TC-Labeled Cyclic RGDfK Tetramers for Breast Cancer Imaging

描述（由申请人提供）：乳腺癌是妇女中最常见的癌症，也是全世界妇女死亡的第二大原因。今年将有超过20万人被确诊，其中4万人将死于该病。虽然乳腺癌的确切病因尚不清楚，但如果能在早期发现乳腺癌，大多数乳腺癌患者在手术、放疗、化疗或综合治疗后都能存活下来。因此，快速和准确的早期检测是非常必要的，以便在原发肿瘤广泛扩散之前给予各种治疗方案。本项目涉及使用99mtc标记的环状RGDfK四聚体作为乳腺癌成像的放射性示踪剂。该方案中描述的方法包括将99mTc螯合物直接或通过连接物连接到环状RGDfK四聚体，该四聚体以高亲和力和选择性结合肿瘤细胞和肿瘤新生血管上过表达的整合素avp3。该项目专门研究99mTc螯合物、PKM连接物和肽多样性对肿瘤和其他器官（如肾脏和肝脏）摄取“to”标记的环状RGDfK四聚体的影响。这些研究的目的是最大限度地提高肿瘤的吸收，并尽量减少其他主要器官，如肝脏和肾脏的吸收；从而提高目标与背景（T/B）比率。较高的肿瘤摄取和较好的T/B比值相结合，将导致更好的检测灵敏度，这对于乳腺癌生长早期的小病变尤为重要。该项目的目标是开发一种临床有用的靶向整合素avp3的99mTc放射性示踪剂，用于乳腺癌的早期检测。我们的长期目标是开发一种靶向整合素ccvp3的99mTc放射示踪剂，不仅可以用于不同来源的快速生长和转移性肿瘤的早期诊断，还可以用于监测肿瘤转移和抗血管生成治疗的治疗效果。一种靶向整合素avp3的99mTc放射示踪剂的成功开发，不仅能够在早期发现乳腺癌，而且能够监测肿瘤的生长和转移，将帮助医生确定治疗方案；(2)为特定的治疗方案选择合适的患者；(3)优化个体患者抗血管生成治疗的剂量和方案。一旦我们能够实现这个项目的目标，我们将在未来探索所选择的药物在各种肿瘤模型中监测化疗疗效的适用性。值得注意的是，整合素avp3在黑色素瘤、骨肉瘤、神经母细胞瘤、胶质母细胞瘤、肺癌、卵巢癌、乳腺癌、前列腺癌和膀胱癌中也有过表达。因此，本项目开发的新型放射性示踪剂也可用于其他快速生长和转移性实体瘤的早期检测。

DESCRIPTION (provided by applicant): 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.