GMP Synthesis and Binding Studies of a Molecular Probe to Glycosaminoglycans

摘要 目前，还没有专门设计用于定量成像的分子探针。 关节软骨健康。在骨关节炎（OA）中，关节软骨退化， 来自软骨基质的糖胺聚糖（GAG）作为疾病的早期生物标志物 过程因此，如果OA是局部性的，则存在减轻患者软骨损伤的临床机会。 在其最早的阶段。Ionic Pharmaceuticals正在开发一种新型阳离子CT造影剂， 关节软骨中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（CA 4+）在成像时更敏感 离体和体内关节软骨的造影剂比目前可获得的商业阴离子造影剂更好。这 阳离子造影剂的上级性能归因于 阳离子造影剂和带负电荷的GAG存在于关节软骨中。两个关键 该技术的商业化和该造影剂在临床中的使用的步骤是 本提案中涉及：1）GMP合成规模扩大，后续药代动力学需要 研究;和2）表征CA 4+和GAG之间的相互作用，沿着 CA 4+以量化人关节软骨中的GAG和机械性质。因此， 这些建议是： 具体目标1：GMP合成CA 4+（500 g）并建立分析方法。 具体目标2：表征在细胞中发现的CA 4+和糖胺聚糖之间的相互作用。 人关节软骨组织，并确定CECT衰减、GAG 含量和软骨机械性能。

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.