Positron emission tomography imaging of CD105 expression with 89Zr-Df-TRC105.
Positron emission tomography imaging of CD105 expression with 89Zr-Df-TRC105.
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DOI：
10.1007/s00259-011-1930-x
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发表时间：
2012-01
影响因子：
9.1
通讯作者：
Cai W
中科院分区：
文献类型：
--
作者：
Hong H;Severin GW;Yang Y;Engle JW;Zhang Y;Barnhart TE;Liu G;Leigh BR;Nickles RJ;Cai W
高肿瘤微血管密度（MVD）与多种实体瘤类型的不良预后相关。评估MVD的临床金标准是石蜡包埋肿瘤标本的CD 105免疫组化。本研究的目的是开发一种基于89 Zr的正电子发射断层扫描（PET）示踪剂，用于CD 105表达的非侵入性成像。将嵌合抗CD 105单克隆抗体TRC 105与对异硫氰基苄基去铁胺（Df-Bz-NCS）偶联并用89 Zr标记。进行FACS分析和显微镜研究以比较TRC 105和Df-TRC 105的CD 105结合亲和力。对4 T1鼠乳腺肿瘤荷瘤小鼠进行PET成像、生物分布、阻断和离体组织学研究，以评价89 Zr-Df-TRC 105的药代动力学和肿瘤靶向功效。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Df-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。89 Zr标记具有较高的产率和比活性。连续PET成像显示，89 Zr-Df-TRC 105的4 T1肿瘤摄取在注射后5、24、48、72和96小时分别为6.1 ± 1.2、14.3 ± 1.2、12.4 ± 1.5、7.1 ± 0.9和5.2 ± 0.3%ID/g（n = 4），高于从注射后24小时开始的所有器官，这提供了极好的肿瘤对比度。通过伽马计数测量的生物分布数据与PET结果一致。阻断实验、用89 Zr-Df-西妥昔单抗的对照研究以及离体组织学都证实了89 Zr-Df-TRC 105的体内靶特异性。在这里，我们报告了第一个成功的PET成像的CD 105表达与89锆作为放射性标记。在4 T1肿瘤中观察到89 Zr-Df-TRC 105的快速、持续、CD 105特异性摄取。
High tumor microvessel density (MVD) correlates with poor prognosis in multiple solid tumor types. The clinical gold standard for assessing MVD is CD105 immunohistochemistry on paraffin-embedded tumor specimens. The goal of this study was to develop an 89Zr-based positron emission tomography (PET) tracer for non-invasive imaging of CD105 expression. TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to p-isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS) and labeled with 89Zr. FACS analysis and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and Df-TRC105. PET imaging, biodistribution, blocking, and ex vivo histology studies were performed on 4T1 murine breast tumor-bearing mice to evaluate the pharmacokinetics and tumor targeting efficacy of 89Zr-Df-TRC105. 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 Df-TRC105, which was further validated by fluorescence microscopy. 89Zr-labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the 4T1 tumor uptake of 89Zr-Df-TRC105 was 6.1 ± 1.2, 14.3 ± 1.2, 12.4 ± 1.5, 7.1 ± 0.9, and 5.2 ± 0.3 %ID/g at 5, 24, 48, 72, and 96 h post-injection respectively (n = 4), higher than all organs starting from 24 h post-injection, which provided excellent tumor contrast. Biodistribution data as measured by gamma counting were consistent with the PET findings. Blocking experiments, control studies with 89Zr-Df-cetuximab, as well as ex vivo histology all confirmed the in vivo target specificity of 89Zr-Df-TRC105. Herein we report the first successful PET imaging of CD105 expression with 89Zr as the radiolabel. Rapid, persistent, CD105-specific uptake of 89Zr-Df-TRC105 in the 4T1 tumor was observed.