Selective visualization of cyclooxygenase-2 in inflammation and cancer by targeted fluorescent imaging agents.
Selective visualization of cyclooxygenase-2 in inflammation and cancer by targeted fluorescent imaging agents.
复制标题
DOI：
10.1158/0008-5472.can-09-2664
复制
发表时间：
2010-05-01
期刊：
影响因子：
11.2
通讯作者：
Marnett LJ
中科院分区：
文献类型：
--
作者：
Uddin MJ;Crews BC;Blobaum AL;Kingsley PJ;Gorden DL;McIntyre JO;Matrisian LM;Subbaramaiah K;Dannenberg AJ;Piston DW;Marnett LJ
由于造影剂在正常组织中的非选择性积累的干扰，通过分子成像有效诊断炎症和癌症是具有挑战性的。在这里，我们报告了一系列新的荧光成像剂，有效地靶向环氧合酶-2（考克斯-2），这是正常情况下缺乏的细胞，但发现在高水平的炎性病变，并在许多癌前病变和恶性肿瘤。在腹膜内或静脉内注射后，与正常组织相比，这些试剂在发炎或肿瘤组织中变得高度富集，并且这种积累为体内荧光成像提供了足够的信号。此外，我们表明，只有完整的母体化合物被发现在感兴趣的区域。使用携带考克斯-2靶向缺失的动物并通过在体外和体内模型中用高亲和力抑制剂阻断考克斯-2活性位点，明确证实了考克斯-2特异性递送。由于它们的高特异性、对比度和可检测性，这些考克斯-2信标是检测炎性病变或早期表达考克斯-2的人类癌症（如食管、口咽和结肠中的癌症）的理想候选物。
Effective diagnosis of inflammation and cancer by molecular imaging is challenging because of interference from non-selective accumulation of the contrast agents in normal tissues. Here we report a series of novel fluorescence imaging agents that efficiently target cyclooxygenase-2 (COX-2), which is normally absent from cells, but is found at high levels in inflammatory lesions, and in many premalignant and malignant tumors. After either intraperitoneal or intravenous injection, these reagents become highly enriched in inflamed or tumor tissue compared to normal tissue and this accumulation provides sufficient signal for in vivo fluorescence imaging. Further, we show that only the intact parent compound is found in the region of interest. COX-2-specific delivery was unambiguously confirmed using animals bearing targeted deletions of COX-2 and by blocking the COX-2 active site with high affinity inhibitors in both in vitro and in vivo models. Because of their high specificity, contrast, and detectability, these COX-2 beacons are ideal candidates for detection of inflammatory lesions or early-stage COX-2-expressing human cancers, such as those in the esophagus, oropharynx, and colon.