Radiolabeled RGD Peptides for Breast Cancer Imaging and Therapy

性状（由申请人提供）：细胞粘附分子整联蛋白？v？3在肿瘤血管生成和转移过程中上调。在生长的肿瘤中发芽的内皮细胞上和在各种来源的肿瘤细胞上这种G蛋白受体的独特和/或过表达为应用抗血管生成和抗转移策略提供了一个强大的平台。我们以前已经开发了一系列的单，双和多聚体的RGD肽放射性示踪剂的正电子发射断层扫描（PET）成像肿瘤整合素的表达。特别是，四聚体和八聚体的RGD肽示踪剂已经证明了非常高的和持久的整合素特异性肿瘤摄取和有利的体内动力学。64 Cu和90 Y标记的RGD四聚体也有效减缓乳腺癌肿瘤生长。本提案的目的是开发一个多聚体的RGD肽库，我们期望从中确定高度有效的整合素特异性药物的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，并重点关注以下四个领域：1）我们将筛选许多原位和自发性乳腺癌模型，以鉴定高度整合素阳性的肿瘤模型用于RGD肽探针评估; 2）我们将进行系统的结构活性关系（SAR）研究，以鉴定更有效的多聚体RGD肽，用于64 Cu和86 Y标记乳腺癌靶向; 3）我们将评估64 Cu和86 Y标记的多聚体RGD肽在体内可视化和定量整联蛋白表达以及检测乳腺癌异种移植模型中的肺转移的能力; 4）我们将确定内部辐射剂量并评估64 Cu和90 Y标记的多聚体RGD肽在乳腺癌模型的原发性肿瘤和肺转移中的治疗功效。将检测单次给药和多次给药的效果。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。非侵入性可视化和量化的能力？v？3整联蛋白表达水平将提供新的机会来记录肿瘤（肿瘤细胞和出芽的肿瘤脉管系统）受体表达，更适当地选择考虑抗整联蛋白治疗的患者并监测整联蛋白阳性患者的治疗功效。用治疗性同位素标记的相同配体将允许整联蛋白阳性肿瘤的靶向内部放射治疗。

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.