The ability to image specific molecular biomarkers in vivo would have important applications in the earliest detection of cancer, in assessing specific targeted therapies and for monitoring dynamic changes in expression patterns during disease progression. Many of such molecular biomarkers however, exist at low concentrations, necessitating novel amplification strategies. The overall goal of the proposal is to investigate a new enzyme-mediated MR signal amplification strategy (Mramp) for imaging model molecular targets associated with vascular and extravascular targets in tumors. The strategy relies on enzyme-mediated polymerization of paramagnetic substrates yielding products with significantly higher atomic relaxivity (r1 and r2). This method potentially has several advantages: 1) it utilizes low molecular weight lanthanide complexes which are converted into large molecules """"""""on site"""""""", 2) the development of these low MW precursors is clinically viable, 3) the so far observed relaxivity changes are higher than with other amplification strategies, 4) the oligomerized products can be designed to reside locally and 5) the method can be used in a variety of generic ways potentially allowing the read-out of many different targets. So far, we have shown that the method holds promise in the 1) MR detection of a model ligand using an enzyme-linked immunoadsorbent assay format and 2) in imaging of a pro-inflammatory marker, E-selectin on the surface of endothelial cells. Two primary targets will be investigated in proposed research: a mutant, constitutively active deltaEGFR and angiogenesis-modulated E-selectin. deltaEGFR expression strongly upregulates VEGF expression which, in turn, upregulates E-selectin and tube formation in endothelial cells. These targets were chosen because of their importance in tumor proliferation, modulation by chemotherapy (e.g. EGFR tyrosine kinase inhibitors [Chan, 2002 #2547]) and the current absence of imaging markers directed against them. To further increase the sensitivity of MRamp we will investigate novel paramagnetic substrates exploiting changes in T1 (Gd) and T2/T2* effect (Dy), The latter may be of particular interest for imaging at higher resolution and higher field strengths.
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