New class of collagen-targeted contrast agents for Magnetic Resonance Imaging

用于磁共振成像的新型胶原蛋白靶向造影剂

• 批准号: 10258404
• 负责人: Valerie Humblet
• 金额: $ 28.71万
• 依托单位: COLLAGEN MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10258404
• 关键词: Affinity; Alcohol abuse; Alkanesulfonates; Alkynes; Animal Model; Azides; Binding; Biopsy; Blood Vessels; Chelating Agents; Chronic Hepatitis; Clinical Research; Collagen; Collagen Type I; Contrast Media; Coupling; Detection; Diagnosis; Disease; Dopamine; Dose; Epidemic; Fibrosis; Filtration; Functional disorder; Gadolinium; Goals; Hemorrhage; Human; In Vitro; Infection; Inflammation; Interobserver Variability; Intravenous; Kidney; Lead; Left; Libraries; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; MRI Scans; Magnetic Resonance Imaging; Malignant neoplasm of liver; Medical; Metabolic; Methods; Monitor; Morbidity - disease rate; Oral; Outcome; Output; Patients; Peptides; Phase; Plasma; Play; Primary carcinoma of the liver cells; Reaction; Regimen; Risk; Running; Sampling; Serum; Signal Transduction; Small Business Innovation Research Grant; Specificity; Staging; Techniques; Technology; Time; Unhealthy Diet; Viral hepatitis; Water; accurate diagnosis; base; biomarker panel; chronic liver disease; clinical practice; cost; cost effective; detection sensitivity; effective therapy; elastography; imaging probe; iron oxide nanoparticle; lead candidate; mortality; mouse model; nanoparticle; nonalcoholic steatohepatitis; novel; standard of care; superparamagnetism; tool; treatment response

Project Summary Chronic liver disease is one of the leading and most rapidly rising causes of mortality worldwide. Chronic liver disease is multifactorial and can be brought upon from damages ranging from viral hepatitis infection to alcohol abuse to poor diet. Leading these is the epidemic of nonalcoholic steatohepatitis (NASH), but all chronic liver diseases progress to liver fibrosis if unchecked. Fibrosis may resolve following effective treatment, but when left untreated liver fibrosis can progress to liver failure or liver cancer. Accurate diagnosis, staging, and surveillance of liver fibrosis is key to chronic liver disease patient management. The present standard of care for diagnosis and staging of liver fibrosis is biopsy, which runs the risk of internal bleeding, samples only a small portion of liver, and suffers from interobserver variability. Fibrosis stage, and not steatosis nor inflammation, is the only feature of disease associated with worse outcomes in NASH. Besides biopsy we lack good tools to noninvasively detect liver fibrosis, stage fibrosis, or monitor response to treatment. Elastography methods are not sensitive to early changes in disease. Serum biomarkers and biomarker panels to identify NASH and/or liver fibrosis, are also limited and lack accuracy for staging. None of these techniques has the accuracy to monitor treatment. An accurate, safe method to diagnose and monitor NASH and associated fibrosis is of utmost importance in both clinical practice and clinical research. Collagen Medical has developed type I collagen-binding peptides (CBP) conjugated to gadolinium chelates for noninvasive MRI staging of liver fibrosis. These probes (EP-3533 and CM-101) are injected intravenously, binding to fibrotic liver in proportion to the degree of fibrosis, while the unbound probe is rapidly renally eliminated. Despite efficacy in multiple animal models at low doses of probe (5 – 10 µmol/kg), the anticipated cost of goods at this dose is expected to be too high to be commercially viable. This Phase I SBIR proposal seeks to reduce the cost of goods of a collagen-targeted MR imaging probe by combining Collagen Medical’s CBP technology with exceedingly small iron-oxide nanoparticle (ESPION) technology developed at MIT. ESPIONs provide strong positive contrast in T1-weighted MRI scans, are small enough to extravasate from blood vessels, and are eliminated via renal filtration. The relaxivity of ESPIONs is 5 – 20 times higher than CM-101. A higher relaxivity should equate to a lower dose and we hypothesize that an ESPION-CBP conjugate would be as effective at a 5 – 20 fold lower dose than CM-101, and thus a significantly lower cost of goods. Furthermore, ESPIONs can are prepared from cheap raw materials whereas synthesis of the bifunctional Gd-chelates that have been previously conjugated to the CBP require multiple synthetic steps and costly chromatographic purification. Our approach is to synthesize a small library of ESPION-CBP conjugates and screen for relaxivity, collagen-binding affinity, collagen specificity, and metabolic stability in vitro. We will then demonstrate that our lead ESPION-CBP conjugate is capable of visualizing liver fibrosis with superior detection sensitivity to the previously studied Gd-based collagen-targeting probe CM-101 in a murine model of liver fibrosis.

