Advancement in the design of imaging agents has many far-reaching implications for the future directions of molecular imaging and radiological sciences including: (1) The early detection of disease (e.g. atherosclerosis, cancer, etc.) by the identification of early molecular signatures (2) The evaluation of various treatments and therapeutics (i.e. efficacy and dosing) (3) The high-throughput screening of various compounds during pharmaceutical development. I am interested in applying powerful combinatorial approaches to the development and design of targeted, multimodal, and amplifiable imaging agents. Using this method of attack, I have generated imaging agents capable of the early detection in vivo of colon, pancreatic, lung, and prostate cancers as well as specific targets in atherosclerosis and inflammation. These agents have also been used to evaluate therapeutic response at the molecular level in vivo. In addition to the generation of imaging agents, the ?hits? identified from these approaches represent a snapshot of the proteome in aberrant cells and are useful for the delineation of the underlying signal transduction pathways important to disease progression. Therefore, I am also interested in the target identification of novel imaging agents, which enables us to expand our biological understanding of specific disease states.

My laboratory currently uses several different strategies including phage display, small molecule display on nanoparticles, and SELEX to identify lead candidates for the development of amplifiable targeted imaging agents. In one specific example, using phage display, we successfully developed a magneto-optical probe targeting early-stage atherosclerotic lesions. We have shown that VCAM-1 expression in inflamed endothelium could be specifically identified optically and via MRI in mouse models of atherosclerosis. The utility of this probe extended to the in vivo detection of the therapeutic efficacy of statin treatment for lowering VCAM-1 levels in plaque. In addition to phage display, we have also created nanoparticle libraries that achieve specificity through multivalent modification with small molecules. We were able to rapidly screen the library against a variety of cell lines and have discovered a series of novel nanoparticles with specificity for endothelial cells, activated human macrophages or pancreatic cancer cells. The method and described materials could have important applications for the development of functional nanomaterials for biology, functional differentiation of cell lines, and targeting.

A second research interest is target identification of novel imaging agents identified through the above screens and determining their importance in pathologies. For example, we previously identified the peptide sequence RPMC as one, which specifically targets colon cancer and subsequently demonstrated it to be a target for the ?5?1 integrin. Similarly, we identified VCAM-1 targeted peptide sequences with homology to the protein SPARC or osteonectin, which has been shown to play an important role in tumorogenesis and metastasis. The interaction of VCAM-1 and SPARC provided important insights into the mechanisms of transendothelial leukocyte migration.