Targeting of alpha v beta 6 integrin in oral cancer

α v beta 6 整合素在口腔癌中的靶向作用

• 批准号: 7283144
• 负责人: JULIE L SUTCLIFFE
• 金额: $ 41.41万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-10 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7283144
• 关键词: Targeting; alpha; beta; integrin; oral

DESCRIPTION (provided by applicant): The goal is to develop novel ava6-targeting peptides that selectively locate to ava6 positive tumors in vivo. Oral squamous cell carcinoma (SCC) accounts for 5.5% of all human malignancies worldwide. Primary treatment is radical often mutilating surgery. Since mortality from oral SCC has remained at greater than 50% for decades, novel strategies to limit its recurrence and invasive-potential are desperately needed. We believe that the cell surface expressed integrin ava6 offers and excellent target for both imaging (early detection) and therapy of oral cancer. Novel ava6-targeting peptides will be identified using the "One-Bead-One-Compound" random and rational combinatorial cyclic-peptide libraries. 4-[19F]-fluorobenzoyl will be incorporated into the peptide library as an approach to transition the identified sequences into a radiolabeled peptide for imaging using MicroPET II and fluorine-18 chemistry. The peptide libraries will be screened against immobilized integrins as well as cell lines to establish their selectivity and specificity. Peptide radiolabeling will be performed using a solid-phase approach. The peptidyl resin will be radiolabeled using 4-[18F]fluorobenzoic acid. This method is highly flexible, is rapid and amenable to automation. Once successful candidates have been identified as highly selective towards ava6 high resolution screening in mice in vivo using MicroPET II will be performed. By the end of year 2 it is anticipated that several potential ava6-targetingpeptides will be identified. The second part of this proposal we will investigate the ava6-targetingpeptides in vivo in mice using the small animal scanner MicroPET II. Standard immunohistochemistry and phosphor imaging technologies will be used to correlate radiotracer distribution in tumors with integrin expression. In vitro and structural activity experiments will be performed to explain sequence specificity and affinity.

描述（由申请人提供）： 目的是开发新的ava 6靶向肽，其选择性地定位于体内ava 6阳性肿瘤。口腔鳞状细胞癌（SCC）占全球所有人类恶性肿瘤的5.5%。主要治疗是根治性的，通常是毁损性手术。由于口腔鳞状细胞癌的死亡率几十年来一直保持在50%以上，因此迫切需要限制其复发和侵袭潜力的新策略。我们认为，细胞表面表达的整合素ava 6为口腔癌的早期诊断和治疗提供了一个很好的靶点。 新的ava 6靶向肽将使用“一珠一化合物”随机和合理的组合环状肽文库来鉴定。将4-[19 F]-氟苯甲酰基掺入肽文库中，作为将鉴定的序列转变为放射性标记肽的方法，用于使用MicroPET II和氟-18化学进行成像。将针对固定的整联蛋白以及细胞系筛选肽文库以确定其选择性和特异性。将使用固相方法进行肽放射性标记。肽基树脂将使用4-[18 F]氟苯甲酸进行放射性标记。这种方法是高度灵活的，是快速的和易于自动化。一旦成功的候选物被鉴定为对ava 6具有高度选择性，将使用MicroPET II在小鼠体内进行高分辨率筛选。到第二年年底，预计将鉴定出几种潜在的ava 6靶向肽。第二部分我们将利用MicroPET II小动物扫描仪在小鼠体内研究ava 6靶向肽.标准的免疫组织化学和荧光成像技术将用于关联肿瘤中放射性示踪剂分布与整合素表达。将进行体外和结构活性实验以解释序列特异性和亲和力。