The overall goal of this proposal is to characterize and evaluate magnetic resonance (MR) pharmaceuticals for receptor imaging. These proposed agents should improve tissue selectivity and thus enhance detection of cancer, the second most common cause of death in the United States. Superparamagnetic iron oxide (SPIO) particles possess-high relaxivity to make feasible receptor imaging by MR. Commercially available SPIO preparations, however, are either too large for transcapillary passage (e.g., AMI-25) or do not readily form stable compounds with carrier molecules such as polypeptides (e.g., AMI-227). The basis of this research is formed by the recent discovery in our laboratory of a monocrystalline iron oxide nanocompound (MION) that can be readily attached to a variety of carrier molecules by noncovalent binding and thus be delivered to receptor sites in vivo and be detected by MR imaging. The intent of this proposal is to extend previous feasibility studies in MR receptor imaging research. The scope of the research includes the physical and biochemical characterization of the parent compound (MION) and MION targeted to different receptors on hepatocytes and pancreatic cells. The small size of MION (2.86 +/- 0.9 nm), which facilitates transcapillary passage, results in a relatively low relaxivity in vitro. A more dramatic effect, however, is observed in vivo. A unique component of this research will test the hypothesis that clustering of particles occurs in vivo resulting in higher tissue relaxivity. The preclinical utility of these agents will be assessed in vivo in animal models and in vitro in studies of benign and malignant human tissue. The long term goals of this research are to: a) improve the detection of cancer, and b) allow determination of organ function in vivo. It is anticipated that receptor targeted MR contrast agents may ultimately replace or complement the nonspecific interstitial and RES contrast agents for cancer detection and tumor therapy monitoring.
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