Department of Translational Imaging, Houston Methodist Research Institute , Weill Medical College of Cornell University , 6670 Bertner Avenue, Houston, Texas 77030, United States.
Bioconjug Chem. 2013 Nov 20;24(11):1937-44. doi: 10.1021/bc400374t. Epub 2013 Oct 23.
Tumor angiogenesis is an important component of cancer biology driven in part by the hypothesis that tumor vessel growth is a necessary requirement for tumor growth. Angiogenesis does not only depend on endothelial cell invasion and proliferation, it also requires pericyte coverage of vascular sprouts for vessel stabilization. These processes are coordinated by vascular endothelial growth factor (VEGF). Vandetanib, also known as ZD6474, is an orally bioavailable small molecule tyrosine kinase inhibitor of multiple growth factors that is an antagonist of the vascular endothelial growth factor receptor-2 (VEGFR-2). ZD6474 was purchased and modified to add a fluorescent dye (6-FAM). A linker was used to couple the ZD6474 monomer to create dimers, and similarly linked to FAM fluorescent dye. The two compounds were compared using human endothelial cell (HUVECs) and the cancer cell lines U-87-MG and MDA-MB-231. We compared cellular uptake and binding specificity, as well as effects on cellular viability and angiogenesis in a series of in vitro and in vivo studies. ZD6474 dimer demonstrated improved uptake in HUVECs and other VEGFR expressing cells over ZD6474 monomer in vitro. Therapeutic effects were mixed, with in vitro studies showing the dimer having the same or weaker effects compared to the monomer, while an in vivo study using pseudotumors (matrigel plug assay) seemed to indicate stronger effects could be obtained from the dimer. Finally, in biodistribution study in a xenograft tumor model, the dimer accumulated 20× greater concentration in the tumor than in the liver, spleen, or kidneys, and also 20× greater than the accumulation of the monomer or the dye alone, all at 24 h following compound injection. This study provides a rationale for the evaluation of dimeric ZD6474 as a potent imaging agent of angiogenic activity in vivo.
肿瘤血管生成是癌症生物学的一个重要组成部分，部分是基于这样的假设，即肿瘤血管生长是肿瘤生长的必要条件。血管生成不仅依赖于内皮细胞的侵袭和增殖，还需要周细胞覆盖血管芽以稳定血管。这些过程由血管内皮生长因子(VEGF)协调。凡德他尼，也称为 ZD6474，是一种口服生物利用的小分子酪氨酸激酶抑制剂，可抑制多种生长因子，是血管内皮生长因子受体-2(VEGFR-2)的拮抗剂。ZD6474 被购买并修改，添加了一个荧光染料(6-FAM)。使用一个接头将 ZD6474 单体连接起来形成二聚体，并与 FAM 荧光染料类似地连接。在一系列体外和体内研究中，比较了这两种化合物在人内皮细胞(HUVEC)和癌细胞系 U-87-MG 和 MDA-MB-231 中的细胞摄取和结合特异性，以及对细胞活力和血管生成的影响。与 ZD6474 单体相比，ZD6474 二聚体在体外显示出在 HUVECs 和其他表达 VEGFR 的细胞中摄取的改善。治疗效果参差不齐，体外研究表明二聚体与单体相比具有相同或较弱的效果，而在使用假性肿瘤(基质胶植入物测定)的体内研究中，似乎表明二聚体可以获得更强的效果。最后，在异种移植肿瘤模型中的生物分布研究中，二聚体在肿瘤中的浓度比在肝脏、脾脏或肾脏中的浓度高 20 倍，比单体或单独染料的浓度高 20 倍，在化合物注射后 24 小时。这项研究为评估二聚体 ZD6474 作为体内血管生成活性的有效成像剂提供了依据。
