Department of Biomedical Engineering, University of California, Davis, Davis, CA, USA.
Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis, Sacramento, CA, USA.
Mol Imaging Biol. 2018 Feb;20(1):103-113. doi: 10.1007/s11307-017-1097-3.
Increased expression of the αβ integrin correlates with advanced tumor grade and poor clinical outcome, identifying αβ as a prognostic indicator and an attractive target for molecular imaging. This work investigated the ability of a disulfide-stabilized [Cu]NOTA-αβ cys-diabody to image αβ expression in vivo using a nu/nu mouse model bearing human melanoma xenografts and positron-emission tomography.
Small-animal positron emission tomography (PET) imaging, quantitative ROI analysis, and ex vivo biodistribution were conducted to ascertain tumor uptake and organ distribution of the [Cu]NOTA-αβ cys-diabody. Immunohistochemical staining of tumors and mouse organs and immunoreactivity assays were utilized to correlate in vivo and ex vivo observations.
PET imaging of the [Cu]NOTA-αβ cys-diabody revealed low tumor uptake at 24 h p.i. in DX3Puroβ tumors (2.69 ± 0.45 %ID/g) with comparable results found in the DX3Puro tumors (2.24 ± 0.15 %ID/g). Quantitative biodistribution confirmed that DX3Puroβ tumor uptake was highest at 24 h p.i. (4.63 ± 0.18 %ID/g); however, uptake was also observed in the stomach (4.84 ± 2.99 %ID/g), small intestines (4.50 ± 1.69 %ID/g), large intestines (4.73 ± 0.97 %ID/g), gallbladder (6.04 ± 1.88 %ID/g), and lungs (3.89 ± 0.69 %ID/g).
Small-animal PET imaging was successful in visualizing αβ-positive tumor uptake of the [Cu]NOTA-αβ cys-diabody. Cys-diabody cross-reactivity was observed between human and murine αβ and immunohistochemical staining confirmed the presence of an endogenous αβ antigen sink, which led to suboptimal tumor contrast in this mouse model. Future investigations will focus on dose escalation studies to overcome the endogenous antigen sink while increasing DX3Puroβ tumor uptake.
αβ 整联蛋白的表达增加与肿瘤的高级别和不良的临床结果相关，将其确定为预后指标和分子成像的有吸引力的靶标。本研究使用携带人黑色素瘤异种移植物的无胸腺裸鼠模型，通过正电子发射断层扫描（PET）研究了二硫键稳定的 [Cu]NOTA-αβ cys-二抗在体内对 αβ 表达的成像能力。
进行小动物 PET 成像、定量 ROI 分析和离体生物分布，以确定 [Cu]NOTA-αβ cys-二抗的肿瘤摄取和器官分布。利用肿瘤和小鼠器官的免疫组织化学染色和免疫反应性测定来关联体内和离体观察结果。
[Cu]NOTA-αβ cys-二抗的 PET 成像显示，在 24 小时时，DX3Puroβ 肿瘤的摄取较低（2.69±0.45%ID/g），在 DX3Puro 肿瘤中发现了类似的结果（2.24±0.15%ID/g）。定量生物分布证实，DX3Puroβ 肿瘤摄取在 24 小时时最高（4.63±0.18%ID/g）；然而，在胃（4.84±2.99%ID/g）、小肠（4.50±1.69%ID/g）、大肠（4.73±0.97%ID/g）、胆囊（6.04±1.88%ID/g）和肺（3.89±0.69%ID/g）中也观察到摄取。
小动物 PET 成像成功地可视化了 [Cu]NOTA-αβ cys-二抗对 αβ 阳性肿瘤的摄取。在人类和鼠类的 αβ 之间观察到 cys-二抗的交叉反应，免疫组织化学染色证实存在内源性 αβ 抗原吸收，这导致在该小鼠模型中肿瘤对比不佳。未来的研究将集中在剂量递增研究上，以克服内源性抗原吸收，同时增加 DX3Puroβ 肿瘤摄取。
