Non-invasive staging of Metastasis by Precision MRI

项目概要/摘要 该SBIR应用程序将开发一种改进的造影剂，用于通过早期和准确的 胰腺导管腺癌（PDAC）肝转移的检测。我们创造了一个创新的平台， 使用新型蛋白质类MRI造影剂（ProCA）进行对比增强MRI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 生物标志物包括胶原I（ProCA32.胶原）。这种细胞外基质蛋白在肿瘤细胞中高度表达。 肿瘤微环境及其表达水平和交联增加， 进展ProCA32.collagen在r1和r2弛豫率方面均表现出10 - 50倍的增加， 临床批准的Gd 3+造影剂，具有出色的成像能力， 通过双MR成像方法，可以检测到不均匀的组织信号。ProCA32.collagen具有强大的胶原蛋白 结合亲和力，能够早期检测<0.2 mm的小肝转移，并允许绘制肿瘤 几种小鼠异种移植肿瘤模型中的异质性;检测限提高100倍 而不是临床造影剂。由于ProCA32.胶原蛋白具有较低的金属毒性相关风险， 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， 生物分布，这允许在低剂量下进行高质量成像。这一提议将检验一个假设，即一个非- 通过检测亚临床肝转移，用于PDAC准确分期的侵入性体内MRI可以 通过进一步优化胶原靶向ProCA32.胶原+造影剂实现。这一系列的临床前 研究将提供向FDA提交研究性新药申请所需的配方和安全性特征等数据。 申请新药（IND）进行早期临床试验。该应用将改善亚临床 转移并对PDAC具有广泛的影响。

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.