IMAGING EGFR WITH MICRO-PET AND I-124

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 非侵入性成像在诊断和管理肿瘤患者中起着至关重要的作用。虽然目前的成像评估最常用的是计算机断层扫描（CT）和正电子发射断层扫描（PET）与氟脱氧葡萄糖（FDG），有一个更准确的探针对肿瘤特异性的目标是需要的。单克隆抗体（mAb）具有高特异性，但太大而不能快速浸润肿瘤。为了开发肺癌的成像探针，我们已经分离出新型单链抗体片段，其大小为mAb的十分之一，其结合肿瘤表面上的过度表达蛋白，表皮生长因子受体（EGFR）。这些抗体片段称为VHH结构域，来源于骆驼和美洲驼的仅重链IgG的可变结构域。它们非常稳定，显示出抗体样特异性，并且由于它们的大小（~16 kDa），预测VHH结构域比mAb更快地浸润肿瘤。我们选择EGFR作为分子成像靶点，因为众所周知，EGFR在许多癌症（包括肺癌）中含量丰富。 目前的提议将继续开发这些探针，然后在人类受试者成像之前在动物模型中进行微PET成像。我们将分离几个高亲和力结合VHH分子，然后用放射性标签标记它们。然后，我们将使用micro-PET系统对携带EGFR过表达肿瘤的无胸腺小鼠进行成像。摄取量将与EGFR的肿瘤细胞水平相关。这一系列实验对于开发新型成像探针至关重要，这将转化为诊断和跟踪患者肿瘤的更准确方法。 参考文献： Gottlin EB，Guan XR，Pegram C，Cannedy A，Campa MJ，Patz Jr EF. 具有诊断或治疗潜力的新型EGFR定向VHH结构域的分离。J Biomolecular Screening 2009;14：77-85. Shankar LK和Sullivan DC。肺癌的功能成像。临床肿瘤学杂志2005; 23：3203-3211。 Eary JF.核医学在癌症诊断中的应用柳叶刀1999; 354：853-857.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Non-invasive imaging plays an essential role in diagnosing and managing oncology patients. While current imaging evaluation most commonly uses computed tomography (CT) and positron emission tomography (PET) with fluro-deoxy-glucose (FDG), there is a need for more accurate probes against tumor-specific targets. Monoclonal antibodies (mAbs) have high specificity but are too large to rapidly infiltrate tumors. In order to develop imaging probes for lung cancer, we have isolated novel single chain antibody fragments one-tenth the size of a mAb that bind to an over-expresssed protein on the tumor surface, epidermal growth factor receptor (EGFR). These antibody fragments, called VHH domains, are derived from the variable domain of the heavy-chain-only IgG of camels and llamas. They are extraordinarily stable, display antibody-like specificities and, because of their size (~16 kDa), VHH domains are predicted to infiltrate tumors much faster than mAbs. We chose EGFR as a molecular imaging target because it is well-known to be abundant in many cancers, including lung cancer. The current proposal will continue to develop these probes and then perform micro-PET imaging in an animal model before imaging in human subjects. We will isolated several high affinity binding VHH molecules, and then label them with a radioactive tag. We will then image athymic mice bearing an EGFR over-expressing tumor using the micro-PET system. The amount of uptake will be correlated with tumor cell levels of EGFR. This series of experiments are essential for developing novel imaging probes, which should translate into a more accurate method for diagnosing and following tumors in patients. References: Gottlin EB, Guan XR, Pegram C, Cannedy A,Campa MJ, Patz Jr EF. Isolation of novel EGFR directed VHH domains with diagnostic or therapeutic potential. J Biomolecular Screening 2009;14:77-85. Shankar LK and Sullivan DC. Functional imaging in lung cancer. J Clin Oncol 2005; 23: 3203-3211. Eary JF. Nuclear medicine in cancer diagnosis. Lancet 1999; 354: 853-857.