GMP Synthesis and Binding Studies of a Molecular Probe to Glycosaminoglycans

糖胺聚糖分子探针的 GMP 合成和结合研究

• 批准号: 8645447
• 负责人: Aaron Henry Colby
• 金额: $ 21.27万
• 依托单位: IONIC PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645447
• 关键词: Address; Affinity; American; Binding; Biochemical; Biological Markers; Blood; Canis familiaris; Cardiovascular system; Cartilage; Cartilage Matrix; Charge; Chemical Structure; Clinic; Clinical; Clinical Research; Contrast Media; Data; Degenerative Disorder; Degenerative polyarthritis; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic radiologic examination; Disease; Dose; Drug Formulations; Drug Kinetics; Drug or chemical Tissue Distribution; Electrostatics; Excretory function; Glycosaminoglycans; Goals; Health; Hemolysis; Human; Image; Imaging technology; Inorganic Sulfates; Joints; Knee; Label; Magnetic Resonance Imaging; Measures; Mechanics; Medical Imaging; Molecular Probes; Monitor; Optics; Oryctolagus cuniculus; Osteoarthrosis Deformans; Outcome; Pain; Patient Care; Patients; Performance; Pharmacologic Substance; Pharmacology; Phase; Physicians; Positioning Attribute; Process; Property; Radioactivity; Rattus; Reporting; Route; Safety; Small Business Innovation Research Grant; Solutions; Staging; Structure; Symptoms; Techniques; Technology; Tissues; Toxic effect; Unspecified or Sulfate Ion Sulfates; Work; X-Ray Computed Tomography; analytical method; articular cartilage; attenuation; carboxylate; commercialization; density; design; extracellular; genotoxicity; human tissue; imaging modality; in vivo; interest; irritation; metabolic abnormality assessment; microbial alkaline proteinase inhibitor; molecular imaging; novel; phase 1 study; phase 2 study; pre-clinical; public health relevance; respiratory; scale up; small molecule; stability testing; validation studies

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.

抽象的 当前，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，关节软骨因损失而降解 来自软骨基质的糖胺聚糖（插科打），作为该疾病的早期生物标志物 过程。因此，如果OA为 在最早的阶段确定。离子药物正在开发一种新型的阳离子CT造影剂 关节插孔含量和机械性能的变化的有针对性的定量成像 软骨。最近的数据表明，阳离子对比剂（CA4+）在成像时更敏感 离体和体内关节软骨比目前可用的商业阴离子对比剂。这 阳离子对比剂的出色性能归因于静电吸引力 关节软骨中存在的阳离子对比剂和负电荷的插科打n。两个关键 该技术商业化的步骤以及在诊所中使用造影剂的使用是 在此提案中解决：1）GMP合成缩放，随后的药代动力学需要 研究； 2）表征CA4+与插科打之间的相互作用以及能力 CA4+以量化人类关节软骨中的插科打and和机械性能。因此， 该建议是： 特定目的1：GMP合成CA4+（500 g）和分析方法的建立。 特定目标2：表征CA4+和糖胺聚糖之间的相互作用 人类关节软骨组织并确定Cect衰减，堵嘴之间的相关性 内容和软骨机械性能。