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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要慢性肝病是全球慢性肝病死亡的主要原因之一。该疾病是多因素造成的，可能是由病毒性肝炎感染和酒精等损害引起的导致这些问题的是非酒精性脂肪性肝炎（NASH）的流行，但都是慢性肝病。如果不加以控制，疾病会发展为肝纤维化。纤维化可能会在有效治疗后消退，但如果不进行治疗的话。未经治疗的肝纤维化可进展为肝衰竭或肝癌。肝纤维化的诊断是慢性肝病患者管理的关键。肝纤维化的分期是活检，存在内出血的风险，仅抽取一小部分样本肝脏，并遭受观察者间变异的影响。纤维化阶段，而不是脂肪变性或炎症，是与更严重的疾病相关的唯一特征除了活检之外，我们还缺乏良好的工具来无创检测肝纤维化、纤维化阶段或肝纤维化。监测治疗反应。弹性成像方法对疾病的早期变化不敏感。用于识别 NASH 和/或肝纤维化的生物标志物和生物标志物组合也有限且缺乏准确性这些技术都无法准确、安全地诊断治疗。监测 NASH 和相关纤维化在临床实践和临床研究中都至关重要。 Collagen Medical 开发了与钆螯合物缀合的 I 型胶原结合肽 (CBP) 用于肝纤维化的无创 MRI 分期这些探针（EP-3533 和 CM-101）通过静脉注射，与纤维化肝脏的结合与纤维化程度成比例，而未结合的探针则迅速通过肾脏消除。尽管低剂量探针（5 – 10 µmol/kg）在多种动物模型中有效，但预期的商品成本预计该剂量太高，不具有商业可行性。该 I 期 SBIR 提案旨在通过以下方式降低胶原蛋白靶向 MR 成像探针的商品成本：将 Collagen Medical 的 CBP 技术与极小的氧化铁纳米颗粒 (ESPION) 相结合麻省理工学院开发的 ESPION 技术可在 T1 加权 MRI 扫描中提供强阳性对比度，且体积较小。 ESPION 的弛豫度为 5。 – 比 CM-101 高 20 倍。较高的弛豫度应相当于较低的剂量，我们将其提升到了一个水平。 ESPION-CBP 缀合物在比 CM-101 低 5 – 20 倍的剂量下同样有效，因此显着此外，ESPION 可以用廉价的原材料制备，而合成则可以。先前已与 CBP 缀合的双功能 Gd 螯合物需要多个合成步骤我们的方法是合成一个小型 ESPION-CBP 文库。缀合物并在体外筛选弛豫性、胶原蛋白结合亲和力、胶原蛋白特异性和代谢稳定性。然后，我们将证明我们的领先 ESPION-CBP 缀合物能够通过以下方式观察肝纤维化：与之前在小鼠中研究的基于 Gd 的胶原蛋白靶向探针 CM-101 相比，其检测灵敏度更高肝纤维化模型。