Han Jingya, Chen Yang, Zhao Yan, Zhao Xinming, Zhang Jingmian, Wang Jianfang, Zhang Zhaoqi
Department of Nuclear Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Front Med (Lausanne). 2022 Feb 16;9:803005. doi: 10.3389/fmed.2022.803005. eCollection 2022.
Human epidermal growth factor receptor 2 (HER2) is an important biomarker in gastric cancer (GC) and directly influences the therapeutic effect. Fluorine is firmly bound to Al forming [F]AlF-1,4,7-triazacyclononanetriacetic acid (NOTA)-HER2 affibody is a promising radiolabeled tracer that can monitor the changes of HER2 expression combining the advantages of simple preparation and the properties of F. The aim of this study was to develop a quick method for the synthesis of [F]AlF-NOTA-HER2 affibody and evaluate its utility for HER2+ GC imaging in mouse models. Moreover, Ga-NOTA-HER2 affibody imaging was also performed to highlight the superiority of [F]AlF-NOTA-HER2 affibody imaging in resolution. The HER2 affibody was conjugated with NOTA and labeled using F based on the complexation of [F]AlF by NOTA. Its quality control and stability were performed by high-pressure liquid chromatography (HPLC). The molecular specificity and binding affinity of the novel radiotracer were evaluated in the GC cell line with HER2 overexpression (NCI-N87) and negative expression (MKN74). Distribution studies and PET/CT imaging were performed in mouse models. Ga-NOTA-HER2 affibody PET/CT imaging was also performed. [F]AlF-NOTA-HER2 affibody was efficiently prepared within 30 min with a non-decay-corrected maximum yield of 32.69% and a radiochemical purity of more than 98%. [F]AlF-NOTA-HER2 affibody was highly stable in incubation medium for 4 h and in the blood of nude mice at 30 min post-injection (p.i.). studies revealed specific binding and high binding affinity of the probe in NCI-N87 cells, while no binding was seen in MKN74 cells. PET imaging showed that NCI-N87 xenografts were differentiated from MKN74 xenografts with excellent contrast and low abdominal background, which was confirmed by the distribution results. High-level accumulation of the [F]AlF-NOTA-HER2 affibody in HER2+ tumors was blocked by excess unlabeled NOTA-HER2 affibody. [F]AlF-NOTA-HER2 affibody has a higher image resolution than that of Ga-NOTA-HER2 affibody. [F]AlF-NOTA-HER2 affibody could be produced facilely with high radiochemical yield and may serve as a novel molecular probe with tremendous clinical potential for the non-invasive whole-body detection of the HER2 status in GC with good image contrast and resolution. This method could provide an understanding of GC biology that will ultimately guide the accurate diagnosis and treatment of GC.
人表皮生长因子受体2（HER2）是胃癌（GC）中的一种重要生物标志物，直接影响治疗效果。氟与铝紧密结合形成[F]AlF-1,4,7-三氮杂环壬烷三乙酸（NOTA）-HER2亲和体，是一种很有前景的放射性标记示踪剂，结合了制备简单的优点和氟的特性，可监测HER2表达的变化。本研究的目的是开发一种快速合成[F]AlF-NOTA-HER2亲和体的方法，并评估其在小鼠模型中对HER2阳性胃癌成像的效用。此外，还进行了镓-NOTA-HER2亲和体成像，以突出[F]AlF-NOTA-HER2亲和体成像在分辨率方面的优势。HER2亲和体与NOTA偶联，并基于NOTA对[F]AlF的络合作用用氟进行标记。通过高压液相色谱（HPLC）进行其质量控制和稳定性检测。在HER2过表达（NCI-N87）和阴性表达（MKN74）的胃癌细胞系中评估了这种新型放射性示踪剂的分子特异性和结合亲和力。在小鼠模型中进行了分布研究和PET/CT成像。还进行了镓-NOTA-HER2亲和体PET/CT成像。[F]AlF-NOTA-HER2亲和体在30分钟内高效制备，未校正衰变的最大产率为32.69%，放射化学纯度超过98%。[F]AlF-NOTA-HER2亲和体在孵育介质中4小时以及在裸鼠注射后30分钟的血液中高度稳定。研究显示该探针在NCI-N87细胞中有特异性结合和高结合亲和力，而在MKN74细胞中未见结合。PET成像显示NCI-N87异种移植瘤与MKN74异种移植瘤有明显区分，对比度良好且腹部背景低，分布结果证实了这一点。过量未标记的NOTA-HER2亲和体可阻断[F]AlF-NOTA-HER2亲和体在HER2阳性肿瘤中的高水平积聚。[F]AlF-NOTA-HER2亲和体的图像分辨率高于镓-NOTA-HER2亲和体。[F]AlF-NOTA-HER2亲和体可以轻松制备，放射化学产率高，可作为一种新型分子探针，在胃癌HER2状态的无创全身检测中具有巨大临床潜力，图像对比度和分辨率良好。该方法有助于理解胃癌生物学，最终指导胃癌的准确诊断和治疗。
