Chen Xiaoyuan, Park Ryan, Tohme Michel, Shahinian Anthony H, Bading James R, Conti Peter S
PET Imaging Science Center, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA.
Bioconjug Chem. 2004 Jan-Feb;15(1):41-9. doi: 10.1021/bc0300403.
Cell adhesion molecules alphavbeta3 and alphavbeta5 play a pivotal role in tumor angiogenesis and metastasis. Antiangiogenic therapy by using small peptide antagonists of alphav-integrins slows tumor growth and prevents tumor spread. The ability to visualize and quantify integrin expression will enable selection of appropriate patients for clinical trials, following determination of treatment efficacy and development of new potent drugs. We have previously labeled cyclic RGD peptide c(RGDyK) with 125I and 18F and applied the radiotracers to both subcutaneous and orthotopic brain tumor models. Here we conjugated c(RGDyK) with 1,4,7,10-tetraaza-1,4,7,10-tetradodecane-N,N',N' ',N' "-tetraacetic acid (DOTA) and labeled the DOTA-RGD conjugate with 64Cu (t1/2) = 12.8 h, 19% beta+) in high radiochemical purity and specific activity. The tumor targeting ability and in vivo kinetics of 64Cu-DOTA-RGD was compared with [18F]FB-RGD and 125I-RGD in orthotopic MDA-MB-435 breast cancer model. All three radiotracers revealed fast blood clearance and high tumor-to-blood and tumor-to-muscle ratios. 125I-RGD had higher tumor uptake than the corresponding 18F and 64Cu analogues. [18F]FB-RGD indicated a fast tumor washout rate and an unfavorable hepatobiliary excretion pathway, resulting in significant activity accumulation in gallbladder and intestines. 64Cu-DOTA-RGD had prolonged tumor retention (1.44 +/- 0.09 %ID/g at 4 h postinjection) and persistent uptake in the liver. All three tracers revealed receptor specific tumor accumulation which were illustrated by effective blocking via coinjection with a blocking dose of c(RGDyK). Static microPET imaging and whole-body autoradiography showed strong contrast from the contralateral background. In conclusion, overall molecular charge and characteristics of radiolabels have profound effects on tumor accumulation and in vivo kinetics of radiolabeled RGD peptide. Further modification of the RGD peptide and optimization of the tracer for prolonged tumor uptake and improved in vivo kinetics are being explored.
细胞黏附分子αvβ3和αvβ5在肿瘤血管生成和转移中起关键作用。使用αv整合素的小肽拮抗剂进行抗血管生成治疗可减缓肿瘤生长并防止肿瘤扩散。在确定治疗效果和开发新的强效药物后，可视化和量化整合素表达的能力将有助于选择合适的患者进行临床试验。我们之前已用125I和18F标记环状RGD肽c(RGDyK)，并将放射性示踪剂应用于皮下和原位脑肿瘤模型。在此，我们将c(RGDyK)与1,4,7,10-四氮杂环十二烷-N,N',N'',N'''-四乙酸（DOTA）偶联，并用64Cu（半衰期 = 12.8小时，19%为β+）标记DOTA-RGD偶联物，其放射化学纯度和比活度均很高。在原位MDA-MB-435乳腺癌模型中，比较了64Cu-DOTA-RGD与[18F]FB-RGD和125I-RGD的肿瘤靶向能力和体内动力学。所有三种放射性示踪剂均显示出快速的血液清除以及高肿瘤与血液和肿瘤与肌肉的比值。125I-RGD的肿瘤摄取高于相应的18F和64Cu类似物。[18F]FB-RGD显示出快速的肿瘤洗脱率和不利的肝胆排泄途径，导致胆囊和肠道中有大量放射性活性积聚。64Cu-DOTA-RGD具有延长的肿瘤滞留时间（注射后4小时为1.44±0.09 %ID/g）和在肝脏中的持续摄取。所有三种示踪剂均显示出受体特异性的肿瘤积聚，通过与阻断剂量的c(RGDyK)共同注射进行有效阻断可证明这一点。静态微型PET成像和全身放射自显影显示与对侧背景有强烈对比。总之，放射性标记物的整体分子电荷和特性对放射性标记的RGD肽的肿瘤积聚和体内动力学有深远影响。正在探索对RGD肽进行进一步修饰以及优化示踪剂以延长肿瘤摄取并改善体内动力学。
