Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
Department of PET/CT Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
Theranostics. 2024 Sep 30;14(16):6337-6349. doi: 10.7150/thno.99025. eCollection 2024.
C-X-C motif chemokine receptor 4 (CXCR4) is an attractive target for the diagnosis and treatment of cancers. Here, we aimed to develop a new CXCR4-targeted PET tracer, and to investigate the translational potential for noninvasive imaging of CXCR4 expression in various cancer entities through preclinical and pilot clinical studies. [F]AlF-NOTA-QHY-04 was synthesized and evaluated by cellular uptake, blocking and biolayer interferometry studies . The pharmacokinetics, biodistribution, and imaging specificity were researched in tumor-bearing mice. [F]AlF-NOTA-QHY-04 PET/CT imaging was performed on 55 patients with different types of cancers. Correlations between CXCR4 expression and PET parameters, and CXCR4 expression characteristics in different tumors were analyzed by histopathological staining in patients. [F]AlF-NOTA-QHY-04 was prepared with high radiolabeling yield and radiochemical purity, exhibiting good stability, high binding affinity and specificity for CXCR4 NCI-H69 (small cell lung cancer, SCLC) tumor-bearing mice showed the highest tumor uptake (4.98 ± 0.98%ID/mL, < 0.0001) on PET imaging except for Daudi lymphoma xenograft model, which was consistent with the results of cellular and histological analyses. Patients with diffuse large B-cell lymphoma showed the highest tumor uptake (SUV, 11.10 ± 4.79) followed by SCLC patients (SUV, 7.51 ± 3.01), which were both significantly higher than other solid tumors ( < 0.05). The radiotracer uptake of high-grade gliomas is significantly higher than that of low-grade gliomas (3.13 ± 0.58 vs. 1.18 ± 0.51, = 0.005). Significant higher tumor-to-normal brain ratio of [F]AlF-NOTA-QHY-04 than [F]FDG was found in primary brain tumors (62.55 ± 43.24 vs 1.70 ± 0.25, = 0.027). Positive correlations between CXCR4 expression and [F]AlF-NOTA-QHY-04 uptake (all < 0.01) were recorded. Multicolor immunofluorescence staining indicated the high tracer uptake in certain patients was mainly due to the high expression of CXCR4 in tumor cells, followed by macrophages. The CXCR4-targeted radiotracer [F]AlF-NOTA-QHY-04 was successfully prepared with favorable yield, high specificity and binding affinity to CXCR4. Preclinical and pilot clinical studies demonstrated its feasibility and potential application in precise diagnosis for not only lymphoma but also SCLC and glioma. [F]AlF-NOTA-QHY-04 PET/CT can also provide a complementary mapping for brain tumors to [F]FDG PET/CT.
C-X-C 基序趋化因子受体 4（CXCR4）是诊断和治疗癌症的有吸引力的靶标。在这里，我们旨在开发一种新的 CXCR4 靶向 PET 示踪剂，并通过临床前和初步临床研究研究非侵入性成像 CXCR4 表达在各种癌症实体中的转化潜力。 [F]AlF-NOTA-QHY-04 通过细胞摄取、阻断和生物层干涉研究进行了合成和评估。在荷瘤小鼠中研究了[F]AlF-NOTA-QHY-04 的药代动力学、生物分布和成像特异性。对 55 名患有不同类型癌症的患者进行了[F]AlF-NOTA-QHY-04 PET/CT 成像。通过患者的组织病理学染色分析了 CXCR4 表达与 PET 参数之间的相关性，以及不同肿瘤中 CXCR4 表达的特征。 [F]AlF-NOTA-QHY-04 具有高放射性标记产率和高放射性化学纯度，表现出良好的稳定性，对 NCI-H69（小细胞肺癌，SCLC）荷瘤小鼠的 CXCR4 具有高结合亲和力和特异性。除了 Daudi 淋巴瘤异种移植模型外，SCLC 患者的肿瘤摄取率最高（4.98±0.98%ID/mL， < 0.0001），与细胞和组织学分析结果一致。弥漫性大 B 细胞淋巴瘤患者的肿瘤摄取率最高（SUV，11.10±4.79），其次是 SCLC 患者（SUV，7.51±3.01），均明显高于其他实体瘤（ < 0.05）。高级别胶质瘤的放射性示踪剂摄取明显高于低级别胶质瘤（3.13±0.58 比 1.18±0.51， = 0.005）。在原发性脑肿瘤中，[F]AlF-NOTA-QHY-04 的肿瘤与正常脑比值明显高于[F]FDG（62.55±43.24 比 1.70±0.25， = 0.027）。记录到 CXCR4 表达与[F]AlF-NOTA-QHY-04 摄取之间存在正相关（均 < 0.01）。多色免疫荧光染色表明，某些患者的高示踪剂摄取主要归因于肿瘤细胞中 CXCR4 的高表达，其次是巨噬细胞。成功制备了 CXCR4 靶向放射性示踪剂[F]AlF-NOTA-QHY-04，其产率高、特异性和与 CXCR4 的结合亲和力高。临床前和初步临床研究证明，它不仅对淋巴瘤，而且对 SCLC 和神经胶质瘤具有精确诊断的可行性和潜在应用。[F]AlF-NOTA-QHY-04 PET/CT 还可以为 [F]FDG PET/CT 提供脑肿瘤的补充映射。
