Characterizing electrostatic interactions between glycosaminoglycans and cationic

表征糖胺聚糖和阳离子之间的静电相互作用

• 批准号: 8297793
• 负责人: MARK W. GRINSTAFF
• 金额: $ 26.98万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-05 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297793
• 关键词: Academic Medical Centers; Address; Affinity; Anterior Cruciate Ligament; Area; Binding; Biological Models; Biomedical Engineering; Boston; Carbohydrates; Cartilage; Charge; Chemical Structure; Chemistry; Collection; Contrast Media; Data; Data Analyses; Degenerative polyarthritis; Development; Drug Kinetics; Electrostatics; Environment; Femur; Generations; Glycosaminoglycans; Image; Imaging Techniques; Iodine; Kinetics; Knee; Laboratories; Learning; Measurement; Measures; Medical Imaging; Medicine; Monitor; Morphology; New Zealand; Nucleic Acids; Orthopedic Surgery procedures; Orthopedics; Oryctolagus cuniculus; Play; Polysaccharides; Property; Proteins; Publications; Radiology Specialty; Reporting; Research; Role; Sampling; Science; Series; Structure; Structure-Activity Relationship; Testing; Thermodynamics; Thick; Tissues; Toxic effect; Translating; Work; X-Ray Computed Tomography; abstracting; articular cartilage; attenuation; base; bone; covalent bond; design; in vivo; in vivo Model; interest; macromolecule; medical schools; novel; professor; reconstruction; small molecule

DESCRIPTION (provided by applicant): Abstract This revised proposal describes the mechanism of binding in ex vivo, and in vivo models between small molecules and negatively charged polysaccharides, and applies its findings to the development of new X- ray computed tomography (CT) contrast agents for imaging articular cartilage. Specifically, we expand on our recent reports (J. Am. Chem. Soc., 2009, 131, 2469-2471; Osteoarthritis and Cartilage, 2010, 18, 184- 191; J. Orthopaedic Res., 2011, 29, 704-709; Osteoarthritis and Cartilage, 2011, in press/on line) of using cationic iodinated contrast agents for CT imaging of negatively-charged glycosaminoglycans (GAGs) in articular cartilage. Clinically today, cartilage is not imaged using CT and several research groups are exploring the use of known CT contrast agents, which possess an overall anionic charge, to image GAGs. We hypothesize that the use of a cationic contrast agent will result in a more sensitive technique for imaging cartilage due to its affinity or the negatively-charged GAGs. Importantly, we have preliminary data demonstrating that these cationic iodinated contrast agents bind GAG in a GAG concentration dependent manner and can be used for ex vivo and in vivo imaging of cartilage via X-ray CT. The specific aims of this proposal are: Aim 1: Synthesize a series of cationic, anionic, and neutral iodinated CT contrast agents, Aim 2: Determine the kinetics and binding affinities of the CT contrast agents to GAGs present in ex vivo cartilage tissue, Aim 3: Ascertain the correlation of CT attenuation vs. GAG concentration and develop a quantitative relationship, Aim 4: (A) Perform serial in vivo contrast enhanced computed tomography (CECT) imaging of rabbit knees before and after anterior cruciate ligament (ACL) transection to demonstrate the ability of CECT using cationic contrast agents to measure progressive changes in cartilage GAG compared to direct measurements after sacrifice, (B) Perform pharmacokinetic/toxicity studies in New Zealand White rabbits. Successful completion of these studies will result in: 1) the development of structure-activity relationships and design requirements for highly sensitive cartilage CT imaging agents for quantitative measurements of GAG; 2) imaging of healthy and degraded cartilage in vivo; 3) the pharmacokinetic profile of the contrast agent after administration; and 4) collection of robust data for analysis, discussion, and further hypothesis generation. PUBLIC HEALTH RELEVANCE: The study of the binding of small molecules to biologics is of fundamental importance, and the results of such studies are applicable to many areas of medicine - including medical imaging. This proposal investigates the design, synthesis and characterization of novel computed tomography contrast agents for binding and imaging of the glycosaminoglycans present in cartilage.

描述(申请人提供)：本修订方案描述了小分子与带负电荷的多糖之间的体外结合机制和体内模型，并将其结果应用于开发用于关节软骨成像的新型X射线计算机断层扫描(CT)造影剂。具体地说，我们详述了我们最近的报告(J.Am化学。2009年，131,2469-2471；骨性关节炎和软骨，2010，18,184-191；J·骨科研究，2011，29,704-709；骨性关节炎和软骨，2011，印刷/在线)使用阳离子碘化造影剂对关节软骨中带负电荷的糖胺聚糖(GAG)进行CT成像。在临床上，软骨不是用CT成像的，几个研究小组正在探索使用已知的CT造影剂来成像GAG，这种造影剂具有整体的阴离子电荷。我们假设，阳离子造影剂的使用将导致一种更灵敏的软骨成像技术，因为它的亲和力或带负电荷的GAG。重要的是，我们有初步的数据表明，这些阳离子碘化造影剂以GAG浓度依赖的方式结合GAG，并可用于通过X射线CT进行体外和体内软骨成像。该建议的具体目的是：目标1：合成一系列阳离子、阴离子和中性碘化CT造影剂，目的2：测定CT造影剂与存在于体外软骨组织中的GAG的动力学和结合亲和力，目标3：确定CT衰减与GAG浓度的关系并建立定量关系，目标4：(A)在兔膝关节前交叉韧带(ACL)横断前后进行一系列在体对比增强CT(CECT)成像，以显示使用阳离子造影剂的CECT与牺牲后直接测量软骨GAG进行性变化的能力，(B)在新西兰大白兔身上进行药代动力学/毒性研究。这些研究的成功完成将导致：1)开发用于定量测量GAG的高灵敏度软骨CT成像剂的结构-活性关系和设计要求；2)在活体内对健康和退化的软骨进行成像；3)给药后造影剂的药代动力学特征；以及4)收集用于分析、讨论和进一步假设生成的可靠数据。 公共卫生相关性：研究小分子与生物制品的结合具有根本重要性，这种研究的结果适用于许多医学领域--包括医学成像。该方案研究了新型计算机断层扫描造影剂的设计、合成和表征，用于结合和成像存在于软骨中的糖胺多聚糖。