摘要

Expression of CXCR4 in cancer has been found to correlate with poor prognosis and resistance to chemotherapy. In this study we developed a derivative of the CXCR4 peptide antagonist, T140-2D, that can be labeled easily with the PET isotope copper-64, and thereby enable in vivo visualization of CXCR4 in tumors. T140 was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono (N-hydroxysuccinimide ester) (DOTA-NHS) to give T140-2D, which contains a DOTA molecule on each of the two lysine residues. 64Cu-T140-2D was evaluated in vitro by migration and binding experiments, and in vivo by microPET imaging and biodistribution, in mice bearing CXCR4-positive and CXCR4-negative tumor xenografts. T140-2D was labeled with copper-64 to give 64Cu-T140-2D in a high radiochemical yield of 86 ± 3% (not decay-corrected) and a specific activity of 0.28 - 0.30 mCi/µg (10.36 - 11.1 MBq/µg). 64Cu-T140-2D had antagonistic and binding characteristics to CXCR4 that were similar to those of T140. In vivo, 64Cu-T140-2D tended to bind to red blood cells and had to be used in a low specific activity form. In this new form 64Cu-T140-2D enabled specific imaging of CXCR4-positive, but not CXCR4-negative tumors. Undesirably, however, 64Cu-T140-2D also displayed high accumulation in the liver and kidneys. In conclusion, 64Cu-T140-2D was easily labeled and, in its low activity form, enabled imaging of CXCR4 in tumors. It had high uptake, however, in metabolic organs. Further research with imaging tracers targeting CXCR4 is required.

译文

已发现 CXCR4 在癌症中的表达与不良预后和化疗耐药性相关。在这项研究中,我们开发了一种 CXCR4 肽拮抗剂 T140-2D 的衍生物,它可以很容易地用 PET 同位素铜-64 标记,从而使 CXCR4 在肿瘤中的体内可视化成为可能。T140 与 1,4,7,10-tetraazacyclododecane-1,4,7,10-四乙酸单 (N-羟基琥珀酰亚胺酯) (DOTA-NHS) 结合形成 T140-2D, 其中两个赖氨酸残基上都含有 DOTA 分子。64Cu-T140-2D 在体外通过迁移和结合实验进行评估,在体内通过微型 pet 成像和生物分布评估,在荷 CXCR4-positive 和 CXCR4-negative 移植瘤的小鼠中进行评估。T140-2D 用铜-64 标记,使 64Cu-T140-2D 的高放射化学产率为 86 ± 3% (未衰减校正) 和 0.28-0.30 mCi/μ g (10.36-11.1 MBq/μ g) 的特定活性。64Cu-T140-2D 与 CXCR4 具有类似 t140 的拮抗和结合特性。在体内,64Cu-T140-2D 倾向于与红细胞结合,并且必须以低比活性形式使用。在这种新的形式 64Cu-T140-2D 使 CXCR4-positive 的特异性成像,而不是 CXCR4-negative 的肿瘤。然而,令人不快的是,64Cu-T140-2D 也在肝脏和肾脏中显示出高蓄积。总之,64Cu-T140-2D 易于标记,并且在其低活性形式下,能够在肿瘤中成像 CXCR4。然而,它在代谢器官中有很高的摄取。需要针对 CXCR4 的成像示踪剂的进一步研究。

antagonist

肿瘤 激动剂 临床研究术语
概述  :  

来源于受体-配体结合与产生的生物学效应:拮抗剂(antagonist)与激动剂(agonist)相对,拮抗剂指那些与受体结合后,但不能产生效应或效应微弱物质,而激动剂则能产生较大效应。拮抗剂在疾病治疗以及药物研发方面发挥了巨大的作用。根据作用方式不同,又分为竞争性拮抗剂和非竞争性拮抗剂。前者是通过自身与受体结合阻止相应的物质再与受体结合,后者是与受体结合不会影响相应的物质与受体的结合,但是会阻止受体产生后续反应。 应用举例G蛋白欧联趋化因子受体CXCR4在癌细胞表面广泛表达,癌细胞

Antagonist   英 /æn'tæg(ə)nɪst/   美 /æn'tæɡənɪst/

释    义   n. 敌手;[解剖] 对抗肌;[生化] 拮抗物;反协同试剂;复数 antagonists

同根词   antagonistic adj. 敌对的;对抗性的;反对的;antagonism n. 对抗,敌对;对立;敌意;antagonize vi. 引起反抗;antagonise vi. 引起对抗/反感;antagonize vt. 使…敌对;使…对抗;对…起反作用;antagonise vt. 使敌对;抵销

例    句   Objective: To study the therapeutic effect of the calcium channel antagonist nimodipine on the proliferative retinopathy and it′s interaction with vascular endothelial growth factor (VEGF). 目的:研究钙通道拮抗剂尼莫地平在增生性视网膜病变中的治疗作用及其与血管内皮生长因子(VEGF)的相互作用。

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