[Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 is a highly efficient radiotherapeutic for glucagon-like peptide-1 receptor-targeted therapy for insulinoma
[Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 is a highly efficient radiotherapeutic for glucagon-like peptide-1 receptor-targeted therapy for insulinoma
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DOI：
10.1158/1078-0432.ccr-06-2965
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发表时间：
2007-06-15
影响因子：
11.5
通讯作者：
Christofori, Gerhard
中科院分区：
文献类型：
--
作者：
Wicki, Andreas;Wild, Damian;Christofori, Gerhard
目的：虽然代谢变化使胰岛素瘤的诊断相对容易，但手术切除因定位困难而受阻，恶性胰岛素瘤目前尚无有效的治疗方法。我们先前已经证明，人胰岛素瘤细胞中高密度的胰升糖素样肽-1受体(GLP-1R)为分子成像和内放射治疗提供了一个有吸引力的靶点。在这项研究中，我们研究了(111)ln标记的GLP-1激动剂[Lys(40)(AHX-DTPA-(111)ln)NH2]-Exendin-4在人胰岛素瘤转基因小鼠模型中的治疗潜力。实验设计：[Lys(40)(AHX-DTPA-(111)ln)NH2]-Exendin-4在Rip1Tag2小鼠胰腺β细胞癌变模型中进行评估，显示出与人胰岛素瘤相似的GLP-1R表达。小鼠分别注射1.1、5.6或28MBq的放射性多肽，7天后处死。结果：肿瘤摄取为200%注射活度/克，剂量沉积为3GY/MBq，剂量沉积为40 pmol[Lys(40)(AHX-DTPA-(111)ln)NH2]-Exendin-4。其他GLP-1R阳性器官显示>；=30倍的低剂量沉积。单次注射[Lys(40)(AHX-DTPA-(111)ln)NH2]-Exendin-4可使肿瘤体积缩小94%，且呈剂量依赖关系，没有明显的急性器官毒性。结论：Lys(40)(AHX-DTPA-(111)ln)NH2[Lys(40)(AHX-DTPA-(111)ln)NH2]-Exendin-4是一种有选择性靶向胰岛素瘤的放射性多肽。此外，如果肿瘤摄取率高，发射俄歇的放射性药物如(111)In能够产生显著的治疗效果。
Purpose: Although metabolic changes make diagnosis of insulinoma relatively easy, surgical removal is hampered by difficulties in locating it, and there is no efficient treatment for malignant insulinoma. We have previously shown that the high density of glucagon-like peptide-1 receptors (GLP-1R) in human insulinoma cells provides an attractive target for molecular imaging and internal radiotherapy. In this study, we investigated the therapeutic potential of [Lys(40)(Ahx-DTPA-(111)ln)NH2]-Exendin-4, an (111)ln-labeled agonist of GLP-1, in a transgenic mouse model of human insulinoma.Experimental Design: [Lys(40)(Ahx-DTPA-(111)ln) NH2] -Exendin-4 was assessed in the Rip1Tag2 mouse model of pancreatic beta-cell carcinogenesis, which exhibits a GLP-1R expression comparable with human insulinoma. Mice were injected with 1.1, 5.6, or 28 MBq of the radiopeptide and sacrificed 7 days after injection. Tumor uptake and response, the mechanism of action of the radiopeptide, and therapy toxicity were investigated.Results: Tumor uptake was > 200% injected activity per gram, with a dose deposition of 3 Gy/MBq at 40 pmol [Lys(40)(Ahx-DTPA-(111)ln) NH2] -Exendin-4. Other GLP-1R - positive organs showed >= 30 times lower dose deposition. A single injection of [Lys(40)(Ahx-DTPA-(111)ln) NH2]- Exendin-4 resulted in a reduction of the tumor volume by up to 94% in a dose-dependent manner without significant acute organ toxicity. The therapeutic effect was due to increased tumor cell apoptosis and necrosis and decreased proliferation.Conclusions: The results suggest that [Lys(40)(Ahx-DTPA-(111)ln) NH2] -Exendin-4 is a promising radiopeptide capable of selectively targeting insulinoma. Furthermore, Auger-emitting radiopharmaceuticals such as (111)ln are able to produce a marked therapeutic effect if a high tumor uptake is achieved.