Noninvasive detection of carboxypeptidase G2 activity in vivo
Noninvasive detection of carboxypeptidase G2 activity in vivo
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DOI：
10.1002/nbm.1597
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发表时间：
2011-05-01
影响因子：
2.9
通讯作者：
Payne, Geoffrey S.
中科院分区：
文献类型：
--
作者：
Jamin, Yann;Smyth, Lynette;Payne, Geoffrey S.
假单胞菌蛋白羧肽酶G2（CPG 2）是一种前药活化酶，用于抗体和基因导向酶前药治疗（ADEPT和GDEPT）的靶向化疗策略。我们已经开发了一种非侵入性成像方法来监测体内CPG 2活性，这将有助于基于CPG 2的ADEPT和GDEPT策略的临床前和临床开发。使用F-19 MRSI监测CPG 2在经工程化以稳定表达CPG 2的人结肠腺癌WiDr异种移植物中对新型报告探针3，5-二氟苯甲酰基-L-谷氨酸（3，5-DFBGlu）的切割。由3，5-DFBGlu的两个MR等效F-19核提供的高信噪比和CPG 2介导的裂解上的1.4ppm F-19化学位移差异使得能够评价肿瘤中3，5-DFBGlu及其CPG 2介导的裂解的表观药代动力学的动力学和定量。此外，3，5-二氟苯甲酸浓度的表观增加速率还可以提供接受基于CPG 2的治疗的患者的肿瘤中CPG 2活性水平的生物标志物，以及治疗反应的生物标志物。向由CPG 2切割的前药的设备中添加体内报告探针，如3，5-DFBGlu，为CPG 2作为转基因表达的基因报告物提供了新的应用。版权所有（C）2010约翰威利父子有限公司
The pseudomonad protein, carboxypeptidase G2 (CPG2), is a prodrug-activating enzyme utilized in the targeted chemotherapy strategies of antibody-and gene-directed enzyme prodrug therapy (ADEPT and GDEPT). We have developed a noninvasive imaging approach to monitor CPG2 activity in vivo that will facilitate the preclinical and clinical development of CPG2-based ADEPT and GDEPT strategies. Cleavage of the novel reporter probe, 3,5-difluorobenzoyl-L-glutamic acid (3,5-DFBGlu), by CPG2, in human colon adenocarcinoma WiDr xenografts engineered to stably express CPG2, was monitored using F-19 MRSI. The high signal-to-noise ratio afforded by the two MR-equivalent F-19 nuclei of 3,5-DFBGlu, and the 1.4 ppm F-19 chemical shift difference on CPG2-mediated cleavage, enabled the dynamics and quantification of the apparent pharmacokinetics of 3,5-DFBGlu and its CPG2-mediated cleavage in the tumor to be evaluated. In addition, the apparent rate of increase of 3,5-difluorobenzoic acid concentration could also provide a biomarker of CPG2 activity levels in tumors of patients undergoing CPG2-based therapies, as well as a biomarker of treatment response. The addition of in vivo reporter probes, such as 3,5-DFBGlu, to the armamentarium of prodrugs cleaved by CPG2 affords new applications for CPG2 as a gene reporter of transgene expression. Copyright (C) 2010 John Wiley & Sons, Ltd.