Claudin-4-targeted optical imaging detects pancreatic cancer and its precursor lesions
Claudin-4-targeted optical imaging detects pancreatic cancer and its precursor lesions
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DOI：
10.1136/gutjnl-2012-302577
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发表时间：
2013-07-01
期刊：
影响因子：
24.5
通讯作者：
Michl, Patrick
中科院分区：
文献类型：
--
作者：
Neesse, Albrecht;Hahnenkamp, Anke;Michl, Patrick
目的基于特定分子靶点的新型成像方法可以检测已确诊的肿瘤及其前体病变，这在癌症医学中是非常需要的。以前，我们确定了紧密连接的组成部分claudin-4，在包括胰腺癌在内的各种胃肠道肿瘤中高度表达。在这里，我们调查潜在的靶向claudin-4与天然存在的配体可视化胰腺癌及其前体病变在体外和体内通过近红外成像approaches.Design一个无毒的C-末端片段的claudin-4配体产气荚膜梭菌肠毒素（C-CPE）标记的花青染料（Cy5.5）。在体外对claudin-4阳性和阴性细胞以及在体内对肿瘤异种移植物分析光学示踪剂的结合。此外，胰腺上皮内瘤变（PanIN）和胰腺癌的两种基因工程小鼠模型用于体内验证。结果在体外实验中，肽-染料偶联物与claudin-4阳性的CAPAN 1细胞表现出较高的结合亲和力，而claudin-4阴性的HT 1080细胞则表现出很低的荧光或无荧光。在体内，claudin-4阳性肿瘤异种移植物、内源性胰腺肿瘤、肝转移以及预侵袭PanIN病变，与claudin-4阴性的异种移植物和正常胰腺组织相比，在注射后48 h内通过FRI和FMT显示出显著更高的平均荧光染料浓度。claudin-4阳性鼠胰腺肿瘤及其前体病变的侵入性可视化，代表了早期诊断成像的有希望的方式。
Objectives Novel imaging methods based on specific molecular targets to detect both established neoplasms and their precursor lesions are highly desirable in cancer medicine. Previously, we identified claudin-4, an integral constituent of tight junctions, as highly expressed in various gastrointestinal tumours including pancreatic cancer. Here, we investigate the potential of targeting claudin-4 with a naturally occurring ligand to visualise pancreatic cancer and its precursor lesions in vitro and in vivo by near-infrared imaging approaches.Design A non-toxic C-terminal fragment of the claudin-4 ligand Clostridium perfringens enterotoxin (C-CPE) was labelled with a cyanine dye (Cy5.5). Binding of the optical tracer was analysed on claudin-4 positive and negative cells in vitro, and tumour xenografts in vivo. In addition, two genetically engineered mouse models for pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer were used for in vivo validation. Optical imaging studies were conducted using 2D planar fluorescence reflectance imaging (FRI) technology and 3D fluorescence-mediated tomography (FMT).Results In vitro, the peptide-dye conjugate showed high binding affinity to claudin-4 positive CAPAN1 cells, while claudin-4 negative HT1080 cells revealed little or no fluorescence. In vivo, claudin-4 positive tumour xenografts, endogenous pancreatic tumours, hepatic metastases, as well as preinvasive PanIN lesions, were visualised by FRI and FMT up to 48 h after injection showing a significantly higher average of fluorochrome concentration as compared with claudin-4 negative xenografts and normal pancreatic tissue.Conclusions C-CPE-Cy5.5 combined with novel optical imaging methods enables non-invasive visualisation of claudin-4 positive murine pancreatic tumours and their precursor lesions, representing a promising modality for early diagnostic imaging.