Evaluation of an (111)In-DOTA-rhenium cyclized alpha-MSH analog: a novel cyclic-peptide analog with improved tumor-targeting properties.
Evaluation of an (111)In-DOTA-rhenium cyclized alpha-MSH analog: a novel cyclic-peptide analog with improved tumor-targeting properties.
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发表时间：
2001-12
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通讯作者：
J. Chen;Z. Cheng;N. Owen;T. Hoffman;Y. Miao;S. Jurisson;T. Quinn
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作者：
J. Chen;Z. Cheng;N. Owen;T. Hoffman;Y. Miao;S. Jurisson;T. Quinn
本研究的目的是检查铼介导的肽环化对黑色素瘤靶向、生物分布和α-黑素细胞刺激激素（α-MSH）类似物1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）偶联ReO环化的清除动力学的影响[Cys(3,4,10),D-Phe(7)]α-MSH(3-13) (DOTA-ReCCMSH)。方法 DOTA-ReCCMSH 与其还原的非金属化线性同系物 DOTA-CCMSH 以及铼环化被二硫键环化取代的类似物 DOTA-[Cys(4,10),D-Phe(7)]alpha-MSH(4-13) (CMSH) 进行比较。 DOTA 还缀合至亲和力最高的 α-MSH 受体结合肽之一 [Nle(4),D-Phe(7)]α-MSH (NDP) 的氨基末端，作为线性肽标准品。 DOTA 缀合的 α-MSH 类似物用 (111)In 进行放射性标记，并检查其与 B16/F1 鼠黑色素瘤细胞的体外受体结合亲和力，并在携带黑色素瘤肿瘤的 C57 小鼠中评估和比较其体内生物分布特性。结果 (111)In-DOTA-ReCCMSH 的肿瘤摄取值显着高于其他密切相关的 (111)In-DOTA-α-MSH 缀合物。即使在注射后 24 小时，也比较了 (111)In-DOTA 偶联的 ReCCMSH（4.86 +/- 1.52 注射剂量百分比 [%ID]/g）、CCMSH（1.91 +/- 0.56 %ID/g）、CMSH（3.09 +/- 0.32 %ID/g）和 NDP（2.47 +/- 0.79）的肿瘤摄取值%ID/g) 强调了 ReCCMSH 的高肿瘤保留特性。铼协调环化导致 (111)In-DOTA-ReCCMSH (8.98 +/- 0.82 %ID/g) 的肾放射性累积量低于 (111)In-DOTA-CCMSH (63.2 +/- 15.6 %ID/g)、(111)In-DOTA-CMSH (38.4 +/- 3.6 %ID/g) 和(111)In-DOTA-NDP (12.0 +/- 1.96 %ID/g) 注射后 2 小时，并显着增加其在尿液中的清除率（注射后 2 小时为 92 %ID）。 (111)In-DOTA-ReCCMSH 获得了肿瘤与正常组织的高放射性摄取比（例如，注射后 4 小时，血液、肌肉、肺和肝脏分别为 489、159、100 和 49）。结论 DOTA-ReCCMSH 的新型 ReO 配位环状结构对其增强的肿瘤靶向和肾脏清除特性做出了重大贡献，并使 DOTAReCCMSH 成为黑色素瘤放射检测和放射治疗的优秀候选者。
UNLABELLED The aim of this study was to examine the effect of rhenium-mediated peptide cyclization on melanoma targeting, biodistribution, and clearance kinetics of the alpha-melanocyte-stimulating hormone (alpha-MSH) analog 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) coupled ReO-cyclized [Cys(3,4,10),D-Phe(7)]alpha-MSH(3-13) (DOTA-ReCCMSH). METHODS DOTA-ReCCMSH was compared with its reduced nonmetalated linear homolog, DOTA-CCMSH, and an analog in which rhenium cyclization was replaced by disulfide bond cyclization, DOTA-[Cys(4,10),D-Phe(7)]alpha-MSH(4-13) (CMSH). DOTA was also conjugated to the amino terminus of one of the highest-affinity alpha-MSH receptor-binding peptides, [Nle(4),D-Phe(7)]alpha-MSH (NDP), as a linear peptide standard. The DOTA-conjugated alpha-MSH analogs were radiolabeled with (111)In and examined for their in vitro receptor-binding affinity with B16/F1 murine melanoma cells, and their in vivo biodistribution properties were evaluated and compared in melanoma tumor-bearing C57 mice. RESULTS The tumor uptake values of (111)In-DOTA-ReCCMSH were significantly higher than those of the other closely related (111)In-DOTA-alpha-MSH conjugates. Even at 24 h after injection, a comparison of the tumor uptake values for (111)In-DOTA-coupled ReCCMSH (4.86 +/- 1.52 percentage injected dose [%ID]/g), CCMSH (1.91 +/- 0.56 %ID/g), CMSH (3.09 +/- 0.32 %ID/g), and NDP (2.47 +/- 0.79 %ID/g) highlighted the high tumor retention property of ReCCMSH. Rhenium-coordinated cyclization resulted in less renal radioactivity accumulation of (111)In-DOTA-ReCCMSH (8.98 +/- 0.82 %ID/g) than of (111)In-DOTA-CCMSH (63.2 +/- 15.6 %ID/g), (111)In-DOTA-CMSH (38.4 +/- 3.6 %ID/g), and (111)In-DOTA-NDP (12.0 +/- 1.96 %ID/g) at 2 h after injection and significantly increased its clearance into the urine (92 %ID at 2 h after injection). A high radioactivity uptake ratio of tumor to normal tissue was obtained for (111)In-DOTA-ReCCMSH (e.g., 489, 159, 100, and 49 for blood, muscle, lung, and liver, respectively, at 4 h after injection). CONCLUSION The novel ReO-coordinated cyclic structure of DOTA-ReCCMSH contributes significantly to its enhanced tumor-targeting and renal clearance properties and makes DOTAReCCMSH an excellent candidate for melanoma radiodetection and radiotherapy.