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Tc-99m Labeled Multivalent RGD peptide for Breast Cancer Imaging
BACKGROUND: Breast cancer is the most commonly diagnosed cancers in woman and the second leading cause of deaths among women. Most patients will survive after surgery, radiation therapy, and chemotherapy or a combination thereof if breast cancer can be detected at the early stage. Thus, rapid and accurate early detection is highly desirable.
OBJECTIVE/HYPOTHESIS: Breast cancer is angiogenesis dependent. The integrin avb3 receptors are over-expressed on breast cancer cells and tumor neovasculature, but not in normal tissues. The over-expression of integrin avb3 is correlated with the invasiveness of metastatic breast cancer. Therefore, the Tc-99m labeled multivalent RGD peptide can provide a measurement of integrin avb3 expression during growth and metastasis of breast cancer. The overall objective of this project is to develop an optimal Tc-99m labeled multivalent RGD peptide useful not only for early detection and but also for monitoring tumor growth and metastasis.
SPECIFIC AIMS (1) Optimization of Tc-99m labeled RGD peptides; (2) demonstration of the radiotracer's ability to image integrin avb3 expression on tumor neovasculature, and (3) demonstration of the radiotracer's suitability to monitor the growth and metastasis of breast cancer.
STUDY DESIGN: We will use cyclic RGD peptide tetramers to increase the tumor targeting capability and water-soluble PKM linkers to improve excretion kinetics of Tc-99m labeled RGD peptides. Athymic nude mice bearing MDA-MB-435 human breast cancer xenografts will be used for preliminary screening and monitoring tumor growth and metastasis. Nude mice bearing MDA-MB-468 human breast cancer xenografts will be used for demonstration of imaging the integrin avb3 expression on tumor neovasculature.
POTENTIAL OUTCOMES AND BENEFIT OF THE RESEARCH: Successful development of a new integrin avb3 targeted radiotracer, which is able not only to detect breast cancer but also to monitor the tumor growth and metastasis, will definitely help physicians (1) to determine the therapeutic options; (2) to select appropriate patients for a specific therapeutic regiment, and (3) to optimize the dose and schedue for anti-angiogenic therapy in an individual patient.
Breast cancer is the most commonly diagnosed cancers in woman and the second leading cause of deaths among women worldwide. More than 200,000 individuals will be diagnosed this year and 40,000 will die from it. Although the exact cause of breast cancer remains unknown, most patients will survive after surgery, radiation therapy, and chemotherapy or a combination thereof if breast cancer can be detected at the early stage. Therefore, rapid and accurate early detection is highly desirable so that various therapeutic regiments can be given before the primary tumors become widely spread.
Mammography is an established and effective method for detection of primary breast cancer; but it has its limitations. In particular, mammography is less effective in detecting lesions in women under 50 as they tend to have more dense breasts (1-3). It is less accurate in women with breast implants, and it cannot always distinguish between cancerous and non¬cancerous tumors. Nuclear imaging of breast cancer has become more common in recent years using SPECT and PET. SPECT and PET imaging uses radiopharmaceuticals such as 99mTc-sestamibi and 18F-FDG, respectively. Both modalities have very limited sensitivity for smaller (<1 cm) primary breast lesions. It has been suggested that the failure of these agents to detect smaller lesions is, at least in part, caused by a mismatch between the radiotracer and early breast cancer biology. Therefore, it would be desirable to develop a radiotracer that could recognize a marker expressed early in breast cancer cells.
This project is related to the use of 99mTc-labeled multivalent RGD peptides as radiopharmaceuticals for breast cancer imaging. The approach described in this proposal involves attachment of a 99mTc chelate either directly or through a linker to a multivalent RGD peptide that bind with high affinity and selectivity to integrin avb3 receptors over-expressed on tumor cells and tumor neovasculature. The objective of this project is to maximize tumor uptake and minimize the uptake in other major organs, particularly liver and kidneys; thereby improving the target-to-background ratios. The goal of this project is to develop an integrin avb3-targeted 99mTc imaging agent for both early detection of breast caner, and monitoring tumor growth and metastasis, which will have a significant impact on the treatment planning and welfare of breast cancer patients.