Zhu Keying, Tang Shimin, Pan Donghui, Wang Xinyu, Xu Yuping, Yan Junjie, Wang Lizhen, Chen Chongyang, Yang Min
School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, 214063, Wuxi, China.
Eur J Nucl Med Mol Imaging. 2025 Jan 31. doi: 10.1007/s00259-025-07107-3.
Low-dose CT (LDCT) screening effectively reduces lung adenocarcinoma (LUAD) mortality. However, accurately evaluating the malignant potential of indeterminate lung nodules remains a challenge. Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6), a potential biomarker for distinguishing benign pulmonary nodules from LUAD, may be leveraged for noninvasive positron emission tomography (PET) imaging to aid LUAD diagnosis.
This study utilized mRNA, protein, and survival datasets of LUAD patients, along with an animal model of malignant pulmonary nodules, to investigate CEACAM6 expression specificity and its correlation with LUAD. Targeting ligands for CEACAM6 were designed using the Rosetta platform, labeled with [Ga]Ga, and screened through high-throughput PET imaging to identify the optimal tracer.
CEACAM6 was found to be specifically overexpressed in LUAD and was significantly associated with poor prognosis and disease progression. In vivo, [Ga]Ga-NODA-P3 demonstrated high specificity for delineating CEACAM6-positive A549 xenografts, a LUAD model, via PET imaging, achieving a highest target-to-background ratio of 7.68 ± 0.44. Region of interest (ROI) analysis showed significantly higher tracer uptake in A549 xenografts compared to CEACAM6-negative Huh7 xenografts (a hepatocellular carcinoma model) at 30 min post-injection (1.81 ± 0.10%ID/g vs. 0.54 ± 0.06%ID/g). Pre-treatment with an excess of unlabeled NODA-P3 significantly reduced tumor uptake to 0.52 ± 0.07%ID/g.
These preclinical findings indicate that [Ga]Ga-NODA-P3 is a candidate radiotracer for the non-invasive visualization of CEACAM6-positive LUAD, demonstrating favorable imaging contrast. Although the current tumor uptake limits its immediate clinical application, ongoing optimization efforts are expected to improve its efficacy, enabling earlier and more accurate diagnosis of malignant pulmonary nodules in LUAD.
低剂量计算机断层扫描（LDCT）筛查可有效降低肺腺癌（LUAD）死亡率。然而，准确评估肺内不确定结节的恶性潜能仍是一项挑战。癌胚抗原细胞粘附分子6（CEACAM6）作为一种区分良性肺结节与LUAD的潜在生物标志物，可用于非侵入性正电子发射断层扫描（PET）成像以辅助LUAD诊断。
本研究利用LUAD患者的mRNA、蛋白质和生存数据集以及恶性肺结节动物模型，研究CEACAM6的表达特异性及其与LUAD的相关性。使用Rosetta平台设计针对CEACAM6的靶向配体，用[Ga]Ga标记，并通过高通量PET成像进行筛选以确定最佳示踪剂。
发现CEACAM6在LUAD中特异性过表达，且与预后不良和疾病进展显著相关。在体内，[Ga]Ga-NODA-P3通过PET成像对描绘CEACAM6阳性A549异种移植瘤（一种LUAD模型）具有高特异性，实现了7.68±0.44的最高靶本比。感兴趣区（ROI）分析显示，注射后30分钟时，A549异种移植瘤中的示踪剂摄取显著高于CEACAM6阴性的Huh7异种移植瘤（一种肝细胞癌模型）（1.81±0.10%ID/g对0.54±0.06%ID/g）。用过量未标记的NODA-P3预处理可将肿瘤摄取显著降低至0.52±0.07%ID/g。
这些临床前研究结果表明，[Ga]Ga-NODA-P3是用于CEACAM6阳性LUAD非侵入性可视化的候选放射性示踪剂，显示出良好的成像对比度。尽管目前的肿瘤摄取限制了其立即临床应用，但正在进行的优化努力有望提高其疗效，从而能够更早、更准确地诊断LUAD中的恶性肺结节。
