Positron Emission Tomography Imaging of Platelet-Derived Growth Factor Receptor β in Colorectal Tumor Xenograft Using Zirconium-89 Labeled Dimeric Affibody Molecule
Positron Emission Tomography Imaging of Platelet-Derived Growth Factor Receptor β in Colorectal Tumor Xenograft Using Zirconium-89 Labeled Dimeric Affibody Molecule
复制标题
使用 Zircium-89 标记的二聚 Affibody 分子对结直肠肿瘤异种移植物中血小板衍生生长因子受体 β 进行正电子发射断层扫描成像
DOI：
10.1021/acs.molpharmaceut.8b01317
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发表时间：
2019-05-01
影响因子：
4.9
通讯作者：
Li, Lin
中科院分区：
文献类型：
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作者：
Cai, Huawei;Shi, Qiuxiao;Li, Lin
血小板衍生生长因子受体β（PDGFRβ）在多种恶性肿瘤中过表达，在肿瘤血管生成中起着关键作用，并且已被证实是癌症治疗的一个有价值靶点。在这项初步研究中，制备了一种二聚体亲和体分子Z(PDGFR)β，并使用正电子发射放射性核素锆 - 89进行放射性标记，以便通过靶向体内PDGFRβ的表达对结直肠肿瘤进行正电子发射断层扫描（PET）成像。通过流式细胞术、免疫荧光染色和全身光学成像评估二聚体亲和体与PDGFRβ的结合能力。随后，将Z(PDGFR)β与DFO - Bn - NCS偶联，并用锆 - 89进行放射性标记。通过体外细胞实验和体内微型PET/CT成像研究了Zr - 89 - DFO - Z(PDGFR)β与表达PDGFRβ的细胞的靶向结合能力。二聚体Z(PDGFR)β亲和体与表达PDGFRβ的周细胞的结合能力明显高于与LS - 174T癌细胞的结合能力，并且通过流式细胞术和免疫荧光测定显示其与肿瘤新生血管良好共定位。通过DFO螯合，Z(PDGFR)β成功地用锆 - 89标记，标记产率为94.1 ± 3.53%。Zr - 89 - DFO - Z(PDGFR)β在体外显示出与表达PDGFRβ的细胞保持特异性结合能力，并且对PDGF - β配体具有有效抑制能力（P < 0.05）。生物分布情况表明，Zr - 89 - DFO - Z(PDGFR)β在肿瘤中的摄取在注射后2小时达到峰值，为6.93 ± 0.64%ID/g，肿瘤与血液的比值为5.5 ± 0.6。在注射Zr - 89 - DFO - Z(PDGFR)β亲和体偶联物后的1至4小时内，通过微型PET/CT成像能够清晰地观察到LS - 174T异种移植瘤。总之，Zr - 89 - DFO - Z(PDGFR)β偶联物对结直肠肿瘤表现出特异性和高结合能力，这表明其有可能作为一种放射性药物，用于通过PET/CT对肿瘤相关血管进行诊断成像。
Platelet-derived growth factor receptor beta (PDGFR beta) is overexpressed in a variety of malignant cancers, plays a critical role in tumor angiogenesis, and has been proven as a valuable target for cancer treatment. In this pilot study, a dimeric affibody molecule, Z(P)(DGFR)(beta), was prepared and radiolabeled with positron emission radionuclide zirconium-89 for PET imaging of colorectal tumors by targeting PDGFR beta expression in vivo. The PDGFR beta-binding capability of dimeric affibody was evaluated by flow cytometry, immunofluorescent staining, and whole-body optical imaging. Then, Z(P)(DGFR beta) was conjugated with DFO-Bn-NCS and radiolabeled with Zr-89. Targeted binding capability of Zr-89-DFO-Z(P)(DGFR beta) to PDGFR beta expressing cells was investigated by cellular assay in vitro and microPET/CT imaging in vivo. Dimeric Z(PDG)(FR beta )affibody had specifically higher binding capability with PDGFR beta expressing pericytes rather than LS-174T cancer cells, and well colocalized with tumor neovasculature by flow cytometry and immunofluorescent assay. Z(P)(DGFR beta )was successfully labeled with Zr-89 by DFO chelating with yield of 94.1 +/- 3.53%. Zr-89-DFO-Z(PDGFR beta) indicated preserved specific binding ability with PDGFR beta expressing cells and effective inhibiting capability to PDGF-beta ligands (P < 0.05) in vitro. Biodistribution indicated that tumor uptake of Zr-89-DFO-Z(PDGFR beta) reached the peak of 6.93 +/- 0.64%ID/g, and the tumor-to-blood ratio was 5.5 +/- 0.6 at 2 h post-injection. LS-174T xenografts were clearly visualized by microPET/CT imaging through 1 to 4 h post-injection of Zr-89-DFO-Z(PDGFR beta) affibody conjugate. In conclusion, the Zr-89-DFO-Z(PDGFR beta) conjugate demonstrated specific and high binding ability with colorectal tumor, which indicated its use as a potential radiopharmaceutical for diagnostic imaging of tumor associate vasculatures with PET/CT.