用 18F 标记的亲和体分子 ZHER2:2395 对人表皮生长因子受体 2 表达的成像：卵巢癌小鼠模型。

Imaging of human epidermal growth factor receptor type 2 expression with 18F-labeled affibody molecule ZHER2:2395 in a mouse model for ovarian cancer.

机构信息

Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

出版信息

J Nucl Med. 2012 Jan;53(1):146-53. doi: 10.2967/jnumed.111.093047. Epub 2011 Dec 15.

DOI:10.2967/jnumed.111.093047

PMID:22173842

Abstract

UNLABELLED

Affibody molecules are small (7 kDa) proteins with subnanomolar targeting affinity. Previous SPECT studies in xenografts have shown that the Affibody molecule (111)In-DOTA-Z(HER2)(:2395) can discriminate between high and low human epidermal growth factor receptor type 2 (HER2)-expressing tumors, indicating that radiolabeled Affibody molecules have potential for patient selection for HER2-targeted therapy. Compared with SPECT, PET with positron-emitting radionuclides, such as (18)F, may improve imaging of HER2 expression because of higher sensitivity and improved quantification of PET. The aim of the present study was to determine whether the (18)F-labeled NOTA-conjugated Affibody molecule Z(HER2)(:2395) is a suitable agent for imaging of HER2 expression. The tumor-targeting properties of (18)F-labeled Z(HER2)(:2395) were compared with (111)In- and (68)Ga-labeled Z(HER2)(:2395) in mice with HER2-expressing SK-OV-3 xenografts.

METHODS

Z(HER2)(:2395) was conjugated with NOTA and radiolabeled with (18)F, (68)Ga, and (111)In. Radiolabeling with (18)F was based on the complexation of Al(18)F by NOTA. The 50% inhibitory concentration values for NOTA-Z(HER2)(:2395) labeled with (19)F, (69)Ga, and (115)In were determined in a competitive cell-binding assay using SK-OV-3 cells. Mice bearing subcutaneous SK-OV-3 xenografts were injected intravenously with radiolabeled NOTA-Z(HER2)(:2395). One and 4 h after injection, PET/CT or SPECT/CT images were acquired, and the biodistribution was determined by ex vivo measurement.

RESULTS

The 50% inhibitory concentration values for (19)F-, (69)Ga-, and (115)In-NOTA-Z(HER2)(:2395) were 5.0, 6.3, and 5.3 nM, respectively. One hour after injection, tumor uptake was 4.4 ± 0.8 percentage injected dose per gram (%ID/g), 5.6 ± 1.6 %ID/g, and 7.1 ± 1.4 %ID/g for (18)F-, (68)Ga-, and (111)In-NOTA-Z(HER2)(:2395), respectively, and the respective tumor-to-blood ratios were 7.4 ± 1.8, 8.0 ± 1.3, and 4.8 ± 1.3. Tumor uptake was specific, because uptake could be blocked efficiently by coinjection of an excess of unlabeled Z(HER2)(:2395). PET/CT and SPECT/CT images clearly visualized HER2-expressing SK-OV-3 xenografts.

CONCLUSION

This study showed that (18)F-NOTA-Z(HER2)(:2395) is a promising new imaging agent for HER2 expression in tumors. Affibody molecules were successfully labeled with (18)F within 30 min, based on the complexation of Al(18)F by NOTA. Further research is needed to determine whether this technique can be used for patient selection for HER2-targeted therapy.

摘要

背景

亲和体分子是具有亚纳摩尔靶向亲和力的小（7 kDa）蛋白。以前的 SPECT 研究表明，亲和体分子（111）In-DOTA-Z（HER2）（：2395）可区分高和低人表皮生长因子受体 2（HER2）表达的肿瘤，表明放射性标记的亲和体分子具有用于 HER2 靶向治疗的患者选择的潜力。与 SPECT 相比，使用正电子发射放射性核素（如 18F）的 PET 可能会改善 HER2 表达的成像，因为它具有更高的灵敏度和改进的 PET 定量。本研究旨在确定（18）F 标记的 NOTA 缀合亲和体分子 Z（HER2）（：2395）是否是用于 HER2 表达成像的合适试剂。在具有 HER2 表达的 SK-OV-3 异种移植瘤的小鼠中，比较了（18）F 标记的 Z（HER2）（：2395）与（111）In 和（68）Ga 标记的 Z（HER2）（：2395）的肿瘤靶向特性。

方法

NOTA 与 Z（HER2）（：2395）缀合并用（18）F、（68）Ga 和（111）In 标记。（18）F 的放射性标记基于 Al（18）F 与 NOTA 的络合。使用 SK-OV-3 细胞进行竞争性细胞结合测定，确定用（19）F、（69）Ga 和（115）In 标记的 NOTA-Z（HER2）（：2395）的 50%抑制浓度值。在注射后 1 和 4 小时，采集 PET/CT 或 SPECT/CT 图像，并通过离体测量确定生物分布。

结果

（19）F、（69）Ga 和（115）In-NOTA-Z（HER2）（：2395）的 50%抑制浓度值分别为 5.0、6.3 和 5.3 nM。注射后 1 小时，（18）F-、（68）Ga-和（111）In-NOTA-Z（HER2）（：2395）的肿瘤摄取分别为 4.4±0.8%ID/g、5.6±1.6%ID/g 和 7.1±1.4%ID/g，相应的肿瘤与血液比分别为 7.4±1.8、8.0±1.3 和 4.8±1.3。肿瘤摄取是特异性的，因为通过共注射过量未标记的 Z（HER2）（：2395）可以有效地阻断摄取。PET/CT 和 SPECT/CT 图像清楚地可视化了具有 HER2 表达的 SK-OV-3 异种移植瘤。