Project #3 is developed to address the critical needs of novel molecular imaging approaches for early detection of breast cancer. We have identified a moleculer target, urokinase plasminogen activator receptor (uPAR) for receptor targeted MR imaging of breast cancer. uPAR is highly expressed in human breast cancer cells at levels of 14,000 to 500,000 uPAR/cell relative to 2,500/cell in normal mammary epithelial cells. An increased level of uPAR is considered to be associated with tumor aggressiveness, the presence of distant metastasis and poor prognosis. Previous studies have shown that the amino terminal fragment (ATF) peptide of uPAR is responsible for recognition and specific binding to the tumor cell. We propose to develop a uPAR-targeted paramagnetic iron oxide (IO) nanoparticle imaging probe for molecular Magnetic Resolnance Imaging (MRI) of breast cancer. This imaging strategy takes advantages of our experience and ability to produce the ATF in large quantity, our technology of formulating and synethsizing IO nanoparticles for optimal MRI contrast via T2- shortening effect and the chemistry of functionalizing particle surface for conjugating tumor targeting peptides. Given the capability of uPAR targeting with the ATF peptide and strong MRI contrast induced by IO nanoparticles, we hypothesize that this receptor-targeted MRI probe may lead to the accumulation of ATF conjugated IO nanoparticles in the tumor, producing sufficient contrast to detect tumors with elevated level of uPAR. Our preliminary data demonstrated that this breast cancer targeted molecular MRI can be achieved in a mouse mammary tumor model.
Specific aims of this project are: 1) to optimize the method for conjugating the ATF peptide to IO nanoparticles and to examine the specificity of the uPAR targeted-imaging probe in normal and breast cancer cells in vitro; 2) to investigate the specificity and sensitivity of uPAR targeted ATF-IO nanoparticles in detection of breast cancer using mouse mammary tumor, human tumor xenograft, and transgenic tumor models; 3) to examine the biodistribution and toxicity of ATF-IO nanoparticles;and 4) to characterize MRI contrast properties of ATF-IO nanoparticles and to develop imaging methods appropriate for imaging of receptor targeted IO nanoprobes in vivo. It is anticipated that this tumor receptor-targeted MRI probe and imaging method can improve the specificity of breast cancer imaging be translated to clinical applications in the future.
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