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: 8438410
• 负责人: MARK W. GRINSTAFF
• 金额: $ 30.01万
• 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/8438410
• 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.

描述（由申请人提供）：摘要本修订后的提案描述了小分子与带负电多糖之间的离体和体内模型结合机制，并将其发现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。具体来说，我们扩展了最近的报告（J. Am. Chem. Soc., 2009, 131, 2469-2471；Osteoarthritis and Cartilage, 2010, 18, 184-191；J. Orthopedic Res., 2011, 29, 704-709；Osteoarthritis and Cartilage, 2011年，出版/在线）使用阳离子碘造影剂进行CT成像 关节软骨中带负电荷的糖胺聚糖（GAG）。如今，在临床上，软骨不使用 CT 进行成像，一些研究小组正在探索使用已知的 CT 造影剂（其总体带有阴离子电荷）来对 GAG 进行成像。我们假设，由于阳离子造影剂的亲和力或带负电的 GAG，使用阳离子造影剂将导致软骨成像技术更加灵敏。重要的是，我们有初步数据证明这些阳离子碘化造影剂以 GAG 浓度依赖性方式结合 GAG，并且可用于通过 X 射线 CT 进行软骨的离体和体内成像。该提案的具体目标是：目标 1：合成一系列阳离子、阴离子和中性碘化 CT 造影剂，目标 2：确定 CT 造影剂与离体软骨组织中存在的 GAG 的动力学和结合亲和力，目标 3：确定 CT 衰减与 GAG 浓度的相关性并建立定量关系，目标 4：（A）执行系列 前交叉韧带 (ACL) 横断前后兔膝盖的体内对比增强计算机断层扫描 (CECT) 成像，以证明与处死后直接测量相比，CECT 使用阳离子造影剂测量软骨 GAG 渐进变化的能力，(B) 在新西兰白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）健康和退化软骨的体内成像； 3) 造影剂给药后的药代动力学特征； 4) 收集可靠的数据用于分析、讨论和进一步的假设生成。