Zhao Haitao, Gao Hannan, Zhai Luoping, Liu Xujie, Jia Bing, Shi Jiyun, Wang Fan
Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University , Beijing 100191, China.
Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences , Beijing 100101, China.
Bioconjug Chem. 2016 May 18;27(5):1259-66. doi: 10.1021/acs.bioconjchem.6b00098. Epub 2016 May 3.
Integrins, a large family of cell adhesion receptors, have been shown to play an important role for glioma proliferation and invasion. Several integrin receptors, including αvβ3, αvβ5, and α5β1, have generated clinical interest for glioma diagnosis and antitumor therapy. Integrin α5β1 has been highlighted as a prognostic and diagnostic marker in glioma, and its expression is correlated with a worse prognosis in high-grade glioma. However, unlike extensively studied integrins αvβ3 and αvβ5, very few integrin α5β1-specific radiotracers have been reported. Developing α5β1-specific radiotracers may provide alternative diagnosis and evaluation options in addition to well-studied αvβ3/αvβ5-specific tracers, and they may add new documents for profiling tumor progression. Here, a novel integrin α5β1-specific probe (99m)Tc-HisoDGR was fabricated for SPECT (single-photon emission computed tomography) imaging of glioma. To confirm its selective targeting of integrin α5β1 in vivo, the mouse models of α5β1-positive U87MG human glioma were subjected to SPECT/CT scans, and biodistribution experiments and blocking studies were performed. Small-animal SPECT/CT imaging experiments demonstrated that the tumors were clearly visualized in both subcutaneous and orthotopic glioma tumor models with clear background at 0.5, 1, and 2 h p.i. The tumor accumulation of (99m)Tc-HisoDGR showed significant reduction when excess cold isoDGR peptide was coinjected, suggesting that the tumor uptake was specifically mediated. Our work revealed that (99m)Tc-HisoDGR represented a powerful molecular probe for integrin α5β1-positive cancer imaging; moreover, it might be a promising tool for evaluating malignancy, predicting prognosis, selecting subpopulations of patients who might be sensitive to integrin α5β1-targeted drugs, and assessing and monitoring the response to integrin α5β1-targeted drugs in clinical trials.
整合素是一大类细胞黏附受体，已被证明在胶质瘤的增殖和侵袭中起重要作用。包括αvβ3、αvβ5和α5β1在内的几种整合素受体已引起胶质瘤诊断和抗肿瘤治疗的临床关注。整合素α5β1已被视为胶质瘤的预后和诊断标志物，其表达与高级别胶质瘤的不良预后相关。然而，与被广泛研究的整合素αvβ3和αvβ5不同，报道的整合素α5β1特异性放射性示踪剂非常少。开发α5β1特异性放射性示踪剂除了能为研究充分的αvβ3/αvβ5特异性示踪剂提供替代诊断和评估选择外，还可能为描绘肿瘤进展增添新资料。在此，制备了一种新型整合素α5β1特异性探针（99m）Tc-HisoDGR用于胶质瘤的单光子发射计算机断层扫描（SPECT）成像。为了在体内证实其对整合素α5β1的选择性靶向，对α5β1阳性U87MG人胶质瘤小鼠模型进行了SPECT/CT扫描，并进行了生物分布实验和阻断研究。小动物SPECT/CT成像实验表明，在皮下和原位胶质瘤肿瘤模型中，在注射后0.5、1和2小时肿瘤均清晰可见，背景清晰。当共同注射过量的冷isoDGR肽时，（99m）Tc-HisoDGR的肿瘤摄取显著降低，表明肿瘤摄取是特异性介导的。我们的研究表明，（99m）Tc-HisoDGR是一种用于整合素α5β1阳性癌症成像的强大分子探针；此外，它可能是评估恶性程度、预测预后、选择可能对整合素α5β1靶向药物敏感的患者亚群以及在临床试验中评估和监测对整合素α5β1靶向药物反应的有前景的工具。
