Radiolabeled RGD Peptides for Breast Cancer Imaging and Therapy

描述（申请人提供）：细胞粘附分子整合素？v？3在肿瘤血管生成和转移过程中表达上调。这种g蛋白受体在生长中的肿瘤和各种来源的肿瘤细胞的发芽内皮细胞上的独特和/或过表达，为抗血管生成和抗转移策略的应用提供了一个强大的平台。我们之前已经开发了一系列单、双和多聚RGD肽放射性示踪剂，用于肿瘤整合素表达的正电子发射断层扫描（PET）成像。特别是，四聚体和八聚体RGD肽示踪剂已经显示出非常高和持续的整合素特异性肿瘤摄取和有利的体内动力学。64Cu-和90y标记的RGD四聚体也能有效减缓乳腺癌肿瘤的生长。本提案的目的是建立一个多聚RGD肽库，我们希望从中找到高效的整合素特异性药物，用于诊断和治疗局部和转移性乳腺癌。我们的研究计划将扩大这一努力，并将重点放在以下四个方面：1)我们将筛选一些原位和自发性乳腺癌模型，以确定一个高度整合素阳性的肿瘤模型，用于RGD肽探针评估；2)我们将进行系统的构效关系（SAR）研究，以确定更有效的64Cu和86Y标记乳腺癌靶向的多聚RGD肽；3)我们将评估64Cu和86y标记的多聚RGD肽在体内可视化和量化整合素表达以及检测乳腺癌异种移植模型肺转移的能力；4)我们将测定64Cu-和90y标记的多聚RGD肽在乳腺癌原发肿瘤和肺转移模型中的内辐射剂量，并评价其治疗效果。将测试单次和多次给药的效果。该项目的成功将导致快速转化为肿瘤检测和治疗的临床试验。无创可视化和量化的能力？3整合素的表达水平将为记录肿瘤（肿瘤细胞和新生肿瘤血管）受体表达提供新的机会，更合理地选择考虑抗整合素治疗的患者，并监测整合素阳性患者的治疗效果。用治疗性同位素标记的相同配体将允许整合素阳性肿瘤的靶向内放疗。

DESCRIPTION (provided by applicant): The cell adhesion molecule integrin ?v?3 is up-regulated during tumor angiogenesis and metastasis. The unique and/or overexpression of this G-protein receptor on sprouting endothelial cells in growing tumors and on tumor cells of various origins provides a robust platform for application of anti-angiogenic and antimetastatic strategies. We have previously developed a series of mono-, di- and multimeric RGD peptide radiotracers for positron emission tomography (PET) imaging of tumor integrin expression. In particular, tetrameric and octameric RGD peptide tracers have demonstrated extraordinarily high and persistent integrin specific tumor uptake and favorable in vivo kinetics. Both 64Cu- and 90Y-labled RGD tetramers were also effective in slowing breast cancer tumor growth. The purpose of this proposal is to develop a multimeric RGD peptide library, from which we expect to identify highly effective integrin-specific agents for diagnosis and treatment of localized and metastasized breast cancer. Our research plan will extend this effort and focus on the following four areas: 1) we will screen a number of orthotopic and spontaneous breast cancer models in order to identify a highly integrin positive tumor model for RGD peptide probe evaluation; 2) we will perform a systematic structure-activity relationship (SAR) study to identify more potent multimeric RGD peptides for 64Cu and 86Y labeling for breast cancer targeting; 3) we will evaluate the capabilities of 64Cu and 86Y-labeled multimeric RGD peptides to visualize and quantify integrin expression in vivo and to detect lung metastasis in breast cancer xenograft models; 4) we will determine the internal radiation dosimetry and evaluate the treatment efficacy of 64Cu- and 90Y-labeled multimeric RGD peptides in primary tumor and lung metastasis of breast cancer models. The effect of both single dose and multiple dose administration will be tested. The success of this project will lead to rapid translation into clinical trials for tumor detection and treatment. The ability to non-invasively visualize and quantify ?v?3 integrin expression level will provide new opportunities to document tumor (tumor cells and sprouting tumor vasculature) receptor expression, more appropriately select patients considered for anti-integrin treatment and monitor treatment efficacy in integrin-positive patients. The same ligands labeled with therapeutic isotopes will allow targeted internal radiotherapy of integrin positive tumors.