项目摘要 慢性肝病是世界范围内死亡率上升最快的主要原因之一。慢性肝 疾病是多因素的，可以从病毒性肝炎感染到酒精的损害引起 滥用不良饮食。非酒精性脂肪性肝炎（NASH）的流行是其中的主要原因，但所有慢性肝病患者都是NASH患者。 如果不加以控制，疾病会发展为肝纤维化。纤维化可能会解决后，有效的治疗，但当左 未经治疗的肝纤维化可发展为肝衰竭或肝癌。准确的诊断、分期和监测 肝纤维化是慢性肝病患者管理的关键。目前的诊断护理标准 肝纤维化的分期是活组织检查，这有内出血的风险，只采集一小部分肝纤维化的样本。 肝脏，并患有观察者间变异性。 纤维化阶段，而不是脂肪变性或炎症，是疾病恶化的唯一特征。 NASH的结果。除了活检，我们缺乏良好的工具来无创检测肝纤维化，分期纤维化，或 监测对治疗的反应。弹性成像方法对疾病的早期变化不敏感。血清 用于鉴定NASH和/或肝纤维化的生物标志物和生物标志物组也是有限的，并且缺乏对NASH和/或肝纤维化的准确性。 分期付款这些技术都不具有监测治疗的准确性。一种准确、安全的诊断方法 并且监测NASH和相关的纤维化在临床实践和临床研究中都是极其重要的。 Collagen Medical开发了与钆螯合物结合的I型胶原蛋白结合肽（CBP） 用于肝纤维化的非侵入性MRI分期。静脉注射这些探针（EP-3533和CM-101）， 与纤维化程度成比例地结合到纤维化肝脏，而未结合的探针被快速地肾清除。 尽管低剂量探针（5 - 10 µmol/kg）在多个动物模型中有效，但预期的商品成本 预期该剂量太高而不能商业化。 该I期SBIR提案旨在通过以下方式降低胶原靶向MR成像探头的商品成本： 将Collagen Medical的CBP技术与极小氧化铁纳米颗粒（ESPION）相结合 MIT开发的技术。ESPION在T1加权MRI扫描中提供强阳性对比，体积小 足以从血管外渗，并通过肾过滤排出。ESPION的弛豫率为5 - 比CM-101高20倍。较高的弛豫率应等同于较低的剂量，我们假设， ESPION-CBP缀合物在比CM-101低5 - 20倍的剂量下将是有效的，并且因此显著降低了剂量。 降低商品成本。此外，ESPION可以由廉价的原材料制备，而 先前已经与CBP缀合的双官能Gd螯合物需要多个合成步骤 和昂贵的色谱纯化。我们的方法是合成一个小的ESPION-CBP文库 结合物，并筛选松弛性、胶原结合亲和力、胶原特异性和体外代谢稳定性。 然后，我们将证明我们的领先ESPION-CBP结合物能够可视化肝纤维化， 在小鼠中，对先前研究的基于Gd的胶原靶向探针CM-101的上级检测灵敏度 肝纤维化模型。