Breast cancer is the most commonly diagnosed cancer 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 the breast cancer remains unknown, most breast cancer 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. This project is related to the use of 99mTc-labeled cyclic RGDfK tetramers as radiotracers for breast cancer imaging. The approach described in this proposal involves attachment of a 99mTc chelate either directly or through a linker to a cyclic RGDfK tetramer that bind with high affinity and selectivity to the integrin avp3 overexpressed on both tumor cells and tumor neovasculature. This project is specifically designed to examine the impact of 99mTc chelate, PKM linkers and peptide multiplicity on the uptake """"""""""""""""To-labeled cyclic RGDfK tetramers in tumor and other organs, such as kidneys and liver. The purpose of these studies is to maximize tumor uptake and minimize the uptake in other major organs, such as liver and kidneys;thereby improving the target-to-background (T/B) ratios. The combination of higher tumor uptake and better T/B ratios will result in better detection sensitivity, which is particularly important for small lesions at early stage of the breast cancer growth. The goal of this project is to develop a clinically useful integrin avp3-targeted 99mTc radiotracer for early detection of breast caner. Our long-term goal is to develop an integrin ccvp3- targeted 99mTc radiotracer not only for early diagnosis of rapidly growing and metastatic tumors of different origin, but also for monitoring tumor metastasis and therapeutic efficacy of anti-angiogenic treatment. Successful development of an integrin avp3-targeted 99mTc radiotracer, which is not only able to detect breast cancer at early stage but also able to monitor tumor growth and metastasis, will help physicians (1) to determine therapeutic options;(2) to select right patients for a specific therapeutic regiment;and (3) to optimize the dose and schedule for the antiangiogenic treatment in an individual patient. Once we are able to achieve the goals of this project, we will explore the suitability of the selected agent for monitoring efficacy of chemotherapy in various tumor models in the future. It is very important to note that the integrin avp3 overexpression has also been demonstrated in melanoma, osteosarcoma, neuroblastoma, glioblastoma, lung carcinomas, ovarian, breast, prostate, and bladder cancers. Thus, the new radiotracer developed in this project should also be useful for the early detection of other rapidly growing and metastatic solid tumors.
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