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Quantitative Imaging of the Hypoxia-Related Marker CAIX in Head and Neck Squamous Cell Carcinoma Xenograft Models
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2018-12-14 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00950
Fokko J. Huizing , Bianca A. W. Hoeben , Gerben M. Franssen , Otto C. Boerman , Sandra Heskamp , Johan Bussink

Tumor hypoxia plays a major role in radio- and chemotherapy resistance in solid tumors. Carbonic Anhydrase IX (CAIX) is an endogenous hypoxia-related protein, which is associated with poor patient outcome. The quantitative assessment of CAIX expression of tumors may steer cancer treatment by predicting therapy response or patient selection for antihypoxia or CAIX-targeted treatment. Recently, the single-photon emission computerized tomography (SPECT) tracer [111In]In-DTPA-girentuximab-F(ab′)2 was developed and validated for targeting CAIX. The aim of this study was to optimize quantitative microSPECT/CT of CAIX expression in vivo in head and neck tumor models. Athymic mice with subcutaneous SCCNij153 and SCCNij202 head and neck squamous cell carcinoma xenografts were injected with [111In]In-DTPA-girentuximab-F(ab′)2. First, the protein dose, timing, and image acquisition settings were optimized. Tracer uptake was determined by quantitative SPECT, ex vivo radioactivity counting, and by autoradiography of tumor sections. The same tumor sections were immunohistochemically stained for CAIX expression and hypoxia. Highest tumor-normal-tissue contrast was obtained at 24 h after injection of the tracer. A protein dose of 10 μg resulted in the highest tumor-to-muscle ratio at 24 h p.i. Ex vivo biodistribution studies showed a tumor uptake of 3.0 ± 0.6%ID/g and a tumor-to-muscle ratio of 8.7 ± 1.4 (SCCNij153). Quantitative analysis of the SPECT images enabled us to distinguish CAIX antigen blocked from nonblocked tumors, fractions positive for CAIX expression: 0.22 ± 0.02 versus 0.08 ± 0.01 (p < 0.01). Immunohistochemical, autoradiographic, and microSPECT/CT analyses showed a distinct intratumoral spatial correlation between localization of the radiotracer and CAIX expression. Here, we demonstrate that [111In]In-DTPA-girentuximab-F(ab′)2 specifically targets CAIX-expressing cells in head and neck cancer xenografts. SPECT imaging with indium-labeled girentuximab-F(ab′)2 allows quantitative assessment of the fraction of CAIX positive tissue in head and neck cancer xenografts. These results indicate that [111In]In-DTPA-girentuximab-F(ab′)2 is a promising tracer to image hypoxia-related CAIX expression.

中文翻译:

缺氧相关标志物CAIX在头颈部鳞状细胞癌异种移植模型中的定量成像。

肿瘤缺氧在实体瘤的放疗和化疗耐药中起主要作用。碳酸酐酶IX(CAIX)是一种内源性缺氧相关蛋白,与患者预后不良相关。对CAIX肿瘤表达的定量评估可以通过预测治疗反应或针对低氧或CAIX靶向治疗的患者选择来指导癌症治疗。最近,开发了单光子发射计算机断层扫描(SPECT)示踪剂[ 111 In] In-DTPA-girentuximab-F(ab')2并验证了其可用于靶向CAIX。这项研究的目的是优化体内CAIX表达的定量microSPECT / CT在头颈部肿瘤模型中。将[ 111 In] In-DTPA-girentuximab-F(ab')2注射至皮下SCCNij153和SCCNij202头颈部鳞状细胞癌异种移植的无胸腺小鼠。首先,对蛋白质剂量,时间和图像采集设置进行了优化。通过定量SPECT,离体放射性计数和肿瘤切片的放射自显影确定示踪剂摄取。对相同的肿瘤切片进行免疫组织化学染色以检测CAIX表达和缺氧情况。注射示踪剂后24小时获得了最高的肿瘤正常组织对比度。蛋白剂量为10μg,在离体后24 h的肿瘤与肌肉比例最高生物分布研究表明,肿瘤吸收率为3.0±0.6%ID / g,肿瘤与肌肉的比例为8.7±1.4(SCCNij153)。SPECT图像的定量分析使我们能够区分CAIX抗原和非阻断肿瘤,CAIX表达阳性的分数为:0.22±0.02与0.08±0.01(p <0.01)。免疫组织化学,放射自显影和microSPECT / CT分析显示,放射性示踪剂的定位与CAIX表达之间存在明显的肿瘤内空间相关性。在这里,我们证明[ 111 In] In-DTPA-girentuximab-F(ab')2特异性靶向头颈部癌异种移植物中表达CAIX的细胞。铟标记的girentuximab-F(ab')2的SPECT成像可以定量评估头颈部癌异种移植物中CAIX阳性组织的比例。这些结果表明[ 111 In] In-DTPA-girentuximab-F(ab')2是图像缺氧相关的CAIX表达的有前途的示踪剂。
更新日期:2018-12-14
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