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: 8607191
• 负责人: MARK W. GRINSTAFF
• 金额: $ 28.68万
• 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/8607191
• 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; in vivo imaging; 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.

说明（由申请人提供）：摘要该修订的提案描述了小分子和带负电荷的多糖之间的离体和体内模型中的结合机制，并将其发现应用于开发用于关节软骨成像的新的X射线计算机断层扫描（CT）造影剂.具体来说，我们扩大我们最近的报告（J。化学会，2009，131，2469-2471; Osteoarthritis and Carcinoma，2010，18，184- 191; J. Orthopathy Res.，2011，29，704-709; Osteoarthritis and Carpendum，2011，in press/on line）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。目前临床上，软骨不使用CT成像，几个研究小组正在探索使用已知的CT造影剂，其具有总的阴离子电荷，以成像GAG。我们假设，使用阳离子造影剂将导致一个更敏感的技术成像软骨由于其亲和力或带负电荷的糖胺酸。重要的是，我们有初步的数据表明，这些阳离子碘化造影剂结合GAG的GAG浓度依赖性的方式，可用于体外和体内成像的软骨通过X射线CT。本提案的具体目的是：目的1：合成一系列阳离子、阴离子和中性碘化CT造影剂，目的2：确定CT造影剂与存在于离体软骨组织中的GAG的动力学和结合亲和力，目的3：确定CT衰减与GAG浓度的相关性并建立定量关系，目的4：（A）在前交叉韧带（ACL）横切之前和之后对兔膝进行连续的体内对比增强计算机断层扫描（CECT）成像，以证明与处死后的直接测量相比，使用阳离子造影剂的CECT测量软骨GAG的进行性变化的能力，（B）在新西兰白色兔中进行药代动力学/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）体内健康和退化软骨的成像; 3）给药后造影剂的药代动力学特征;和4）收集用于分析、讨论和进一步假设生成的稳健数据。