In vivo near-infrared fluorescence imaging of CD105 expression during tumor angiogenesis.
In vivo near-infrared fluorescence imaging of CD105 expression during tumor angiogenesis.
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DOI：
10.1007/s00259-011-1886-x
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发表时间：
2011-11
影响因子：
9.1
通讯作者：
Cai, Weibo
中科院分区：
文献类型：
--
作者：
Yang, Yunan;Zhang, Yin;Hong, Hao;Liu, Glenn;Leigh, Bryan R.;Cai, Weibo
关键词：
血管生成是肿瘤发生发展过程中不可缺少的一个过程。目前公认的定量肿瘤血管生成的标准方法是基于CD 105染色评估微血管密度（MVD），这是大多数实体瘤类型患者生存的独立预后因素。本研究的目的是通过近红外荧光（NIRF）成像CD 105表达来评估小鼠模型中的肿瘤血管生成。TRC 105是一种人/鼠嵌合抗CD 105单克隆抗体，与NIRF染料（IRDye 800 CW; Ex：778 nm; Em：806 nm）偶联。进行FACS分析和显微镜研究以比较TRC 105和800 CW-TRC 105的CD 105结合亲和力。对4 T1鼠乳腺肿瘤荷瘤小鼠进行体内/离体NIRF成像、阻断研究和离体组织学，以评价800 CW-TRC 105靶向肿瘤血管生成的能力。另一种嵌合抗体西妥昔单抗用作同种型匹配的对照。HUVEC的FACS分析显示TRC 105和800 CW-TRC 105之间的CD 105结合亲和力没有差异，这通过荧光显微镜进一步验证。TRC 105的800 CW缀合以优异的产率（> 85%）实现，每个TRC 105平均具有0.4个800 CW分子。静脉注射800 CW-TRC 105后的连续NIRF成像显示，早在注射后30分钟，4 T1肿瘤就可以清楚地可视化。定量感兴趣区域（ROI）分析显示，肿瘤摄取在注射后约16小时达到峰值。基于注射后48小时的离体NIRF成像，800 CW-TRC 105的肿瘤摄取高于大多数器官，因此提供了优异的肿瘤对比度。阻断实验、800 CW-Cetuximab和800 CW的对照研究以及离体组织学都证实了800 CW-TRC 105的体内靶特异性。这是第一个成功的CD 105在体内表达的NIRF成像研究。在小鼠模型中观察到肿瘤血管生成期间探针的快速、显著、持续和CD 105特异性摄取。800 CW-TRC 105可用于临床，对靠近皮肤表面的病变、内窥镜可触及的组织或图像引导手术期间的肿瘤血管生成进行成像。
Angiogenesis is an indispensable process during tumor development. The currently accepted standard method for quantifying tumor angiogenesis is to assess microvessel density (MVD) based on CD105 staining, which is an independent prognostic factor for survival in patients of most solid tumor types. The goal of this study is to evaluate tumor angiogenesis in a mouse model by near-infrared fluorescence (NIRF) imaging of CD105 expression. TRC105, a human/murine chimeric anti-CD105 monoclonal antibody, was conjugated to a NIRF dye (IRDye 800CW; Ex: 778 nm; Em: 806 nm). FACS analysis and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and 800CW-TRC105. In vivo/ex vivo NIRF imaging, blocking studies, and ex vivo histology were performed on 4T1 murine breast tumor-bearing mice to evaluate the ability of 800CW-TRC105 to target tumor angiogenesis. Another chimeric antibody, Cetuximab, was used as an isotype-matched control. FACS analysis of HUVECs revealed no difference in CD105 binding affinity between TRC105 and 800CW-TRC105, which was further validated by fluorescence microscopy. 800CW conjugation of TRC105 was achieved in excellent yield (> 85%), with an average of 0.4 800CW molecules per TRC105. Serial NIRF imaging after intravenous injection of 800CW-TRC105 revealed that the 4T1 tumor could be clearly visualized as early as 30 minutes post-injection. Quantitative region-of-interest (ROI) analysis showed that the tumor uptake peaked at about 16 h post-injection. Based on ex vivo NIRF imaging at 48 h post-injection, tumor-uptake of 800CW-TRC105 was higher than most organs thus providing excellent tumor contrast. Blocking experiments, control studies with 800CW-Cetuximab and 800CW, as well as ex vivo histology all confirmed the in vivo target specificity of 800CW-TRC105. This is the first successful NIRF imaging study of CD105 expression in vivo. Fast, prominent, persistent, and CD105-specific uptake of the probe during tumor angiogenesis was observed in mouse models. 800CW-TRC105 may be used in the clinic for imaging tumor angiogenesis within the lesions close to the skin surface, tissues accessible by endoscopy, or during image-guided surgery.
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