Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Hungary; Doctoral School of Clinical Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary.
Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Hungary; Gyula Petrányi Doctoral School of Allergy and Clinical Immunology, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary.
Int J Pharm. 2020 Nov 15;589:119881. doi: 10.1016/j.ijpharm.2020.119881. Epub 2020 Sep 16.
Aminopeptidase N (APN/CD13) plays an important role in neoangiogenic process in malignancies. Our previous studies have already shown that Ga-labelled NOTA conjugated asparagine-glycine-arginine peptide (c[KNGRE]-NH) specifically bind to APN/CD13 expressing tumors. The aim of this study was to evaluate and compare the APN/CD13 specificity of newly synthesized Ga-labelled NGR derivatives in vivo by PET/MRI imaging using hepatocellular carcinoma (He/De) and mesoblastic nephroma (Ne/De) tumor models. PET/MRI and ex vivo biodistribution studies were performed 11 ± 1 days after subcutaneous injection of tumor cells and 90 min after intravenous injection of Ga-NOTA-c(NGR), Ga-NODAGA-c(NGR), Ga-NODAGA-c(NGR) (MG1) or Ga-NODAGA-c(NGR) (MG2). The APN/CD13 selectivity was confirmed by blocking experiments and the APN/CD13 expression was verified by immunohistochemistry. Ga-labelled c(NGR) derivatives were produced with high specific activity and radiochemical purity. In control animals, low radiotracer accumulation was found in abdominal and thoracic organs. Using tumor-bearing animals we found that the Ga-NOTA-c(NGR), Ga-NODAGA-c(NGR), and Ga-NODAGA-c(NGR) (MG1) derivatives showed higher uptake in He/De and Ne/De tumors, than that of the accumulation of Ga-NODAGA-c(NGR) (MG2). APN/CD13 is a very promising target in PET imaging, however, the selection of the appropriate Ga-labelled NGR-based radiopharmaceutical is critical for the precise detection of tumor neo-angiogenesis and for monitoring the efficacy of anticancer therapy.
天冬氨酰蛋白酶 N（APN/CD13）在恶性肿瘤新生血管过程中发挥重要作用。我们之前的研究已经表明，Ga 标记的 NOTA 共轭天冬酰胺-甘氨酸-精氨酸肽（c[KNGRE]-NH）特异性结合表达 APN/CD13 的肿瘤。本研究旨在通过使用肝细胞癌（He/De）和间胚细胞瘤（Ne/De）肿瘤模型的 PET/MRI 成像评估和比较新合成的 Ga 标记的 NGR 衍生物的体内 APN/CD13 特异性。在皮下注射肿瘤细胞后 11 ± 1 天和静脉注射 Ga-NOTA-c（NGR）、Ga-NODAGA-c（NGR）、Ga-NODAGA-c（NGR）（MG1）或 Ga-NODAGA-c（NGR）（MG2）90 分钟后进行 PET/MRI 和离体生物分布研究。通过阻断实验证实了 APN/CD13 的选择性，并用免疫组织化学法验证了 APN/CD13 的表达。Ga 标记的 c（NGR）衍生物具有高比活度和高放射化学纯度。在对照动物中，在腹部和胸部器官中发现低放射性示踪剂积累。在荷瘤动物中，我们发现 Ga-NOTA-c（NGR）、Ga-NODAGA-c（NGR）和 Ga-NODAGA-c（NGR）（MG1）衍生物在 He/De 和 Ne/De 肿瘤中的摄取高于 Ga-NODAGA-c（NGR）（MG2）。APN/CD13 是 PET 成像中非常有前途的靶点，然而，选择合适的 Ga 标记的基于 NGR 的放射性药物对于精确检测肿瘤新生血管形成和监测抗癌治疗的疗效至关重要。
