Non-invasive staging of Metastasis by Precision MRI

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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.