Radiolabeled RGD Peptides for Breast Cancer Imaging and Therapy

描述(申请人提供)：细胞黏附分子整合素？V？3在肿瘤血管生成和转移过程中上调。这种G蛋白受体在生长中的肿瘤中的萌发内皮细胞和不同来源的肿瘤细胞上的独特和/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、双和多聚体RGD多肽放射性示踪剂，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多肽示踪剂已经显示出非常高的和持续的整合素特异性肿瘤摄取和良好的体内动力学。64Cu和90Y标记的RGD四聚体在减缓乳腺癌肿瘤生长方面也是有效的。这项建议的目的是开发一个多聚体RGD多肽文库，从中我们有望找到高效的整合素特异性药物来诊断和治疗局部和转移性乳腺癌。我们的研究计划将集中在以下四个方面：1)我们将筛选一些原位和自发性乳腺癌模型，以确定用于RGD多肽探针评估的高整合素阳性肿瘤模型；2)我们将进行系统的构效关系(SAR)研究，以寻找更有效的针对乳腺癌64Cu和86Y标记的多聚体RGD多肽；3)我们将评估64Cu和86Y标记的多聚体RGD多肽在体内可视化和定量整合素表达以及检测乳腺癌移植瘤肺转移的能力；4)建立乳腺癌原发肿瘤和肺转移模型，测定内照射剂量，评价64Cu和90Y标记的多聚体RGD多肽对乳腺癌模型的治疗效果。将测试单剂量和多剂量给药的效果。该项目的成功将导致肿瘤检测和治疗的临床试验迅速转化为临床试验。非侵入性可视化和定量V？3整合素表达水平的能力将为记录肿瘤(肿瘤细胞和萌发的肿瘤血管)受体表达，更恰当地选择考虑进行抗整合素治疗的患者和监测整合素阳性患者的治疗效果提供新的机会。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定向内放射治疗。

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.