DEVELOPMENT OF DENDRIMER LINKED NITROXIDES AS MRI AGENTS

骨关节炎是最常见的关节疾病，对75岁以上的老年人有80%以上的不良影响。因此，骨关节炎是老年人疼痛和残疾的主要原因。此外，骨关节炎的经济影响是巨大的。除了直接医疗费用（与医生就诊、诊断测试、药物、适应性辅助设备和装置、物理和职业治疗、住院和手术有关的费用）外，美国骨关节炎患者每年损失的工作时间超过6800万天。目前评估骨关节炎的技术要么本质上是定性的——简单地问病人感觉如何——要么不切实际，比如对病人关节软骨活检样本进行一系列生化和组织学分析。具有特殊宏观技术的x线摄影已被证明对测量骨关节炎软骨厚度变化有价值，然而，这些技术不能检测到骨关节炎的早期变化，即软骨基质中蛋白聚糖的丢失。我们之前已经表明，MRI结合带正电荷的氮氧化物作为对比增强剂，可能是评估软骨蛋白聚糖损失的可靠方法。氮氧化物弛豫性差，降低了它们的选择性。为了克服这一限制，本研究提出开发树突连接的氮氧化物作为选择性对比增强剂，以帮助MRI评估骨关节炎患者的软骨状态。该I期资助将(a)合成在生理pH值下带正电荷的树突连接氮氧化物，确定其体外稳定性；(b)测试其体外与软骨结合的能力，并测量树突连接氮氧化物选择性与软骨蛋白聚糖结合的体内药代动力学。拟议的商业应用：如果拟议的I期和II期研究项目成功，树状分子连接的氮氧化物和MRI的开发将使医生能够以非侵入性的方式监测骨关节炎的进展。此外，随着大量制药公司从事通过抑制蛋白多糖分解来延缓骨关节炎进展的治疗剂的开发，该技术可用于监测这些新治疗剂的疗效

Osteoarthritis is the most common joint disease, adversely effecting more than 80% of individuals older than 75 years of age. Osteoarthritis is, therefore, a major cause of pain and disability in the elderly. Furthermore, the economic impact of osteoarthritis is immense. In addition to direct medical costs (costs associated with physician visits, diagnostic testing, medications, adaptive aids and devices, physical and occupation therapy, hospitalizations and surgery), patients with osteoarthritis in the United States loose greater than 68 million days of work per year. Current techniques at evaluating osteroarthritis are either qualitative in nature - simply asking the patient how he/she feels - or impractical, such as a series of biochemical and histological analyses of biopsy samples of cartilage in the joint of the patient. Radiography with special macroscopic techniques has proven valuable for measuring cartilage thickness changes in osteoarthritis, however, these techniques cannot detect the earliest changes of osteoarthritis i.e. proteoglycan loss from the cartilage matrix. We have previously shown that MRI in combination positively-charged nitroxides, as a contrast enhancing agent, may be a reliable method to evaluate proteoglycan loss in cartilage. Poor relaxivity of nitroxides diminishes their selectivity. To overcome this limitation, it is proposed in this SBIR to develop dendrimeric-linked nitroxides, as selective contrast enhancing agents to assist MRI in evaluating cartilage status in humans with osteoarthritis. This Phase I grant will (a) synthesize dendrimer-linked nitroxides that are positively charged at physiological pH, determining their in vitro stability and (b)test for their ability to bind to cartilage in vitro and measuring the in vivo pharmacokinetics of dendrimer-linked nitroxides that selectively bind to proteoglycans in cartilage. PROPOSED COMMERCIAL APPLICATIONS: If the proposed research in the Phase I and Phase II program is successful - the development of dendrimer-linked nitroxides and MRI - will allow physicians to monitor the progress of osteoarthritis in a non-invasive manner. Further, with the large number of pharmaceutical companies engaged in the development of therapeutic agents that will retard the progression of osteoarthritis by inhibiting the breakdown of proteoglycan, this technology can be used to monitor the efficacy of these new therapeutic agents