TC-Labeled Cyclic RGDfK Tetramers for Breast Cancer Imaging

描述（由申请人提供）：乳腺癌是女性最常见的癌症，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4万人将死于乳腺癌。虽然乳腺癌的确切原因尚不清楚，但如果乳腺癌能在早期发现，大多数乳腺癌患者将在手术、放射治疗和化疗或其组合后存活。因此，非常需要快速和准确的早期检测，以便在原发性肿瘤广泛扩散之前可以给予各种治疗方案。该项目涉及使用99 mTc标记的环状RGDfK四聚体作为乳腺癌成像的放射性示踪剂。本提案中描述的方法涉及直接或通过接头将99 mTc螯合物连接至环状RGDfK四聚体，所述环状RGDfK四聚体以高亲和力和选择性结合在肿瘤细胞和肿瘤新血管系统上过表达的整合素α ν β 3。该项目专门设计用于检查99 mTc螯合物、PKM接头和肽多样性对肿瘤和其他器官（如肾脏和肝脏）中摄取“T0”标记的环状RGDfK四聚体的影响。这些研究的目的是使肿瘤摄取最大化，并使其他主要器官（如肝脏和肾脏）中的摄取最小化;从而改善靶-背景（T/B）比。更高的肿瘤摄取和更好的T/B比值的组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特别重要。本项目的目的是开发一种临床上有用的整合素α ν β 3靶向的99 mTc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整合素ccvp 3靶向的99 mTc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性肿瘤，而且用于监测肿瘤转移和抗血管生成治疗的疗效。整合素α ν β 3靶向的99 mTc放射性示踪剂的成功开发不仅能够在早期阶段检测乳腺癌，而且还能够监测肿瘤生长和转移，这将有助于医生（1）确定治疗方案;（2）为特定的治疗方案选择正确的患者;和（3）优化个体患者抗血管生成治疗的剂量和时间表。一旦我们能够实现本项目的目标，我们将探索所选药物在未来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avp 3过表达也已在黑素瘤、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得到证实。因此，本项目中开发的新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.