Imaging Alpha (v)beta(3) Integrin Expression

Alpha (v)beta(3) 整合素表达成像

• 批准号: 7140095
• 负责人: XIAOYUAN CHEN
• 金额: $ 16.38万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140095
• 关键词: athymic mouse; autoradiography; bioimaging /biomedical imaging; breast neoplasms; chelating agents; copper; diagnosis design /evaluation; diagnostic tests; disease /disorder model; gene expression; immunocytochemistry; inhibitor /antagonist; integrins; metastasis; molecular /cellular imaging; neoplasm /cancer diagnosis; neoplastic cell; neoplastic process; pharmacokinetics; positron emission tomography; protein quantitation /detection; radionuclides; radiotracer; receptor binding; technology /technique development

DESCRIPTION (provided by applicant): Overexpression of alpha(v)beta(3) integrin on the surfaces of tumor cells and activated endothelial cells as compared to normal cells and rest endothelial cells implicates the application of radiolabeled alpha(v)beta(3) integrin antagonist for imaging of alpha(v)beta(3) expression levels in alpha(v)beta(3) positive tumors. The goal of this proposal is to develop copper-64 (t1/2 = 12.7 h) labeled RGD peptide antagonists of alpha(v)beta(3) integrin for breast cancer targeting by means of positron emission tomography (PET). We hypothesize that conjugation and radiolabeling of RGD peptides will have significant effect on the receptor binding affinity and specificity, as well as the in vivo pharmacokinetics of these radiotracers. To make the tracers clinically applicable for patient segmentation based upon alpha(v)beta(3) integrin expression levels, systematic studies have to be performed to optimize the tracer in such a way that the tracer will have fast and high yield radiolabeling, in vivo stability against transchelation, and high receptor binding affinity and specificity. The radiotracer should also be designed to have satisfactory in vivo pharmacokinetics for high quality imaging: high tumor-to-normal tissue ratio, fast circulation clearance, low kidney uptake and fast renal clearance, as well as avoiding hepatobiliary excretion. The research proposed here is to: 1) develop and optimize copper-64 labeled RGD peptides for breast cancer tumor targeting; and 2) correlate the magnitude of tumor uptake with tumor integrin density levels in preclinical animal models. The success of this research will facilitate the rapid translation of this laboratory work into clinical applications, since the features of small animal PET imaging studies closely reflect the settings of a clinical PET study for human beings. We anticipate that noninvasive serial studies of alpha(v)beta(3) expression and functional activity using PET will become an important tool to evaluate the role of alpha(v)beta(3) integrin during tumor progression and metastasis.

描述（由申请人提供）：与正常细胞和其余内皮细胞相比，α（v）β（3）整联蛋白在肿瘤细胞和活化内皮细胞表面上的过表达暗示放射性标记的α（v）β（3）整联蛋白拮抗剂用于α（v）β（3）阳性肿瘤中α（v）β（3）表达水平成像的应用。本提案的目标是通过正电子发射断层扫描（PET）开发用于乳腺癌靶向的α（v）β（3）整联蛋白的铜-64（t1/2 = 12.7 h）标记的RGD肽拮抗剂。我们推测，共轭和放射性标记的RGD肽将有显着的影响受体结合亲和力和特异性，以及在体内的这些放射性示踪剂的药代动力学。为了使示踪剂在临床上适用于基于α（v）β（3）整联蛋白表达水平的患者分割，必须进行系统研究以优化示踪剂，使得示踪剂将具有快速和高产率的放射性标记、针对螯合转移的体内稳定性以及高受体结合亲和力和特异性。放射性示踪剂还应设计成具有令人满意的体内药代动力学以用于高质量成像：高肿瘤与正常组织比、快速循环清除、低肾摄取和快速肾清除，以及避免肝胆排泄。本文提出的研究是：1）开发和优化用于乳腺癌肿瘤靶向的铜-64标记的RGD肽; 2）在临床前动物模型中将肿瘤摄取的大小与肿瘤整合素密度水平相关联。这项研究的成功将促进这项实验室工作迅速转化为临床应用，因为小动物PET成像研究的特点密切反映了人类临床PET研究的设置。我们预计，使用PET对α（v）β（3）表达和功能活性的非侵入性系列研究将成为评估α（v）β（3）整合素在肿瘤进展和转移中作用的重要工具。