The MRamp strategy was designed with the goal of improving the molecular sensitivity of MR imaging by modulating the MR signal output on two levels simultaneously: 1) specificity: the use of a pair of the receptor- targeted enzymes that co-localize in the specific tissue compartment and enable rapid modification of low molecular weight paramagnetic substrates resulting in their local retention at the reaction site;and 2) sensitivity: this local retention results in rapid accumulation of paramagnetic substrates that gives rise to an amplified MR signal generated by both the high density and increased relaxivity of the paramagnetic products of the enzymatic reaction. Our seminal work eventually culminated in: 1) imaging of endogenous peroxidases (e.g. myeloperoxidase) in many disease states by several research groups, and;2) imaging of receptor expression in cancer models. In this renewal we propose to harness the MRamp technique to meet the challenges of MR molecular imaging of epidermal growth factor (EGF) receptor and EpCAM cell-surface molecule as potential markers for targeted imaging of metastasis. Human epidermal growth factor receptor (EGFR) is overexpressed in 15-20% of all breast carcinomas and its expression level correlates with the ability of breast cancer to metastasize. EGFR signaling is linked to bone degradation, which often occurs in patients with breast cancer. The goal of this proposal is to continue our research aimed at developing and validating novel imaging probes which can be applied to detection of in vivo changes in EGFR expression in bone metastases of mammary adenocarcinoma (MAC) using MRI (high resolution) and ?PET (high sensitivity) techniques. This work is expected to be readily translatable to the design of a new diagnostic capability (monitoring levels of EGFR/EpCAM expression). MAC frequently overexpresses EpCAM while EGFR expression in metastasis is a viable marker for the development of osteolytic tumors. MRamp is one of the few available techniques that would make the detection of the coexpression of two protein markers (receptors) feasible. This work will also provide a new experimental tool for clinical and preclinical investigations regarding the etiology and pathology of metastatic adenocarcinoma.
The development of new drugs that can efficiently eliminate tumor cells or slow heart disease and diabetes requires ample testing in laboratory animals to prove safety and efficacy. The use of medical scanners that detect these cellular processes with high accuracy in live animals has the potential to significantly decrease the time between discovery of and subsequent clinical use of new medicines. This decreased time benefits both patients and taxpayers. We are proposing research approaches that will lead to the development of new tools (imaging drugs and compositions) for use with medical scanners. These tools will have applications for tracking the molecules that are linked to the abnormal cells in breast cancer spread to the bone. This research will help scientists and physicians to detect these cells and follow their response to medicines.
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