Radiolabeled RGD Peptides for Breast Cancer Imaging and Therapy

用于乳腺癌成像和治疗的放射性标记 RGD 肽

• 批准号: 7499113
• 负责人: XIAOYUAN CHEN
• 金额: $ 23.81万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7499113
• 关键词: Affinity; Aftercare; Area; Autoradiography; Avidity; Binding; Biodistribution; Bioluminescence; Breast Cancer Cell; Breast Cancer Model; Cancer cell line; Cell Adhesion Molecules; Cells; Classification; Clinical Trials; Deposition; Detection; Diagnosis; Dose; Drug Kinetics; Endothelial Cells; Evaluation; Excretory function; Firefly Luciferases; GTP-Binding Proteins; Growth; Image; Immunohistochemistry; In Vitro; Integrin Binding; Integrins; Isotopes; Kinetics; Label; Lead; Ligands; Localized; Lung; Mammary Neoplasms; Measures; Metabolic; Metabolism; Metastatic Lesion; Modeling; Monitor; Mono-S; Mus; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Numbers; Patients; Peptide Library; Peptide Receptor; Positron-Emission Tomography; Primary Neoplasm; Protein Overexpression; Purpose; RGD (sequence); Radiation therapy; Radiolabeled; Radiometry; Radiopharmaceuticals; Research; Research Personnel; Research Project Grants; Route; Series; Source; Specificity; Staining method; Stains; Structure-Activity Relationship; Testing; Therapeutic; Tissues; Tracer; Transgenic Mice; Translations; Treatment Efficacy; Tumor Angiogenesis; Tumorigenicity; Variant; Weight; Work; Xenograft Model; base; cancer imaging; density; dimer; dosimetry; hydrophilicity; immunopathology; in vivo; internal radiation; lung lobe; lymph nodes; malignant breast neoplasm; molecular size; monomer; neoplastic cell; programs; radiation effect; radioligand; radiotracer; receptor; receptor binding; receptor expression; research study; success; tumor; tumor growth; tumor xenograft; uptake

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.

描述（由申请人提供）：细胞粘附分子整合素？V？3在肿瘤血管生成和转移期间被上调。该G蛋白受体在生长肿瘤和各种​​起源的肿瘤细胞中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性策略的应用提供了强大的平台。我们以前已经开发了一系列单，DI-和多聚体RGD肽放射性示例，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肽示踪剂表现出非常高的和持续的整联蛋白特异性肿瘤的摄取，并且在体内动力学中有利。 64CU-和90Y的RGD四聚体也有效地减慢了乳腺癌肿瘤的生长。该提案的目的是开发多聚体RGD肽库，我们希望从中确定高效的整合素特异性药物来诊断和治疗局部和转移的乳腺癌。我们的研究计划将延长这项工作，并关注以下四个领域：1）我们将筛选许多原位和自发的乳腺癌模型，以确定用于RGD肽探针评估的高度整合蛋白阳性肿瘤模型； 2）我们将进行系统的结构活性关系（SAR）研究，以确定64CU和86Y标记的更有效的多聚体RGD肽用于乳腺癌的靶向； 3）我们将评估64CU和86Y标记的多聚体RGD肽的能力，以在体内可视化和量化整联蛋白的表达并检测乳腺癌异种移植模型中的肺转移； 4）我们将确定内部辐射剂量测定法，并评估乳腺癌模型原发性肿瘤和肺转移中64CU和90年标记的多聚体RGD肽的治疗功效。单剂量和多剂量给药的效果将被测试。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为记录肿瘤细胞（肿瘤细胞和发芽肿瘤脉管系统）受体表达的新机会，更适当选择的患者被认为接受抗整合蛋白治疗并监测整联蛋白阳性患者的治疗功效。用治疗同位素标记的相同配体将允许靶向内整联蛋白阳性肿瘤的内部放射疗法。