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Imaging Breast Cancer Markers with Nanoparticle Enhanced Ultrasound
BACKGROUND: Molecular alterations in breast cancer occur earlier than morphological abnormalities can be detected by current imaging technologies. The extent of cancer marker expression is frequently correlated to the degree of malignancy and outcome of therapy. Colloidal nanoparticles, due to their unique physical and chemical characteristics, have been targeted to cancer molecular markers for different imaging modalities. Relatively less has been done on nanoparticle enhanced ultrasound breast imaging, and particularly its quantitative analysis, which will potentially improve the sensitivity for early detection and non-invasive diagnosis of breast cancer. OBJECTIVE/HYPOTHESIS: We aim to develop a novel ultrasonic approach to image and evaluate breast tumors using contrast-enhancing and targeted nanoparticles. We hypothesize that surface-modified nanoparticles will selectively deposit on tumors that overexpress specific molecular markers, and create acoustic enhancement through their characteristic physical properties. We further hypothesize that our quantitative data analysis will enable detection and characterization of acoustic enhancement associated with nanoparticle binding. SPECIFIC AIMS: We aim to: 1) Quantitatively characterize nanoparticle-enhanced acoustic contrast in vitro and in vivo; 2) Engineer nanoparticles to bind preferentially to tumor specific molecular markers; 3) Evaluate nanoparticle safety, targeting specificity, and contrast efficacy in vivo. STUDY DESIGN: Nanoparticles will be suspended in tissue-mimicking phantoms to study the contrast effect in vitro using the Vevo 660 imaging system (Visualsonics, Inc). Nanoparticles will be injected intratumorally to nude mice with human breast cancer xenografts to test in vivo contrast feasibility. Polyethylene glycol and antibodies (or ligands) will be covalently bound to nanoparticle surfaces using carbodiimide-coupling techniques. Surface modified particles will be administered systematically via tail vein injection to test safety, targeting specificity and contrast efficacy. POTENTIAL OUTCOME AND BENEFITS: The main element of innovation in the proposed project is the development of tumor targeted nanoparticles to enhance contrast for ultrasound imaging, combined with the use of characterization software for quantitative analysis of the expression of molecular targets. This project will establish a novel category of ultrasound molecular imaging agents, and form the foundation for a non-invasive approach to evaluate molecular expression in vivo.
BACKGROUND: The molecular changes that lead to breast cancer progression often occur much earlier than tissue abnormalities can be detected by current imaging technologies. These molecular markers can be exploited to improve the sensitivity for early detection and non-invasive diagnosis of breast cancer. In addition, expression of certain molecular markers may be correlated with prognosis and therapy choice. Therefore, quantitative information on the expression of these markers is important for breast cancer management. Research worldwide has explored the use of nanoparticles as molecular probes to target tumors for improved detection and drug delivery. Little has been done to use nanoparticles to enhance ultrasound imaging of breast tumors, and to derive quantitative information of molecular expressions. OBJECTIVE/HYPOTHESIS: We propose a novel nanoparticle-enhanced ultrasound approach to image and measure molecular expressions in breast cancer. We hypothesize that nanoparticles can be used to create “signature” responses when imaged by ultrasound. We further hypothesize that quantitative information that correlates with the level of molecular expression will be made available through our ultrasound signal analysis tools. SPECIFIC AIMS: 1) Quantitatively characterize nanoparticle-enhanced acoustic contrast in vitro and in vivo; 2) Engineer nanoparticles to bind preferentially to tumor specific molecular markers; 3) Evaluate nanoparticle safety, targeting specificity, and contrast efficacy in vivo. STUDY DESIGN: Acoustic enhancement will be measured by our state-of-the-art high resolution ultrasound imaging system, and analyzed quantitatively to identify the optimal combination of material, size and dosage for generating acoustic contrast in tissue phantoms, as well as in animal models. The surface of the nanoparticles will be modified so that they will recognize and selectively bind to tumor specific molecules. Nude mice that bear human breast tumor xenografts will be injected with labeled nanoparticles to test whether they localize to tumors, and whether they augment visualization when examined by ultrasound imaging. The ultrasonic signals will be further analyzed to determine the expression level. POTENTIAL OUTCOME AND BENEFITS: This work will establish the foundation for developing a novel category of ultrasound molecular imaging probes for the early detection and non-invasive diagnosis of breast cancer.