Non-invasive staging of Metastasis by Precision MRI

项目摘要/摘要 这项SBIR应用将开发一种改进的造影剂，用于通过早期和准确的 胰腺导管癌(PDAC)肝转移的检测。我们打造了一个创新的平台 使用一种新的基于蛋白质的磁共振造影剂(PROCAS)进行对比增强磁共振成像的技术。我们 已经开发出一种有效的方法来产生针对一系列分子的蛋白质造影剂 生物标志物包括I型胶原(ProCA32)。这种细胞外基质蛋白在细胞内高度表达 肿瘤微环境及其表达水平和交联度增加 进步。ProCA32.胶原蛋白的R1和R2松弛能力都比 临床批准的Gd3造影剂，导致卓越的成像能力，可以识别 通过双重磁共振成像方法获得不同种类的组织信号。ProCA32.胶原蛋白有很强的胶原蛋白 结合亲和力，能够及早发现0.2 mm的小肝转移并绘制肿瘤地图 几种小鼠移植瘤模型的异质性；检测下限提高100倍 而不是临床造影剂。ProCA32.胶原蛋白预计与金属毒性有关的风险较低，因为它 前所未有的金属结合选择性和动力学稳定性，延长血液滞留时间和充足的 生物分布，允许在低剂量下进行高质量成像。这一提议将检验这样一个假设，即一个非 有创的、活体MRI通过检测亚临床肝转移可以准确地对PDAC进行分期 通过进一步优化胶原靶向ProCA32实现胶原造影剂。这一系列临床前研究 研究将提供提交FDA研究新药所需的配方和安全概况等数据 药物(IND)申请进行早期临床试验。这一应用将提高对亚临床的检测 转移，对PDAC有广泛影响。

PROJECT SUMMARY/ABSTRACT This SBIR application will develop an improved contrast agent for precision staging through early and accurate detection of pancreatic ductal adenocarcinoma (PDAC) liver metastasis. We have created an innovative platform technology using a new class of protein-based MRI contrast agents (ProCAs) for contrast-enhanced MRI. We have developed an effective approach to generate protein contrast agents against an array of molecular biomarkers including collagen I (ProCA32.collagen). This extracellular matrix protein is highly expressed in the tumor microenvironment and its expression levels and crosslinking increase upon progression. ProCA32.collagen exhibits 10- to 50-fold increase in both r1 and r2 relaxivities, compared to clinically-approved Gd3+ contrast agents, resulting in exceptional imaging capability that can discern heterogeneous tissue signals via a dual MR imaging methodology. ProCA32.collagen has strong collagen binding affinity, enables early detection of small liver metastases <0.2 mm and allows for mapping tumor heterogeneity in several murine xenograft tumor models; a 100-fold improvement in the detection limit over clinical contrast agents. ProCA32.collagen is expected to have a low risk related to metal toxicity due to its unprecedented metal binding selectivity and kinetic stability, prolonged blood retention and adequate biodistribution, which permits high quality imaging at low doses. This proposal will test the hypothesis that a non- invasive, in vivo MRI for accurate staging of PDAC through detection of subclinical liver metastases can be achieved by further optimizing the collagen targeted ProCA32.collagen+ contrast agent. This series of preclinical studies will provide data such as formulation and safety profile needed to submit an FDA Investigational New Drug (IND) application for an early phase clinical trial. This application will improve detection of subclinical metastasis and have broad impact for PDAC.