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Novel 64Cu Labeled RGD2-BBN Heterotrimers for PET Imaging of Prostate Cancer
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-03-27 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00113 Ermelinda Lucente 1, 2 , Hongguang Liu 1 , Yang Liu 1 , Xiang Hu 1 , Enza Lacivita 2 , Marcello Leopoldo 2 , Zhen Cheng 1
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-03-27 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00113 Ermelinda Lucente 1, 2 , Hongguang Liu 1 , Yang Liu 1 , Xiang Hu 1 , Enza Lacivita 2 , Marcello Leopoldo 2 , Zhen Cheng 1
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Bombesin receptor 2 (BB2) and integrin αvβ3 receptor are privileged targets for molecular imaging of cancer because of their overexpression in a number of tumor tissues. The most recent developments in heterodimer-based radiopharmaceuticals concern BB2- and integrin αvβ3-targeting compounds, consisting of bombesin (BBN) and cyclic arginine-glycine-aspartic acid peptides (RGD), connected through short length linkers. Molecular imaging probes based on RGD-BBN heterodimer design exhibit improved tumor targeting efficacy compared to the single-receptor targeting peptide monomers. However, their application in clinical study is restricted because of inefficient synthesis or unfavorable in vivo properties, which could depend on the short linker nature. Thus, the aim of the present study was to develop a RGD2-BBN heterotrimer, composed of (7-14)BBN-NH2 peptide (BBN) linked to the E[c(RGDyK)]2 dimer peptide (RGD2), bearing the new linker type [Pro-Gly]12. The heterodimer E[c(RGDyK)]2-PEG3-Glu-(Pro-Gly)12-BBN(7-14)-NH2 (RGD2-PG12-BBN) was prepared through conventional solid phase synthesis, then conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODA-GA). In 64Cu labeling, the NODA-GA chelator showed superior radiochemical characteristics compared to DOTA (70% vs 40% yield, respectively). Both conjugates displayed dual targeting ability, showing good αvβ3 affinities and high BB2 receptor affinities which, in the case of the NODA-GA conjugate, were in the same range as the best RGD-BBN heterodimer ligands reported to date (Ki = 24 nM). 64Cu-DOTA and 64Cu-NODA-GA probes were also found to be stable after 1 h incubation in mouse serum (>90%). In a microPET study in prostate cancer PC-3 xenograft mice, both probes showed low tumor uptake, probably due to poor pharmacokinetic properties in vivo. Overall, our study demonstrates that novel RGD-BBN heterodimer with long linker can be prepared and they preserve high binding affinities to BB2 and integrin αvβ3 receptor binding ability. The present study represents a step forward in the design of effective heterodimer or heterotrimer probes for dual targeting.
中文翻译：
用于前列腺癌PET成像的新型64 Cu标记的RGD 2 -BBN杂聚体
铃蟾肽受体2（BB 2）和整合素α v β 3受体是因为它们在许多肿瘤组织的过表达的癌症的分子成像特权目标。最近最发展基于异源二聚体放射性药物关注BB 2 -和整合素α v β 3靶向化合物，由短链连接的短链蛋白（BBN）和环状精氨酸-甘氨酸-天冬氨酸肽（RGD）组成。与单受体靶向肽单体相比，基于RGD-BBN异二聚体设计的分子成像探针显示出更高的肿瘤靶向功效。但是，由于合成效率低下或体内特性不利，它们在临床研究中的应用受到了限制，这可能取决于短连接子的性质。因此，本研究的目的是开发一种RGD 2 -BBN异源三聚体，它由与E [ c（RGDyK）] 2二聚体肽（RGD 2）连接的（7-14）BBN-NH 2肽（BBN）组成。，带有新的链接器类型[Pro-Gly] 12。通过常规固相合成制备异二聚体E [c（RGDyK）] 2 -PEG 3 -Glu-（Pro-Gly）12 -BBN（7-14）-NH 2（RGD 2 -PG 12 -BBN），然后与1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）或1,4,7-三氮环壬烷-1-戊二酸-4,7-二乙酸（NODA-GA）共轭。在64 Cu标记中，与DOTA相比，NODA-GA螯合剂显示出优异的放射化学特性（分别为70％和40％的产率）。两个共轭物显示双重靶向能力，显示出良好的α v β 3倍的亲和性和高BB 2在NODA-GA共轭物的情况下，其受体亲和力与迄今为止报道的最佳RGD-BBN异二聚体配体在同一范围内（K i = 24 nM）。在小鼠血清（> 90％）中孵育1小时后，还发现64种Cu-DOTA和64种Cu-NODA-GA探针是稳定的。在针对前列腺癌PC-3异种移植小鼠的microPET研究中，这两种探针均显示出较低的肿瘤吸收率，这可能是由于体内药代动力学特性差所致。总的来说，我们的研究表明，新型RGD-BBN异源二聚体具有长接头可以准备和他们保持高度的结合亲和力BB 2和整合素α v β 3受体结合能力。本研究代表了针对双重靶向的有效异二聚体或异三聚体探针设计的进步。
更新日期：2018-03-27
中文翻译：
用于前列腺癌PET成像的新型64 Cu标记的RGD 2 -BBN杂聚体
铃蟾肽受体2（BB 2）和整合素α v β 3受体是因为它们在许多肿瘤组织的过表达的癌症的分子成像特权目标。最近最发展基于异源二聚体放射性药物关注BB 2 -和整合素α v β 3靶向化合物，由短链连接的短链蛋白（BBN）和环状精氨酸-甘氨酸-天冬氨酸肽（RGD）组成。与单受体靶向肽单体相比，基于RGD-BBN异二聚体设计的分子成像探针显示出更高的肿瘤靶向功效。但是，由于合成效率低下或体内特性不利，它们在临床研究中的应用受到了限制，这可能取决于短连接子的性质。因此，本研究的目的是开发一种RGD 2 -BBN异源三聚体，它由与E [ c（RGDyK）] 2二聚体肽（RGD 2）连接的（7-14）BBN-NH 2肽（BBN）组成。，带有新的链接器类型[Pro-Gly] 12。通过常规固相合成制备异二聚体E [c（RGDyK）] 2 -PEG 3 -Glu-（Pro-Gly）12 -BBN（7-14）-NH 2（RGD 2 -PG 12 -BBN），然后与1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）或1,4,7-三氮环壬烷-1-戊二酸-4,7-二乙酸（NODA-GA）共轭。在64 Cu标记中，与DOTA相比，NODA-GA螯合剂显示出优异的放射化学特性（分别为70％和40％的产率）。两个共轭物显示双重靶向能力，显示出良好的α v β 3倍的亲和性和高BB 2在NODA-GA共轭物的情况下，其受体亲和力与迄今为止报道的最佳RGD-BBN异二聚体配体在同一范围内（K i = 24 nM）。在小鼠血清（> 90％）中孵育1小时后，还发现64种Cu-DOTA和64种Cu-NODA-GA探针是稳定的。在针对前列腺癌PC-3异种移植小鼠的microPET研究中，这两种探针均显示出较低的肿瘤吸收率，这可能是由于体内药代动力学特性差所致。总的来说，我们的研究表明，新型RGD-BBN异源二聚体具有长接头可以准备和他们保持高度的结合亲和力BB 2和整合素α v β 3受体结合能力。本研究代表了针对双重靶向的有效异二聚体或异三聚体探针设计的进步。
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