将[18F]AlF-NODA-MP-C6-CTHRSSVVC 作为 CD163 阳性肿瘤浸润巨噬细胞的 PET 示踪剂的合成和临床前评估

IF 3.6 4区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING Nuclear medicine and biology Pub Date : 2024-08-10 DOI:10.1016/j.nucmedbio.2024.108946

Bruna Fernandes , Ines F. Antunes , Kavya Prasad , Daniel Aaron Vazquez-Matias , Eduardo Preusser De Mattos , Wiktor Szymanski , Cristina Maria Moriguchi Jeckel , Erik F.J. de Vries , Philip H. Elsinga

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引用次数: 0

摘要

只要有合适的示踪剂，正电子发射断层扫描（PET）就能提供有关肿瘤相关巨噬细胞（TAM）浸润的信息。本研究旨在评估放射性标记肽[18F]AlF-NODA-MP-C6-CTHRSSVVC作为PET示踪剂对CD163受体成像的潜力，CD163受体表达在M2型肿瘤相关巨噬细胞上。共轭肽 NODA-MP-C6-CTHRSSVVC 用[18F]氟化铝标记。分别在体外结合试验和健康 BALB/c 小鼠体内对示踪剂的结合及其生物分布进行了评估。此外，还使用环磷酰胺对肿瘤小鼠进行了不同的处理，以评估示踪剂是否能检测到因 TAM 不同浸润而导致的 CD163 表达差异。治疗7天后，给动物注射[18F]AlF-NODA-MP-C6-CTHRSSVVC，进行60分钟动态PET扫描，然后进行体内外生物分布研究。[18F]AlF-NODA-MP-C6-CTHRSSVVC的放射化学收率为23 ± 6%，在体外结合试验中，它与表达CD163的人体组织匀浆的特异性受体结合率约为50%。在健康 BALB/c 小鼠的正常生理条件下，PET 未检测到 CD163 介导的 [18F]AlF-NODA-MP-C6-CTHRSSVVC 结合。另一方面，CD163 阳性的异种移植肿瘤可通过 PET 清晰观察到，CD163 水平与 PET 图像获得的[18F]AlF-NODA-MP-C6-CTHRSSVVC 肿瘤与肌肉比率（TMR）之间呈正相关（Pearson r = 0.76，p = 0.002）。不同治疗组的肿瘤 CD163 蛋白水平和示踪剂摄取量无明显差异。综上所述，[18F]AlF-NODA-MP-C6-CTHRSSVVC似乎是一种很有希望的候选M2型TAM PET示踪剂，因为它在体外能与CD163特异性结合，而且其肿瘤摄取量与体内CD163表达量有很好的相关性。

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Synthesis and preclinical evaluation of [18F]AlF-NODA-MP-C6-CTHRSSVVC as a PET tracer for CD163-positive tumor-infiltrating macrophages

Positron emission tomography (PET) can provide information about tumor-associated macrophage (TAM) infiltration, as long as a suitable tracer is available. This study aimed to evaluate the radiolabeled peptide [¹⁸F]AlF-NODA-MP-C6-CTHRSSVVC as a potential PET tracer for imaging of the CD163 receptor, which is expressed on M2-type tumor-associated macrophages. The conjugated peptide NODA-MP-C6-CTHRSSVVC was labeled with aluminum [¹⁸F]fluoride. Tracer binding and its biodistribution were evaluated in an in vitro binding assay and in healthy BALB/c mice, respectively. In addition, different treatments with cyclophosphamide in tumor-bearing mice were used to assess whether the tracer could detect differences in CD163 expression caused by differential TAM infiltration. After 7 days of treatment, animals were injected with [¹⁸F]AlF-NODA-MP-C6-CTHRSSVVC, and a 60-min dynamic PET scan was performed, followed by an ex vivo biodistribution study. [¹⁸F]AlF-NODA-MP-C6-CTHRSSVVC was prepared in 23 ± 6 % radiochemical yield and showed approximately 50 % of specific receptor-mediated binding in an in vitro binding assay on human CD163-expressing tissue homogenates. No CD163-mediated binding of [¹⁸F]AlF-NODA-MP-C6-CTHRSSVVC was detected by PET under normal physiological conditions in healthy BALB/c mice. On the other hand, CD163-positive xenograft tumors were clearly visualized with PET and a positive correlation was found between CD163 levels and the [¹⁸F]AlF-NODA-MP-C6-CTHRSSVVC tumor-to-muscle ratio (TMR) obtained from the PET images (Pearson r = 0.76, p = 0.002). No significant differences in the CD163 protein level and in the tracer uptake between treatment groups were found in the tumors. Taken together, [¹⁸F]AlF-NODA-MP-C6-CTHRSSVVC appears a promising candidate PET tracer for M2-type TAM, as it binds specifically to CD163 in vitro and its tumor uptake correlates well with CD163 expression in vivo.

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来源期刊

Nuclear medicine and biology 医学-核医学

CiteScore

6.00

自引率

9.70%

发文量

479

审稿时长

51 days

期刊介绍： Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized. These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field. Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.