Chen Xiaoyuan, Liu Shuang, Hou Yingping, Tohme Michel, Park Ryan, Bading James R, Conti Peter S
PET Imaging Science Center, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
Mol Imaging Biol. 2004 Sep-Oct;6(5):350-9. doi: 10.1016/j.mibio.2004.06.004.
Alphavbeta3 and alphavbeta5 integrins are cell adhesion molecules that play a vital role in tumor angiogenesis and metastasis. The ability to visualize and quantify integrin expression in vivo will foster our understanding of the role of integrins alphavbeta3 and alphavbeta5 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 64Cu-labeled RGD peptide agonists of alphavbeta3 integrin.
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 64Cu(t(1/2)=12.8 h, beta+=19%). Both 64Cu-DOTA-E[c(RGDyK)]2 and 64Cu-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.
At all time points, activity accumulation of 64)Cu-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, 64Cu-DOTA-E[c(RGDyK)]2 yielded better position emission tomography (PET) images in orthotopic MDA-MB-435 bearing mice than did 64Cu-DOTA-E[c(RGDfK)]2. Both radiotracers had alphav-integrin specific tumor activity accumulation, as demonstrated by significant reduction of uptake with a coinjected blocking dose of c(RGDyK).
The radiolabeled dimeric RGD peptides 64Cu-DOTA-E[c(RGDyK)]2 and 64Cu-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.
αvβ3和αvβ5整合素是细胞黏附分子，在肿瘤血管生成和转移中起关键作用。在体内可视化和定量整合素表达的能力将有助于我们理解αvβ3和αvβ5整合素在肿瘤血管生成中的作用，并能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64Cu标记的αvβ3整合素RGD肽激动剂的肿瘤靶向特性。
将二聚体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64Cu（t(1/2)=12.8小时，β+=19%）进行标记。64Cu-DOTA-E[c(RGDyK)]2和64Cu-DOTA-E[c(RGDfK)]2均用于在原位生长MDA-MB-435乳腺癌异种移植瘤的无胸腺雌性裸鼠体内进行生物分布、微型PET成像和全身放射自显影研究。
在所有时间点，与D-Phe类似物相比，64Cu-DOTA-E[c(RGDyK)]2在肿瘤中的活性积累显著更高。D-Tyr衍生物在早期肝脏摄取低于D-Phe衍生物，但随着时间推移差异变得不明显。总体而言，64Cu-DOTA-E[c(RGDyK)]2在原位携带MDA-MB-435的小鼠中产生的正电子发射断层扫描（PET）图像比64Cu-DOTA-E[c(RGDfK)]2更好。两种放射性示踪剂均有αv整合素特异性的肿瘤活性积累，共注射阻断剂量的c(RGDyK)可显著降低摄取量，证明了这一点。
放射性标记的二聚体RGD肽64Cu-DOTA-E[c(RGDyK)]2和64Cu-DOTA-E[c(RGDfK)]2在人乳腺癌异种移植瘤中具有高且特异性的肿瘤摄取，D-Tyr衍生物比D-Phe衍生物显示出更好的体内动力学，很可能是由于D-Tyr亲水性增加。两种二聚体肽均比先前测试的单体RGD对应物显示出更好的肿瘤滞留，推测是由于二价性和表观分子大小增加。
