GMP Synthesis and Binding Studies of a Molecular Probe to Glycosaminoglycans

摘要 目前，还没有专门为定量成像而设计的分子探针 关节软骨健康。在骨关节炎(OA)中，关节软骨退化，关节软骨丢失 软骨基质中的糖胺多聚糖(GAG)是该病的早期生物标志物 进程。因此，临床上有机会减轻患者的软骨损伤，如果OA是 在其最早的阶段就被发现了。离子制药公司正在开发一种新型阳离子CT造影剂，用于 关节GAG含量和力学性能变化的靶向定量成像 软骨。最近的数据表明，阳离子造影剂(Ca4+)在成像中更敏感 体外和体内关节软骨比目前市售的阴离子造影剂要好。这 阳离子造影剂的优异性能归因于两者之间的静电吸引 关节软骨中存在的阳离子造影剂和带负电荷的GAG。两个关键问题 这项技术的商业化和这种造影剂在临床上的使用的步骤是 本提案涉及：1)GMP合成放大，后续药代动力学所必需 2)研究了Ca4+与GaG的相互作用及其能力。 Ca4+用于量化人关节软骨中的GAG和力学性能。因此，它的具体目标是 这项建议包括： 具体目标1：GMP合成Ca4+(500g)并建立分析方法。 具体目标2：表征Ca4+与发现的糖胺聚糖之间的相互作用 并测定人关节软骨CECT衰减与GAG的相关性 含量，以及软骨的力学性能。

Abstract Currently, there are no molecular probes that are specifically designed for quantitative imaging of articular cartilage health. In osteoarthritis (OA), the articular cartilage becomes degraded with loss of glycosaminoglycans (GAGs) from the cartilage matrix serving as an early biomarker of the disease process. As such, there are clinical opportunities to mitigate cartilage damage in patients if OA is identified in its earliest stages. Ionic Pharmaceuticals is developing a novel cationic CT contrast agent for targeted quantitative imaging of changes in GAG content and mechanical properties of articular cartilage. Recent data demonstrates that the cationic contrast agent (CA4+) is more sensitive at imaging ex vivo and in vivo articular cartilage than currently available commercial anionic contrast agents. This superior performance of the cationic contrast agent is attributed to the electrostatic attraction between the cationic contrast agent and the negatively-charged GAGs present in articular cartilage. Two critical steps towards commercialization of this technology and the use of this contrast agent in the clinic are addressed in this proposal: 1) GMP synthetic scale-up, necessitated by subsequent pharmacokinetics studies; and 2) Characterization of the interaction between CA4+ and GAGs along with the capability of CA4+ to quantify GAG and mechanical properties in human articular cartilage. Thus, the specific aims of this proposal are: Specific Aim 1: GMP Synthesis of CA4+ (500 g) and establishment of analytical methods. Specific Aim 2: Characterize the interaction between the CA4+ and glycosaminoglycans found in human articular cartilage tissue and determine the correlations between CECT attenuation, GAG content, and cartilage mechanical properties.