Targeting of alpha v beta 6 integrin in oral cancer

描述(由申请人提供)： 我们的目标是开发新的ava6靶向多肽，选择性地定位于体内ava6阳性肿瘤。口腔鳞状细胞癌占全球所有人类恶性肿瘤的5.5%。主要的治疗方法是根治性的，通常是残缺性的手术。由于几十年来口腔鳞状细胞癌的死亡率一直保持在50%以上，迫切需要新的策略来限制其复发和侵袭潜力。我们认为，细胞表面表达的整合素ava6为口腔癌的成像(早期发现)和治疗提供了良好的靶点。 新的ava6靶向多肽将使用“一珠一化合物”随机和合理的组合环肽文库进行鉴定。4-[19F]-氟苯甲酰基将被加入到多肽文库中，作为一种将识别的序列转换为放射性标记多肽的方法，用于使用microPET II和氟-18化学进行成像。将针对固定化整合素和细胞系对多肽库进行筛选，以确定它们的选择性和特异性。多肽放射性标记将使用固相方法进行。肽树脂将用4-[18F]氟苯甲酸进行放射性标记。该方法具有灵活性高、速度快、易于自动化等特点。一旦成功的候选者被确定为对ava6具有高度选择性，将使用microPET II在小鼠体内进行高分辨率筛查。到第二年年底，预计将识别出几个潜在的ava6靶向多肽。在这项建议的第二部分，我们将使用小型动物扫描仪microPET II在小鼠体内研究ava6靶向多肽。标准的免疫组织化学和荧光成像技术将用于将放射性示踪剂在肿瘤中的分布与整合素的表达联系起来。将进行体外和结构活性实验，以解释序列特异性和亲和力。

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.