A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts.
A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts.
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靶向癌症相关成纤维细胞的一种肿瘤模仿方法。
DOI：
10.2967/jnumed.118.210435
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Haberkorn U
中科院分区：
文献类型：
--
作者：
Loktev A;Lindner T;Mier W;Debus J;Altmann A;Jäger D;Giesel F;Kratochwil C;Barthe P;Roumestand C;Haberkorn U
肿瘤间质占肿瘤质量的很大一部分，代表了用于递送诊断和治疗化合物的有吸引力的靶标。在这里，重点是基质细胞的亚群，称为癌症相关的成纤维细胞，存在于90%以上的上皮癌，包括胰腺癌，结肠癌和乳腺癌。癌症相关的成纤维细胞具有成纤维细胞活化蛋白（FAP）的高表达，其在成人正常组织中检测不到，但与癌症患者的不良预后相关。研究方法：我们开发了一种碘化和DOTA偶联放射性示踪剂的基础上FAP特异性酶抑制剂（FAPI），并评估他们在体外使用摄取，竞争和外排研究以及共聚焦显微镜的荧光标记的变体。此外，我们对荷瘤动物进行了成像和生物分布研究。最后，通过用68 Ga标记的FAPI对患者进行成像来实现概念验证。结果：两种FAPIs在体内外均表现出高度的特异性、亲和性和快速内化到表达FAP的细胞中。对荷瘤小鼠和第一批癌症患者的生物分布研究表明，肿瘤内对示踪剂的摄取较高，身体清除较快，从而产生高对比度图像，健康组织的辐射暴露可忽略不计。在局部晚期肺腺癌患者中，与常用的放射性示踪剂18 F-FDG的比较显示，新的FAP配体明显优于上级。结论：放射性标记的FAPI允许在具有高基质含量的肿瘤中以非常高的对比度快速成像，因此可以用作泛肿瘤剂。这些分子与DOTA或其他螯合剂的偶联允许不仅用68 Ga标记，而且用治疗性同位素如177 Lu或90 Y标记。
The tumor stroma, which accounts for a large part of the tumor mass, represents an attractive target for the delivery of diagnostic and therapeutic compounds. Here, the focus is notably on a subpopulation of stromal cells, known as cancer-associated fibroblasts, which are present in more than 90% of epithelial carcinomas, including pancreatic, colon, and breast cancer. Cancer-associated fibroblasts feature high expression of fibroblast activation protein (FAP), which is not detectable in adult normal tissue but is associated with a poor prognosis in cancer patients. Methods: We developed an iodinated and a DOTA-coupled radiotracer based on a FAP-specific enzyme inhibitor (FAPI) and evaluated them in vitro using uptake, competition, and efflux studies as well as confocal microscopy of a fluorescence-labeled variant. Furthermore, we performed imaging and biodistribution studies on tumor-bearing animals. Finally, proof of concept was realized by imaging patients with 68Ga-labeled FAPI. Results: Both FAPIs showed high specificity, affinity, and rapid internalization into FAP-expressing cells in vitro and in vivo. Biodistribution studies on tumor-bearing mice and on the first cancer patients demonstrated high intratumoral uptake of the tracer and fast body clearance, resulting in high-contrast images and negligible exposure of healthy tissue to radiation. A comparison with the commonly used radiotracer 18F-FDG in a patient with locally advanced lung adenocarcinoma revealed that the new FAP ligand was clearly superior. Conclusion: Radiolabeled FAPIs allow fast imaging with very high contrast in tumors having a high stromal content and may therefore serve as pantumor agents. Coupling of these molecules to DOTA or other chelators allows labeling not only with 68Ga but also with therapeutic isotopes such as 177Lu or 90Y.
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影响因子：
5.5
作者：
Kapoor, V;McCook, BM;Torok, FS
通讯作者：
Torok, FS
影响因子：
9.3
作者：
van der Geest, Tessa;Laverman, Peter;Boerman, Otto C.
通讯作者：
Boerman, Otto C.
影响因子：
5
作者：
Tillmanns, Jochen;Hoffmann, Daniel;Bauersachs, Johann
通讯作者：
Bauersachs, Johann
影响因子：
5.4
作者：
Keane, Fiona M.;Nadvi, Naveed A.;Gorrell, Mark D.
通讯作者：
Gorrell, Mark D.
影响因子：
45.3
作者：
WELT, S;DIVGI, CR;RETTIG, WJ
通讯作者：
RETTIG, WJ