Diagnostic & targeting reagents for lung cancer

描述（由申请人提供）：肺癌是美国男性和女性最大的癌症杀手。肺癌细胞表面受体特异性配体的发现将影响临床问题，包括功能诊断和细胞特异性药物递送。我们的总体目标是产生一组细胞特异性分子，这些分子可用于对肿瘤类型进行分类，然后用于靶向递送治疗剂。利用噬菌体展示技术，我的实验室开发了平台方法来分离结合并介导特定细胞摄取的肽。我们已经成功鉴定了30种不同细胞类型的细胞特异性靶向肽，包括7种癌细胞系。分离的肽显示出显著的细胞特异性，即使在相似的细胞中，并且能够区分正常细胞和癌细胞以及不同的肺肿瘤细胞。这种高分辨力表明，可以鉴定出选择性结合不同肿瘤类型的肽，即使是那些具有相似分类的肿瘤。我们建议分离16种不同肺癌细胞系的细胞靶向肽，然后利用这些肽作为诊断和肿瘤特异性递送试剂。将测定这些肽的亲和力和细胞特异性。将努力将靶向噬菌体翻译成小分子靶向试剂，并且这些肽支架将用于在体外和体内将治疗剂递送至肿瘤细胞。这些肽所显示的细胞特异性表明它们识别不同的细胞表面受体，这些受体可能作为肺癌的生物标志物具有临床价值。因此，我们将利用这些肽来鉴定细胞的这些独特的细胞特征。然后我们将通过免疫组织化学方法探索该受体在一组人肺癌组织中的表达模式，并将其与匹配的正常组织中的表达水平进行比较。实现我们的目标将影响肺癌的诊断和治疗，以及解决靶向药物输送领域的一般挑战。

DESCRIPTION (provided by applicant): Lung cancer is the largest cancer killer of both men and women in the United States. Discovery of ligands specific to receptor(s) on a surface of a lung cancer cell will impact clinical issues including functional diagnosis and cell-specific drug delivery. Our overall goal is to generate a panel of cell specific molecules that could be used to classify tumor types and then be exploited for targeted delivery of therapeutics. Using phage display technologies, my laboratory has developed platform methodologies to isolate peptides that bind to and mediate uptake into specific cells. We have successfully identified cell-specific targeting peptides for 30 different cell types, including 7 cancer cell lines. The isolated peptides display remarkable cell-specificities, even among similar cells, and are able to discriminate between normal and cancerous cells as well as different lung tumor cells. This high discriminating power suggests that peptides could be identified that selectively bind to different tumor types, even those with similar classifications. We propose to isolate cell-targeting peptides for 16 different lung cancer lines and then utilize these peptides as diagnostic and tumor specific delivery reagents. These peptides will be assayed for affinity and cell-specificity. Efforts will be directed towards translating the targeting phage into small molecule targeting reagents and these peptide scaffolds will be utilized to deliver therapeutics to tumor cells both in vitro and in vivo. The cell specificity demonstrated by these peptides indicates that they are recognizing distinct cell surface receptors that may be of clinical value as biomarkers for lung cancer. Thus, we will utilize the peptides to identify the cellular these unique cellular features. We will then explore the expression patterns of the receptor on a panel of human lung cancer tissues by immunohistochemistry and compare this with the expression level in matched normal tissues. Achieving our goals will impact lung cancer diagnosis and treatment as well as solving general challenges in the field of targeted drug delivery.