MicroPET imaging of breast cancer αv-integrin expression with 64Cu-labeled dimeric RGD peptides
MicroPET imaging of breast cancer αv-integrin expression with 64Cu-labeled dimeric RGD peptides
复制标题
DOI：
10.1016/j.mibio.2004.06.004
复制
发表时间：
2004-09-01
影响因子：
3.1
通讯作者：
Conti, PS
中科院分区：
文献类型：
--
作者：
Chen, XY;Liu, S;Conti, PS
目的：α(v)β(3)和α(v)β(5)整合素是细胞黏附分子，在肿瘤血管生成和转移中起着至关重要的作用。能够在体内对整合素表达进行可视化和定量分析，将增进我们对α(v)β(3)和α(v)β(5)整合素在肿瘤血管生成中作用的理解，并能够基于整合素拮抗剂直接评估抗血管生成治疗的疗效。本研究比较了两种二聚体Cu - 64标记的α(v)β(3)整合素RGD肽激动剂的肿瘤靶向特性。
方法：二聚体RGD肽E[c(RGDyK)](2)和E[c(RGDfK)](2)与1,4,7,10 - 四氮杂十二烷 - N,N',N",N"'-四乙酸（DOTA）偶联，并用正电子发射体Cu - 64（半衰期t(1/2)=12.8小时，β(+)=19%）标记。Cu - 64 - DOTA - E[c(RGDyK)](2)和Cu - 64 - DOTA - E[c(RGDfK)](2)都用于在原位生长MDA - MB - 435乳腺癌异种移植物的无胸腺雌性裸鼠中进行生物分布、微型正电子发射断层扫描成像和全身放射自显影研究。
结果：在所有时间点，Cu - 64 - DOTA - E[c(RGDyK)](2)在肿瘤中的放射性活度积累均显著高于D - Phe类似物。在早期时间点，D - Tyr衍生物在肝脏的摄取低于D - Phe衍生物，但随着时间推移差异变得很小。总体而言，在携带原位MDA - MB - 435的小鼠中，Cu - 64 - DOTA - E[c(RGDyK)](2)比Cu - 64 - DOTA - E[c(RGDfK)](2)产生更好的正电子发射断层扫描（PET）图像。两种放射性示踪剂都有α(v) - 整合素特异性的肿瘤放射性活度积累，如共同注射阻断剂量的c(RGDyK)后摄取显著降低所证明的那样。
结论：放射性标记的二聚体RGD肽Cu - 64 - DOTA - E[c(RGDyK)](2)和Cu - 64 - DOTA - E[c(RGDfK)](2)在人乳腺癌肿瘤异种移植物中有高且特异性的肿瘤摄取，D - Tyr衍生物在体内动力学方面优于D - Phe衍生物，很可能是由于D - Tyr的亲水性增加。两种二聚体肽都比先前测试的单体RGD对应物表现出更好的肿瘤滞留，可能是因为其二价性和表观分子大小的增加。（C）2004爱思唯尔公司。保留所有权利。
PURPOSE: Alpha(v)beta(3) and alpha(v)beta(5) integrins are cell adhesion molecules that play a vital role in tumor angiogenesis and metastasis.-The ability to visualize and quantify integin expression in vivo will foster our understanding of the role of integrins alpha(v)beta(3) and alpha(v)beta(5) in tumor angiogenesis and allow for direct assessment of anti-angiogenic treatment efficacy based on integrin antagonists. This study compared the tumor targeting characteristics of two dimeric Cu-64-labeled RGD peptide agonists of alpha(v)beta(3) integrin.PROCEDURES: Dimeric RGD peptides E[c(RGDyK)](2) and E[c(RGDfK)](2) were conjugated with 1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid (DOTA) and labeled with positron emitter Cu-64(t(1/2) = 12.8 h, beta(+) = 19%). Both Cu-64-DOTA-E[c(RGDyK)](2) and Cu-64-DOTA-E[c(RGDfK)](2) were used in biodistribution, microPET imaging and whole-body autoradiography studies in athymic female nude mice with orthotopically growing MDA-MB-435 breast carcinoma xenografts.RESULTS: At all time points, activity accumulation of Cu-64-DOTA-E [c(RGDyK)](2) in tumors was significantly higher compared to the D-Phe analog. Liver uptake of the D-Tyr derivative was lower than the D-Phe derivative at early time points but the difference became marginal with time. Overall, Cu-64-DOTA-E[c(RGDyK)](2) yielded better position emission tomography (PET) images in orthotopic MDA-MB-435 bearing mice than did Cu-64-DOTA-E[c(RGDfK)](2). Both radiotracers had alpha(v)-integrin specific tumor activity accumulation, as demonstrated by significant reduction of uptake with a coinjected blocking dose of c(RGDyK).CONCLUSIONS: The radiolabeled dimeric RGD peptides Cu-64-DOTA-E[c(RGDyK)](2) and Cu-64-DOTA-E[c(RGDfK)](2) have high and specific tumor uptake in a human breast cancer tumor xenograft, with the D-Tyr derivative showing better in vivo kinetics than the D-Phe derivative, most likely due to the increased hydrophilicity of the D-Tyr. Both dimeric peptides showed better tumor retention than the previously tested monomeric RGD counterparts, presumably because of bivalency and increase in apparent molecular size. (C) 2004 Elsevier Inc. All rights reserved.