Cho Eun-Ha, Lim Jae Cheong, Lee So-Young, Jung Sung-Hee
RI Research Division, Research Reactor Utilization Department, Korea Atomic Energy Research Institute (KAERI), Daejeon 305-353, Republic of Korea.
RI Research Division, Research Reactor Utilization Department, Korea Atomic Energy Research Institute (KAERI), Daejeon 305-353, Republic of Korea.
J Pharmacol Sci. 2016 Jul;131(3):209-14. doi: 10.1016/j.jphs.2016.06.006. Epub 2016 Jun 30.
The cholecystokinin (CCK) receptor is known as a receptor that is overexpressed in many human tumors. The present study was designed to investigate the targeting ability of cyclic CCK analogue in AR42J pancreatic cells. The CCK analogues, DOTA-K(glucose)-Gly-Trp-Nle-Asp-Phe (DOTA-glucose-CCK) and DOTA-Nle-cyclo(Glu-Trp-Nle-Asp-Phe-Lys-NH2) (DOTA-[Nle]-cCCK), were synthesized and radiolabeled with (177)Lu, and competitive binding was evaluated. The binding appearance of synthesized peptide with AR42J cells was evaluated by confocal microscopy. And bio-distribution was performed in AR42J xenografted mice. Synthesized peptides were prepared by a solid phase synthesis method, and their purity was over 98%. DOTA is the chelating agent for (177)Lu-labeling, in which the peptides were radiolabeled with (177)Lu by a high radiolabeling yield. A competitive displacement of (125)I-CCK8 on the AR42J cells revealed that the 50% inhibitory concentration value (IC50) was 12.3 nM of DOTA-glucose-CCK and 1.7 nM of DOTA-[Nle]-cCCK. Radio-labeled peptides were accumulated in AR42J tumor in vivo, and %ID/g of the tumor was 0.4 and 0.9 at 2 h p.i. It was concluded that (177)Lu-DOTA-[Nle]-cCCK has higher binding affinity than (177)Lu-DOTA-glucose-CCK and can be a potential candidate as a targeting modality for a CCK receptor over-expressing tumors.
胆囊收缩素（CCK）受体是一种在许多人类肿瘤中过度表达的受体。本研究旨在研究环状CCK类似物在AR42J胰腺细胞中的靶向能力。合成了CCK类似物DOTA-K(葡萄糖)-Gly-Trp-Nle-Asp-Phe（DOTA-葡萄糖-CCK）和DOTA-Nle-环（Glu-Trp-Nle-Asp-Phe-Lys-NH2）（DOTA-[Nle]-cCCK），并用（177）Lu进行放射性标记，并评估了竞争性结合。通过共聚焦显微镜评估合成肽与AR42J细胞的结合情况。并在AR42J异种移植小鼠中进行了生物分布研究。合成肽采用固相合成法制备，纯度超过98%。DOTA是用于（177）Lu标记的螯合剂，其中肽以高放射性标记产率用（177）Lu进行放射性标记。AR42J细胞上（125）I-CCK8的竞争性置换显示，DOTA-葡萄糖-CCK的50%抑制浓度值（IC50）为12.3 nM，DOTA-[Nle]-cCCK为1.7 nM。放射性标记的肽在体内积聚在AR42J肿瘤中，注射后2小时肿瘤的%ID/g分别为0.4和0.9。得出结论，（177）Lu-DOTA-[Nle]-cCCK比（177）Lu-DOTA-葡萄糖-CCK具有更高的结合亲和力，并且可以作为CCK受体过表达肿瘤靶向治疗的潜在候选物。
