Selection of optimal chelator improves the contrast of GRPR imaging using bombesin analogue RM26
Selection of optimal chelator improves the contrast of GRPR imaging using bombesin analogue RM26
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DOI：
10.3892/ijo.2016.3429
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发表时间：
2016-05-01
影响因子：
5.2
通讯作者：
Orlova, Anna
中科院分区：
文献类型：
--
作者：
Mitran, Bogdan;Varasteh, Zohreh;Orlova, Anna
蛙皮素（BN）类似物以高亲和力结合在前列腺癌中上调的胃泌素释放肽受体（GRPR），并且可用于前列腺癌的可视化。本研究的目的是研究放射性核素-螯合剂复合物对In-111标记的蛙皮素拮抗剂PEG（2）-D-Phe-Gln-Trp-Ala-Val-Gly-His-StaLeu-NH 2（PEG（2）-RM 26）生物分布模式的影响，并确定用于SPECT成像的最佳结构。用In-111放射性标记一系列通过PEG（2）间隔基与NOTA、NODAGA、DOTA和DOTAGA N-末端缀合的RM 26类似物，并在体外和体内进行评价。用In-111成功地标记了偶联物，纯度为100%，并保留了与GRPR的结合特异性和高稳定性。所有化合物的细胞加工的特征在于缓慢的内化。IC 50值在低纳摩尔范围内，带正电荷的In-nat-NOTA-PEG（2）-RM 26的IC 50值较低（2.6 +/- 0.1 nM），带负电荷的In-nat-DOTAGA-PEG（2）-RM 26的IC 50值较高（4.8 +/- 0.5 nM）。动力学结合研究显示，KD值在皮摩尔范围内，遵循与IC 50数据相同的模式。在携带PC-3前列腺癌异种移植物的BALB/c nu/nu小鼠中研究所有化合物的生物分布。肿瘤靶向和生物分布研究显示，放射性通过肾脏排泄从血液和正常器官中快速清除。所有缀合物在4 hp. i时在肿瘤中显示出相似的摄取。与含有NOTA和NODAGA的构建体相比，含有DOTA和DOTAGA的构建体在GRPR表达器官中的放射性蓄积显著较低。In-111-NOTA-PEG 2-RM 26与带正电荷的复合物显示出最高的初始摄取和最慢的放射性从肝脏的清除。在4马力时，DOTA-和DOTAGA-偶联类似物与含有NOTA-和NODAGA的变体相比显示出显著更高的肿瘤-器官比率。NODAGA偶联物在肿瘤中表现出最好的放射性保留，并且在24 hp.i.，与血液肌肉和骨骼的对比度最高
Bombesin (BN) analogs bind with high affinity to gastrin-releasing peptide receptors (GRPRs) that are up-regulated in prostate cancer and can be used for the visualization of prostate cancer. The aim of this study was to investigate the influence of radionuclide-chelator complexes on the biodistribution pattern of the In-111-labeled bombesin antagonist PEG(2)-D-Phe-Gln-Trp-Ala-Val-Gly-His-StaLeu-NH2 (PEG(2)-RM26) and to identify an optimal construct for SPECT imaging. A series of RM26 analogs N-terminally conjugated with NOTA, NODAGA, DOTA and DOTAGA via a PEG(2) spacer were radiolabeled with In-111 and evaluated both in vitro and in vivo. The conjugates were successfully labeled with In-111 with 100% purity and retained binding specificity to GRPR and high stability. The cellular processing of all compounds was characterized by slow internalization. The IC50 values were in the low nanomolar range, with lower IC50 values for positively charged In-nat-NOTA-PEG(2)-RM26 (2.6 +/- 0.1 nM) and higher values for negatively charged In-nat-DOTAGA-PEG(2)-RM26 (4.8 +/- 0.5 nM). The kinetic binding studies showed KD values in the picomolar range that followed the same pattern as the IC50 data. The biodistribution of all compounds was studied in BALB/c nu/nu mice bearing PC-3 prostate cancer xenografts. Tumor targeting and biodistribution studies displayed rapid clearance of radioactivity from the blood and normal organs via kidney excretion. All conjugates showed similar uptake in tumors at 4 hp.i. The radioactivity accumulation in GRPR-expressing organs was significantly lower for DOTA-and DOTAGA-containing constructs compared to those containing NOTA and NODAGA. In-111-NOTA-PEG2-RM26 with a positively charged complex showed the highest initial uptake and the slowest clearance of radioactivity from the liver. At 4 hp.i., DOTA-and DOTAGA-coupled analogs showed significantly higher tumor-to-organ ratios compared to NOTA-and NODAGA-containing variants. The NODAGA conjugate demonstrated the best retention of radioactivity in tumors, and, at 24 hp.i., had the highest contrast to blood, muscle and bones.