The goal of this Phase I STTR project is to design, synthesize, and test a new class of biochemically activated magnetic resonance imaging (MRI) contrast agents to detect and monitor enzymatic activity in vivo. The proposal responds to the Program Announcement entitled "Systems and methods for small animal imaging". We base this work on the hypothesis that activation of MRI contrast agents by extracellular proteases represents a particularly promising strategy to detect and image biochemical processes relevant to cancer. This represents a multi-disciplinary effort that brings together expertise in cancer biology, chemistry, enzymology, and physics at industrial and academic institutions to achieve the stated goals; specifically, we propose to determine if tumor-associated matrix metalloproteinase (MMP) activity can be non-invasively imaged by MRI in preclinical models of human cancer. We will approach the generation and testing of reagents useful for MRI detection of protease targets in Phase I of the project with the following specific aims: 1) Design and produce a gadolinium-chelate MRI contrast agent (Proteolytic Contrast Agent, PCA) that has decreased aqueous solubility following MMP cleavage of the agent; 2) Characterize the pharmacodynamic properties of both uncleaved and protease-cleaved PCAs in the context of in vivo mouse models of cancer. The success of the Phase I project will be judged by the completion of two well-defined milestones: 1) Preparation of one or more Gd-based MRI contrast agents that exhibit in vitro at least a 10-fold decrease in aqueous solubility in response to proteolytic cleavage by MMP; and 2) Collection of MRI data in vivo demonstrating a statistical difference in the value of k(out), the efflux transfer rate from the tumor, between MMP-positive and MMP-negative tumors and/or relative to that measured with an uncleavable analog in at least one of two mouse models of human cancer, i.e., by demonstrating a measured difference in the temporal response of the MRI contrast referable to proteolytic cleavage of the PCA. The success of this project has the potential for improved non-invasive detection and evaluation of cancer in small animals and eventually in patients. It provides the basis for Phase II of the project, with the overall goal of developing a commercial PCA product or products to provide for non-invasive clinical assessment to benefit patients with cancer, as well as to advance the use of MRI for functional imaging in clinical practice.
Thesaurus Terms: bioassay, biomarker, contrast media, disease /disorder model, enzyme activity, gadolinium, magnetic resonance imaging, metalloendopeptidase, neoplasm /cancer, technology /technique development breast neoplasm, chelating agent, chemical structure function, chemical synthesis, colon neoplasm, diagnosis design /evaluation, neoplasm /cancer classification /staging, neoplasm /cancer diagnosis, noninvasive diagnosis, pharmacokinetics, solubility, water bioimaging /biomedical imaging, genetically modified animal, laboratory mouse
