Project #3 is developed to address the critical needs of novel molecular imaging approaches for earlydetection of breast cancer. We have identified a moleculer target, urokinase plasminogen activatorreceptor (uPAR) for receptor targeted MR imaging of breast cancer. uPAR is highly expressed inhuman breast cancer cells at levels of 14,000 to 500,000 uPAR/cell relative to 2,500/cell in normalmammary epithelial cells. An increased level of uPAR is considered to be associated with tumoraggressiveness, the presence of distant metastasis and poor prognosis. Previous studies have shownthat the amino terminal fragment (ATF) peptide of uPAR is responsible for recognition and specificbinding 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. Thisimaging 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 targetingpeptides. Given the capability of uPAR targeting with the ATF peptide and strong MRI contrast inducedby IO nanoparticles, we hypothesize that this receptor-targeted MRI probe may lead to theaccumulation of ATF conjugated IO nanoparticles in the tumor, producing sufficient contrast to detecttumors with elevated level of uPAR. Our preliminary data demonstrated that this breast cancertargeted molecular MRI can be achieved in a mouse mammary tumor model.
Specific aims of thisproject are: 1) to optimize the method for conjugating the ATF peptide to IO nanoparticles and toexamine 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 ofbreast 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 MRIcontrast properties of ATF-IO nanoparticles and to develop imaging methods appropriate for imagingof receptor targeted IO nanoprobes in vivo. It is anticipated that this tumor receptor-targeted MRI probeand imaging method can improve the specificity of breast cancer imaging be translated to clinicalapplications in the future.
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