Comparative in vitro and in vivo evaluation of two 64Cu-labeled bombesin analogs in a mouse model of human prostate adenocarcinoma
Comparative in vitro and in vivo evaluation of two 64Cu-labeled bombesin analogs in a mouse model of human prostate adenocarcinoma
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DOI：
10.1016/j.nucmedbio.2005.12.011
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发表时间：
2006-04-01
影响因子：
3.1
通讯作者：
Chen, XY
中科院分区：
文献类型：
--
作者：
Yang, YS;Zhang, XZ;Chen, XY
蛙皮素（BBN）是人胃泌素释放肽（GRP）的类似物，以高亲和力和特异性结合GRP受体（GRPR）。GRPR在大多数雄激素非依赖性前列腺组织中过表达，为前列腺癌的诊断和治疗提供了潜在的靶点。我们先前已经证明了使用Cu-64- 1，4，7，10-四氮杂十二烷-N，N '，N”，N“'-四乙酸（DOTA）-[Lys（3）]BBN的正电子发射断层扫描（PET）成像检测GRPR阳性前列腺癌的可行性。在这项研究中，我们比较了截短的BBN类似物Cu-64-DOTA-Aca-BBN（7-14）与Cu-64-DOTA-[Lys（3）]BBN的受体亲和力、代谢稳定性、肿瘤靶向功效和药代动力学。使用I-125-[Tyr（4）]BBN作为放射性配体，通过竞争性结合测定评估每种DOTA缀合物与PC-3和22 Rv 1前列腺癌细胞上的GRPR的结合。在皮下植入PC-3细胞的雄性裸鼠上测定体内药代动力学。进行动态microPET成像以评价示踪剂的全身分布。采用高效液相色谱法研究了示踪剂在血液、尿液、肿瘤、肝脏和肾脏中的代谢稳定性。结果表明，I-125-[Tyr 4]BBN对PC-3细胞的Kd为14.8 +/- 0.4 nM，PC-3细胞表面的受体浓度约为2.7 +/- 0.1 × 10（6）个受体/细胞。DOTA-Aca-BBN（7-14）的50%抑制浓度值为18.4 +/- 0.2 nM，DOTA-[Lys（3）]BBN的50%抑制浓度值为2.2 +/- 0.5 nM。与DOTA-Aca-BBN相比，DOTA-[Lys（3）]BBN显示出更好的肿瘤对比度和绝对肿瘤活性累积（7-14）。对两种示踪剂在器官匀浆上的代谢稳定性的研究表明，Cu-64-DOTA-[Lys（3）]BBN相对稳定。本研究表明，两种示踪剂均适用于前列腺癌GRPR的靶向PET显像，而Cu-64-DOTA-[Lys（3）]BBN可能具有更好的临床应用前景。(c)2006年爱思唯尔公司All rights reserved.
Bombesin (BBN), an analog of human gastrin-releasing peptide (GRP), binds to the GRP receptor (GRPR) with high affinity and specificity. Overexpression of GRPR has been discovered in mostly androgen-independent human prostate tissues and, thus, provides a potential target for prostate cancer diagnosis and therapy. We have previously demonstrated the feasibility of the positron emission tomography (PET) imaging using Cu-64-1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid (DOTA)-[Lys(3)]BBN to detect GRPRpositive prostate cancer. In this study, we compared the receptor affinity, metabolic stability, tumor-targeting efficacy, and pharmacokinetics of a truncated BBN analog Cu-64-DOTA-Aca-BBN(7-14) with Cu-64-DOTA-[Lys(3)]BBN. Binding of each DOTA conjugate to GRPR on PC-3 and 22Rv1 prostate cancer cells was evaluated with competitive binding assay using I-125-[Tyr(4)]BBN as radioligand. In vivo pharmacokinetics was determined on male nude mice subcutaneously implanted with PC-3 cells. Dynamic microPET imaging was performed to evaluate the systemic distribution of the tracers. Metabolic stability of the tracers in blood, urine, tumor, liver and kidney was studied using high-performance liquid chromatography. The results showed that I-125-[Tyr4]BBN has a K-d of 14.8 +/- 0.4 nM against PC-3 cells, and the receptor concentration on PC-3 cell surface is approximately 2.7 +/- 0.1 X 10(6) receptors per cell. The 50% inhibitory concentration value for DOTA-Aca-BBN(7-14) is 18.4 +/- 0.2 nM, and that for DOTA-[Lys(3)]BBN is 2.2 +/- 0.5 nM. DOTA-[Lys(3)]BBN shows a better tumor contrast and absolute tumor activity accumulation compared to DOTA-Aca-BBN(7-14). Studies on metabolic stability for both tracers on organ homogenates showed that Cu-64-DOTA-[Lys(3)]BBN is relatively stable. This study dernonstrated that both tracers are Suitable for targeted PET imaging to detect the expression of GRPR in prostate cancer, while Cu-64-DOTA-[Lys(3)]BBN may have a better potential for clinical translation. (c) 2006 Elsevier Inc. All rights reserved.