Targeting of a CCK2 receptor splice variant with 111In-labelled cholecystokinin-8 (CCK8) and 111In-labelled minigastrin
Targeting of a CCK2 receptor splice variant with 111In-labelled cholecystokinin-8 (CCK8) and 111In-labelled minigastrin
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DOI：
10.1007/s00259-007-0604-1
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发表时间：
2008-02-01
影响因子：
9.1
通讯作者：
Boerman, Otto C.
中科院分区：
文献类型：
--
作者：
Laverman, Peter;Roosenburg, Susan;Boerman, Otto C.
目的放射性标记胆囊收缩素（CCK）和胃泌素衍生肽可用于肽受体放射性核素治疗（PRRT）。最近，CCK2R的一个剪接变体版本已被确定，命名为CCK2i4svR。该受体的组成表达已在人类结直肠癌和胰腺癌中得到证实，但在正常组织中没有。到目前为止，还没有证据表明放射性标记肽是否能在体内靶向CCK2i4svR。在本文中，我们研究了硫酸酸化In-111标记的泛cckr结合肽DOTA-CCK8 （sCCK8）和CCK2R选择性肽[In-111]DOTA-minigastrin （MG0）靶向CCK2i4svR的潜力。材料和方法采用稳定转染表达CCK2R或CCK2i4svR的HEK293细胞株，测定[In-111]DOTA-sCCK8和[In-111]DOTA-MG0对CCK2R和CCK2i4svR的受体结合亲和力。在HEK293-CCK2i4svR荷瘤胸腺小鼠中研究肿瘤靶向作用。结果[in -111]DOTA-sCCK8和[in -111]DOTA-MG0在低纳摩尔范围内特异性结合CCK2R和CCK2i4svR。体内实验显示，cck2i4svr阳性肿瘤中这两种肽的积累相似（分别为3.21 +/- 0.77和3.01 +/- 0.67%ID/g， sCCK8和MG0, 24 h p.i）。[In-111]DOTA-MG0的肾潴留（32.4 +/- 7.5%ID/g, 24 h p.i.）明显高于[In-111]DOTA-sCCK8 （2.75 +/- 0.31%ID/g, 24 h p.i.）。我们利用放射性标记的硫酸化CCK8肽证明了CCK2i4svR是PRRT的潜在靶点。由于该受体在结直肠和胰腺肿瘤中表达，但在正常组织中不表达，因此这些肿瘤是CCK8和胃泌素类似物的PRRT的潜在新靶点。
Purpose Radiolabelled cholecystokinin (CCK) and gastrin-derived peptides potentially can be used for peptide receptor radionuclide therapy (PRRT). Recently, a splice variant version of the CCK2R has been identified, designated CCK2i4svR. Constitutive expression of this receptor has been demonstrated in human colorectal cancer and in pancreatic cancer, but not in normal tissue. So far, it has never been shown whether radiolabelled peptides can target the CCK2i4svR in vivo. In this paper, we investigated the potential of sulfated In-111-labelled DOTA-CCK8 (sCCK8), a pan-CCKR-binding peptide, and [In-111]DOTA-minigastrin (MG0), a CCK2R selective peptide, for the targeting of the CCK2i4svR.Materials and methods The receptor binding affinity of [In-111]DOTA-sCCK8 and [In-111]DOTA-MG0 for the CCK2R and CCK2i4svR was determined using stably transfected HEK293 cell lines, expressing either CCK2R or CCK2i4svR. Tumour targeting was studied in HEK293-CCK2i4svR tumour-bearing athymic mice.Results [In-111]DOTA-sCCK8 as well as [In-111]DOTA-MG0 specifically bound both CCK2R and CCK2i4svR with affinities in the low nanomolar range. In vivo experiments revealed that accumulation of both peptides in CCK2i4svR-positive tumours was similar (3.21 +/- 0.77 and 3.01 +/- 0.67%ID/g, sCCK8 and MG0, respectively, 24 h p.i.). Kidney retention of [In-111]DOTA-MG0 (32.4 +/- 7.5%ID/g, 24 h p.i.) was markedly higher than that of [In-111]DOTA-sCCK8 (2.75 +/- 0.31%ID/g, 24 h p.i.).Conclusion We demonstrated that the CCK2i4svR is a potential target for PRRT using a radiolabelled sulfated CCK8 peptide. As this receptor is expressed on colorectal and pancreatic tumours, but not in normal tissue, these tumours are potentially new targets for PRRT with CCK8 and gastrin analogs.