Synthesis and in vitro and in vivo evaluation of hypoxia-enhanced 111In-bombesin conjugates for prostate cancer imaging.
Synthesis and in vitro and in vivo evaluation of hypoxia-enhanced 111In-bombesin conjugates for prostate cancer imaging.
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用于前列腺癌成像的缺氧增强 111In-铃蟾肽缀合物的合成及体外和体内评估。
DOI：
10.2967/jnumed.112.117986
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发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Garrison JC
中科院分区：
文献类型：
--
作者：
Zhou Z;Wagh NK;Ogbomo SM;Shi W;Jia Y;Brusnahan SK;Garrison JC
受体靶向药物，如BB2r靶向多肽，已经在临床前和临床研究中得到了广泛的研究。为了提高诊断和/或放射治疗药物的有效性，我们已经开始探索将低氧选择性前药2-硝基咪唑掺入受体靶向多肽。缺氧是许多实体肿瘤的众所周知的特征，包括乳腺癌、前列腺癌和胰腺癌。这种方法的目的是利用2-硝基咪唑的缺氧捕捉能力来增加药物在缺氧、BB2r阳性肿瘤中的滞留。我们已经证明，将一个或多个2-硝基咪唑掺入BB2r靶向多肽可以显著增加药物在低氧前列腺癌细胞中的体外保留率。本文描述的研究是我们首次在PC-3异种移植小鼠模型中研究这些缺氧增强型BB2r靶向制剂的体内特性。合成、标记和纯化了4种111In标记的BB2r-靶向偶联物：111In-1、111In-2、111In-3和111In-4，分别由0-3个2-硝基咪唑基团组成。利用BB2r阳性的人前列腺癌PC-3细胞株，在低氧和常氧环境下，研究了这些放射性结合物的BB2r结合亲和力、外部化和蛋白结合特性。本文研究了~(111)In-1、~(111)In-2和~(111)In-4放射性结合物在荷PC-3肿瘤的SCID小鼠体内的分布及SPECT/CT显像。所有的结合物和NAT结合物都表现出纳摩尔结合亲和力。相应地，111In-1-4在低氧条件下对内在化放射性的保留率为41.4%、60.7%、69.1%和69.4%，而在常氧条件下为34.8%、35.3%、33.2%和29.7%。蛋白质结合研究表明，在低氧条件下，与对照相比，含有BB2r靶向放射性结合物的2-硝基咪唑的结合水平显著更高。根据PC-3肿瘤最初1h的摄取，111In-1、111In-2和111In-4在注射后72h分别显示肿瘤保留率为1.5%、6.7%和21.0%。~(111)In-1、~(111)In-2和~(111)In-4的微SPECT/CT显像显示肿瘤轮廓清晰。基于体外和体内研究，含有2-硝基咪唑部分的BB2r靶向制剂表现出更好的保留率。这些结果表明，有必要进一步探索低氧选择性捕捉剂对BB2r靶向试剂以及其他靶向化合物的潜在作用。
Receptor-targeted agents, such as BB2r-targeted peptides, have been investigated extensively in preclinical and clinical studies. In an attempt to increase the effectiveness of diagnostic and/or radiotherapeutic agents, we have begun to explore the incorporation of the hypoxia-selective prodrug 2-nitroimidazole into receptor-targeted peptides. Hypoxia is a well-known characteristic of many solid tumors, including breast, prostate and pancreatic cancers. The aim of this approach is to utilize the hypoxia trapping capability of 2-nitroimidazoles to increase the retention of the agent in hypoxic, BB2r-positive tumors. We have demonstrated that incorporation of one or more 2-nitroimidazoles into the BB2r-targeted peptide significantly increases the in vitro retention of the agent in hypoxic prostate cancer cells. The study described herein represents our first investigation of the in vivo properties of these hypoxia-enhanced BB2r-targeted agents in a PC-3 xenograft mouse model. Four 111In-labeled BB2r-targeted conjugates, 111In-1, 111In-2, 111In-3 and 111In-4, composed of 0–3 2-nitroimidazole moieties, respectively, were synthesized, labeled and purified. The BB2r binding affinities, externalization and protein association properties of these radioconjugates were assessed using the BB2r-positive PC-3 human prostate cancer cell line under hypoxic and normoxic environments. The in vivo biodistribution and microSPECT/CT imaging of the 111In-1, 111In-2 and 111In-4 radioconjugates were investigated in PC-3 tumor bearing SCID mice. All conjugates and natIn-conjugates demonstrated nanomolar binding affinities. 111In-1-4 demonstrated 41.4, 60.7, 69.1 and 69.4 % retention, correspondingly, of internalized radioactivity under hypoxic conditions relative to 34.8, 35.3, 33.2 and 29.7 % retention under normoxic conditions. Protein-association studies showed significantly higher levels of association under hypoxic conditions for 2-nitroimidazole containing BB2r-targeted radioconjugates compared to control. Based on the initial 1 hour uptake in the PC-3 tumors, 111In-1, 111In-2 and 111In-4 demonstrated tumor retentions of 1.5, 6.7 and 21.0%, respectively, by 72 h post-injection. Micro-SPECT/CT imaging studies of 111In-1, 111In-2 and 111In-4 radioconjugates resulted in clear delineation of the tumors. Based on the in vitro and in vivo studies, the BB2r-targeted agents that incorporated 2-nitroimidazole moieties demonstrated improved retention. These results indicate that further exploration into the potential of hypoxia-selective trapping agents for BB2r-targeted agents, as well as other targeted compounds, is warranted.
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DOI：
10.1016/0360-3016(89)90146-6
发表时间：
1989-11-01
影响因子：
7
作者：
RASEY, JS;KOH, WJ;KROHN, KA
通讯作者：
KROHN, KA
影响因子：
45.3
作者：
Fyles, A;Milosevic, M;Hill, RP
通讯作者：
Hill, RP
影响因子：
15
作者：
BOLTON, JL;MCCLELLAND, RA
通讯作者：
MCCLELLAND, RA
影响因子：
6
作者：
Gugger, M;Reubi, JC
通讯作者：
Reubi, JC
DOI：
10.1016/0360-3016(92)91001-4
发表时间：
1992-01-01
影响因子：
7
作者：
KOH, WJ;RASEY, JS;GRIFFIN, TW
通讯作者：
GRIFFIN, TW