available for preclinical research, these agents utilize time consuming and potentially immunogenic biotin/avidin ligand coupling chemistry. Covalent coupling of the ligand to the agent surface eliminates the biotin/avidin system, greatly increasing the convenience and utility of the agents. The goals of this proposal are (1) to develop covalent ligand coupling strategies suitable for a variety of ligand classes, (2) to create ultrasound contrast agents bearing covalently bound ligands specific for biomarkers of inflammation and angiogenesis, and (3) to quantitatively test targeted adhesion of these ligand-bearing agents to relevant molecular targets in vitro. We will test two ligands for biomarkers of inflammation and angiogenesis, respectively: a selectin-binding oligosaccharide (sialyl Lewisx) and a VEGF receptor binding single-chain VEGF construct. The selectins are critically involved in numerous inflammatory disorders, and have been implicated in therapeutic and pathogenic angiogenesis. With the goal of producing convenient probes for imaging inflammation and angiogenesis, we propose to construct microbubbles bearing covalently bound sLex, a single-chain VEGF, or a combination of both ligands. These ligands are superior to antibodies commonly used as ligands due to the lack of immunogenicity, species-independence, and small size. Additionally, sLex possesses an excellent ability to mediate high-efficiency retention of microparticles, even under conditions of rapid blood flow. We hypothesize that dual-targeted microbubbles bearing both scVEGF and sLex may exhibit synergistic adhesion resulting in enhanced microbubble retention to angiogenic endothelium expressing E- selectin and VEGFR-2. The rapid bond kinetics of sLex can mediate initial tethering of the agent, and once localized at the endothelial surface scVEGF can mediate firm adhesion to VEGF receptors. Microbubbles bearing the sLex ligand alone will be useful for imaging a wide variety of inflammatory disorders, and VEGF- bearing microbubbles will be useful for imaging general angiogenic processes. The knowledge gained will serve to develop a universal targeted microbubble platform able to be conjugated to user-selected ligands using a robust covalent coupling system, and will provide a platform for subsequent pre-targeted formulations. Project Narrative Molecular imaging of biomarker expression can greatly accelerate the pace of drug discovery, and has tremendous potential for clinical translation. The development of microbubbles bearing a robust and versatile covalent ligand-coupling chemistry will expand the utility of these agents in preclinical research, and is necessary for subsequent clinical implementation. Additionally, microbubbles pre-targeted to biomarkers of inflammation and angiogenesis will serve as a convenient and user-friendly product for preclinical molecular imaging.

描述（由申请人提供）：我们建议开发分子成像探针，用于使用对比增强超声成像血管生成和炎症。这些探针是气体封装的微泡，其可以使用稳健的共价偶联化学用对疾病的分子标志物特异性的配体涂覆。本文提出的药物将用于在临床前动物模型中对疾病的严重程度和空间范围进行成像，并具有很强的临床转化潜力。我们建议开发具有多功能共价配体偶联化学的微泡，这将允许临床前用户偶联他们自己的配体。此外，我们将开发两种预靶向药物，其具有特异性的共价结合配体，用于炎症和血管生成的生物标志物。尽管靶向位点的微泡造影剂目前可用于临床前研究，但这些造影剂利用耗时且潜在免疫原性的生物素/抗生物素蛋白配体偶联化学。配体与试剂表面的共价偶联消除了生物素/抗生物素蛋白系统，大大增加了试剂的便利性和实用性。该提案的目标是（1）开发适用于各种配体类别的共价配体偶联策略，（2）创建携带对炎症和血管生成的生物标志物具有特异性的共价结合配体的超声造影剂，以及（3）定量测试这些携带配体的试剂与体外相关分子靶标的靶向粘附。我们将测试两个配体的炎症和血管生成的生物标志物，分别：选择素结合寡糖（唾液酸化Lewisx）和VEGF受体结合单链VEGF构建。选择素与许多炎症性疾病密切相关，并与治疗性和致病性血管生成有关。与生产方便的成像炎症和血管生成的探针的目标，我们建议构建微泡轴承共价结合的sLex，单链VEGF，或两种配体的组合。由于缺乏免疫原性、物种独立性和小尺寸，这些配体上级通常用作配体的抗体。此外，sLex具有优异的介导微粒高效保留的能力，即使在快速血流的条件下。我们假设携带scVEGF和sLex的双靶向微泡可能表现出协同粘附，导致微泡对表达E-选择素和VEGFR-2的血管生成内皮的保留增强。sLex的快速结合动力学可以介导试剂的初始束缚，并且一旦定位在内皮表面，scVEGF可以介导与VEGF受体的牢固粘附。单独携带sLex配体的微泡将可用于对多种炎性疾病进行成像，而携带VEGF的微泡将可用于对一般血管生成过程进行成像。所获得的知识将用于开发能够使用稳健的共价偶联系统与用户选择的配体缀合的通用靶向微泡平台，并将为后续的预靶向制剂提供平台。生物标志物表达的分子成像可以大大加快药物发现的步伐，并具有巨大的临床转化潜力。开发具有强大和通用的共价配体偶联化学的微泡将扩大这些药物在临床前研究中的效用，并且对于后续的临床实施是必要的。此外，预先靶向炎症和血管生成的生物标志物的微泡将作为临床前分子成像的方便和用户友好的产品。