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This project is focussed on developing and assessing novel tumor antigen-specific magnetic resonance imaging (MRI) molecular probes for the in vivo detection of the expression of tumor antigens which may serve as in vivo diagnostic biomarkers for malignant human cancers. The tumor antigen we are developing probes to detect is c-MET, a tyrosine kinase receptor for the multifunctional hepatocyte growth factor /scatter factor. c-MET is crucially involved in invasive cell growth and motility during embryogenesis, and has been detected in invasive tumors, including gliomas, and hepatocarcinomas. The molecular targeting agent we used incorporated a Gd-DTPA (gadolinium (III) complex of diethylentriamine-N,N,N’,N”,N”-pentaacetate) backbone with albumin and co-valent attachment of the anti-cMET antibody to the albumin moiety, which generated strong T1 MR contrast in c-MET expressing cells. MRI images were obtained at the OMRF Small Animal MRI Core Facility on a Bruker Biospec 7.0 Tesla/30cm horizontal-bore imaging spectrometer. T1- weighted images were acquired using a 2D rapid acquisition relaxation enhanced pulse sequence (echo time (TE) 15msec, 5 repetition times (TRs): 200, 400, 800, 1200, 1600 msec, 256x256 matrix). Two cancer models, a liver cancer model (murine transgenic model with a c-Myc/TGF-α double mutation) and a rat C6 glioma model (C6 cells (106/ml) implanted in cortex of male Fischer 344 rats fed a choline-deficient diet), were used in this study to show that the developed technique may be applicable in any cancer model. For the liver cancer model, we imaged mice at 34 weeks (with nodules), at 40 weeks (with tumors) and compared to the CD-1 mouse. Mice or rats were injected intravenously with anti-c MET- biotinyl-albumin-GdDTPA conjugated contrast agents (1 mg antibody/kg). Images were taken before injection, immediately after injection and after 2 hrs. In liver nodules, T1 prior to administration of the anti-c-MET-biotinyl-albumin-GdDTPA contrast agent was 303 ms ms, which decreased to 90ms 2hrs hour following administration of the contrast agent. In comparison, the “normal” region of the liver T1 was 151 ms pre-contrast and 85 ms post contrast (after 2 hrs). In gliomas, T1 prior to administration of the anti-c-MET-biotinyl-albumin-GdDTPA contrast agent was 340 ms ms, which decreased to 210ms 3hrs hour following administration of the contrast agent. In comparison, the “normal” region of the liver T1 was 353 ms pre-contrast and 330 ms post contrast (after 3 hrs).Molecular targeted contrast-enhanced MRI may be used to predict the degree of malignancy of a tumor in vivo during hepatocarcinogenesis and glioma formation. This is the first time c-MET has been detected in vivo using MRI detection methods.

Funds were greatly appreciated from OCAST (Oklahoma Center for the Advancement of Science & Technology) grant AR052-132, and NIH grant R03 CA121359-01.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA