TC-Labeled Cyclic RGDfK Tetramers for Breast Cancer Imaging

描述(申请人提供)：乳腺癌是女性中最常见的癌症，也是全球女性死亡的第二大原因。今年将有超过20万人被确诊，其中4万人将死于此病。虽然乳腺癌的确切原因尚不清楚，但如果能在早期发现乳腺癌，大多数乳腺癌患者在手术、放射治疗和化疗或两者结合后都能存活下来。因此，快速、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。该项目是关于使用99mTc标记的环状RGDfK四聚体作为乳腺癌显影的放射性示踪剂。本方案中描述的方法包括直接或通过连接物将99mTc螯合物连接到环状RGDfK四聚体上，该四聚体与肿瘤细胞和肿瘤新生血管上过度表达的整合素avp3具有高亲和力和选择性。该项目专门设计用来检测99mTc螯合物、PKM连接体和多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增加肿瘤的摄取，并最大限度地减少其他主要器官的摄取，如肝脏和肾脏；从而提高靶与背景(T/B)的比率。更高的肿瘤摄取率和更好的T/B比率将带来更好的检测灵敏度，这对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上有用的整合素avp3靶向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以整合素ccvp3为靶点的99mTc放射性示踪剂，不仅用于早期诊断不同来源的快速生长和转移的肿瘤，而且还用于监测肿瘤转移和抗血管生成治疗的疗效。整合素avp3靶向99mTc放射性示踪剂的成功开发，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，这将帮助医生(1)确定治疗方案；(2)为特定的治疗方案选择合适的患者；(3)优化针对个别患者的抗血管生成治疗的剂量和时间表。一旦我们能够实现这个项目的目标，我们将探索所选择的药物在未来各种肿瘤模型中用于监测化疗效果的适用性。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，本项目开发的新的放射性示踪剂也将有助于其他快速生长和转移的实体肿瘤的早期检测。

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.