99mTc-DTB-Antifol-Pteroyls (RadioDAPs): Theranostics for Rheumatoid Arthritis

描述(申请人提供)：类风湿性关节炎(RA)在美国发生在210万人中，与进行性关节破坏、功能障碍和预期寿命缩短有关。如果没有滑膜炎症，就不会发生关节破坏。类风湿关节炎的治疗方向是抑制炎症，目的是建立一种缓解状态。现在有证据表明，尽管正在进行药物治疗和临床标准明显缓解，患者仍会发生活跃的亚临床滑膜炎和进行性关节破坏。这些数据表明，美国有超过1500,000名患者面临持续关节破坏的风险。即使目前有最有效的疾病修正抗风湿药物(DMARD)，大多数患者也无法实现缓解。因此，即使亚临床滑膜炎可以常规检测到，使用目前可用的DMARDS设备，在大多数患者中完全根除关节炎症可能是站不住脚的。因此，诊断和治疗方法的重大范式转变是必要的。甲氨蝶呤(MTX)是治疗RA的首选药物，但约80%的患者未能获得临床缓解，主要原因是(1)治疗指数较窄，具有剂量限制性毒性；(2)细胞摄取不完全和高度可变。为了提高患者临床和亚临床关节炎症的根治率，我们的目标是寻求一种战略，以改善现有的黄金标准DMARD。2006年，美国有396.9万张MTX处方，新的抗叶酸DMARD标准的潜在影响预计将是重大的，可能会影响数十万RA患者。我们建议开发和测试一系列新型的抗肿瘤药物99mTC-DTB-安替比林-蝶呤(RadioDAPs)，我们假设它将允许高度靶向和集中的抗叶酸(例如氨基蝶呤，AMT)和99mTc放射性核素被输送到亚临床滑膜炎部位，用于SPECT成像治疗和诊断。我们的长期假设是，抗肿瘤药物RadioDAP(I)将通过向显性和亚临床滑膜炎症部位高靶向性和高强度递送抗叶酸来显著增加RA的缓解率，(Ii)将更早和更具特异性地发现亚临床滑膜炎，并进一步具有随着时间的推移监测治疗反应的能力，并将个体患者的这种反应与药物的递送联系起来。这项SBIR赠款提案中的两年实验计划旨在通过使用叶酸运输的体外模型为其化学组装和细胞摄取奠定初步基础，从而启动RadioDAP的开发。 公共卫生相关性：叙述性类风湿性关节炎(RA)在美国发生在210万人中，并与进行性关节破坏、功能残疾和预期寿命缩短有关。建议的RadioDAP技术将用于同时改进RA的治疗和诊断。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) occurs in 2,100,000 people in the United States, and is associated with progressive joint destruction, functional disability and decreased life expectancy. Joint destruction does not occur without synovial inflammation. The treatment of RA is directed to suppressing inflammation, with the aim of establishing a state of remission. There is now evidence that active subclinical synovitis and progressive joint destruction occurs in patients despite ongoing drug therapy and apparent clinical remission by clinical criteria. These data suggest that well over 1,500,000 patients in United States are at risk for continued joint destruction. Even with the most effective disease-modifying antirheumatic drugs (DMARDs) currently available, the majority of patients fail to achieve remission. Thus, even if subclinical synovitis could be routinely detected, completely eradicating joint inflammation in most patients is likely to be untenable using the currently available armamentarium of DMARDs. A major paradigm shift in diagnostic and therapeutic approach is therefore required. Methotrexate (MTX) is the drug of first choice in treating RA, however, it fails to achieve clinical remission in about 80% of patients mainly because of (i) dose-limiting toxicities due to its narrow therapeutic index, and (ii) incomplete and highly variable cellular uptake. To increase the rate of eradicating clinical and subclinical joint inflammation in patients, we aim to pursue a strategy that will improve on the existing goldstandard DMARD. With 3,969,000 prescriptions for MTX in the United States in 2006, the potential impact of a new antifolate DMARD standard would be expected to be major, potentially affecting hundreds of thousands of patients with RA. We propose to develop and test a series of novel theranostic 99mTc-DTB- Antifol-Pteroyls (RadioDAPs) that we hypothesize will allow the highly targeted and concentrated delivery of antifolate (e.g. aminopterin, AMT) and 99mTc radionuclide to sites of subclinical synovitis for treatment and diagnosis by SPECT imaging. Our long-term hypotheses are that a theranositic RadioDAP (i) will significantly increase the rate of remission in RA through highly targeted and intense delivery of antifolate to sites of overt and subclinical synovial inflammation, and (ii) will detect subclinical synovitis earlier and with greater specificity, with the further ability to monitor for response to therapy over time, and relate this response in an individual patient to delivery of the agent. The two-year experimental plan in this SBIR Grant proposal aims to jumpstart the development of RadioDAPs by laying the initial groundwork for their chemical assembly and cellular uptake using in vitro models of folate transport. PUBLIC HEALTH RELEVANCE: Narrative Rheumatoid arthritis (RA) occurs in 2,100,000 people in the United States, and is associated with progressive joint destruction, functional disability and decreased life expectancy. The proposed RadioDAP technology will be used to simultaneously improve RA therapy and diagnosis.