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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要