Müller Martin, Altmann Annette, Sauter Max, Lindner Thomas, Jäger Dirk, Rathke Hendrik, Herold-Mende Christel, Marmé Frederik, Babich John, Mier Walter, Haberkorn Uwe
Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ) Heidelberg.
Department of Nuclear Medicine, University Hospital Heidelberg.
Nuklearmedizin. 2019 Aug;58(4):309-318. doi: 10.1055/a-0894-4127. Epub 2019 May 10.
Integrin αvβ6 shows a high expression rate in several cancer entities. As it is absent in most healthy adult tissues, it represents a promising target for tumor targeting with peptidic radiotracers. This study was performed to pave the way of the recently published αvβ6-binding peptide SFLAP3 for the clinical application in patients with pancreatic cancer.
The expression of integrin αvβ6 on several pancreatic cancer cell lines was assessed using flow cytometry and cell binding assays. The affinity was determined in competition binding assays followed by internalization and efflux studies. To increase the affinity, the binding sequence was modified and trimerization of the SFLAP3 peptide was achieved by oxime ligation. PET and biodistribution assays were conducted in Capan-2 tumor bearing mice. Finally, a first pancreatic tumor patient was examined with Ga-DOTA-SFLAP3.
Flow cytometric analysis and IN VITRO: cell binding revealed high expression of integrin αvβ6 on most pancreatic tumor cell lines. Modification of SFLAP3 led to compounds with improved IN VITRO: binding properties. Unfortunately, these superior properties could not be transferred into improved pharmacokinetics. Consequently, the first pancreatic tumor patient was examined with Ga-DOTA-SFLAP3. The PET revealed specific accumulation (with SUV values in the metastases ranging from 5 to 10) and a long retention in the tumor.
SFLAP3 showed high affinity to integrin αvβ6 on pancreatic cancer cell lines. The IN VITRO: performance could be confirmed in tumor bearing mice and by PET imaging. These data suggest that DOTA-SFLAP3 is a promising tracer for targeting αvβ6-expressing pancreatic tumors.
整合素αvβ6在多种癌症实体中显示出高表达率。由于其在大多数健康成人组织中不存在，它是肽类放射性示踪剂肿瘤靶向治疗的一个有前景的靶点。本研究旨在为最近发表的αvβ6结合肽SFLAP3在胰腺癌患者中的临床应用铺平道路。
使用流式细胞术和细胞结合试验评估几种胰腺癌细胞系上整合素αvβ6的表达。通过竞争结合试验确定亲和力，随后进行内化和外排研究。为了提高亲和力，对结合序列进行了修饰，并通过肟连接实现了SFLAP3肽的三聚化。在荷Capan-2肿瘤的小鼠中进行PET和生物分布试验。最后，对一名胰腺肿瘤患者进行了Ga-DOTA-SFLAP3检查。
流式细胞术分析和体外细胞结合显示大多数胰腺肿瘤细胞系上整合素αvβ6高表达。SFLAP3的修饰导致化合物具有改善的体外结合特性。不幸的是，这些优异的特性未能转化为改善的药代动力学。因此，对第一名胰腺肿瘤患者进行了Ga-DOTA-SFLAP3检查。PET显示有特异性聚集（转移灶的SUV值范围为5至10）且在肿瘤中滞留时间长。
SFLAP3对胰腺癌细胞系上的整合素αvβ6显示出高亲和力。体外性能在荷瘤小鼠中以及通过PET成像得到了证实。这些数据表明DOTA-SFLAP3是靶向表达αvβ6的胰腺肿瘤的一种有前景的示踪剂。
