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Noninvasive Trafficking of Brentuximab Vedotin and PET Imaging of CD30 in Lung Cancer Murine Models
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-03-14 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b01168 Lei Kang 1, 2 , Dawei Jiang 2, 3 , Emily B. Ehlerding 4 , Todd E. Barnhart 4 , Dalong Ni 2 , Jonathan W. Engle 4 , Rongfu Wang 1 , Peng Huang 3 , Xiaojie Xu 5 , Weibo Cai 2, 4, 6
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-03-14 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b01168 Lei Kang 1, 2 , Dawei Jiang 2, 3 , Emily B. Ehlerding 4 , Todd E. Barnhart 4 , Dalong Ni 2 , Jonathan W. Engle 4 , Rongfu Wang 1 , Peng Huang 3 , Xiaojie Xu 5 , Weibo Cai 2, 4, 6
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CD30 has been considered a unique diagnostic and therapeutic target for CD30-positive lymphomas and some lung diseases. Additionally, CD30 has shown high expression in clinical lung cancer samples. In this study, 89Zr-radiolabeled brentuximab vedotin (BV) was developed for in vivo tracking of BV and imaging CD30 expression in lung cancer models via conjugation with desferrioxamine (Df). CD30 expression in three lung cancer cell lines (H460, H358, and A549) was quantified by Western blot. Flow cytometry and saturation binding assays were used to evaluate the binding capabilities of the tracer in vitro. After longitudinal positron emission tomography (PET) imaging and quantitative analysis were performed, ex vivo biodistribution and histological studies were used to verify PET results. Finally, dosimetric extrapolation of murine data to humans was performed. At the cellular level, CD30 was found to be expressed on H460 and A549 cells with the highest and lowest levels of expression, respectively. Both Df-BV and 89Zr-Df-BV displayed high binding affinity to H460 cells. PET images and their quantification verified that BV accumulated in H460 tumor models (9.93 ± 2.70% ID/g at 24 h after injection; n = 4) at the highest level, followed by H358 and A549 tumors (8.05 ± 2.43 and 5.00 ± 1.56% ID/g; n = 4). The nonspecific 89Zr-labeled IgG showed a low tumor uptake of 5.2 ± 1.0% ID/g for H460 models. Ex vivo biodistribution and fluorescence immunohistochemistry also corroborated these findings. Dosimetric results displayed safe dose estimations. Therefore, 89Zr-Df-BV provides a potential agent for evaluating CD30 expression noninvasively in lung cancer, and also for imaging of brentuximab vedotin for better understanding of its pharmacokinetics.
中文翻译：
Brentuximab Vedotin的无创贩运和CD30在肺癌小鼠模型中的PET成像
CD30被认为是CD30阳性淋巴瘤和某些肺部疾病的独特诊断和治疗靶标。此外，CD30在临床肺癌样品中显示出高表达。在这项研究中，开发了89种Zr放射性标记的brentuximab vedotin（BV），可通过与去铁胺（Df）结合在体内追踪BV并在肺癌模型中对CD30表达进行成像。通过蛋白质印迹定量三种肺癌细胞系（H460，H358和A549）中的CD30表达。流式细胞术和饱和结合法被用来评价示踪剂的结合能力在体外。在进行纵向正电子发射断层扫描（PET）成像和定量分析后，离体生物分布和组织学研究用于验证PET结果。最后，进行了鼠类数据对人的剂量学外推。在细胞水平上，发现CD30分别在具有最高和最低表达水平的H460和A549细胞上表达。Df-BV和89 Zr-Df-BV均显示出对H460细胞的高结合亲和力。PET图像及其定量验证表明，H460肿瘤模型中的BV积累最高（注射后24 h为9.93±2.70％ID / g；n = 4），其水平最高，其次是H358和A549肿瘤（8.05±2.43和5.00±1.56） ％ID / g；n＝ 4）。对于H460模型，非特异性89 Zr标记的IgG的肿瘤摄取率低，为5.2±1.0％ID / g。离体生物分布和荧光免疫组织化学也证实了这些发现。剂量学结果显示安全剂量估算。因此，89 Zr-Df-BV为潜在地评估肺癌中CD30的表达提供了一种潜在的药物，同时也为brentuximab vedotin的成像提供了更好的了解其药代动力学的方法。
更新日期：2018-03-14
中文翻译：
Brentuximab Vedotin的无创贩运和CD30在肺癌小鼠模型中的PET成像
CD30被认为是CD30阳性淋巴瘤和某些肺部疾病的独特诊断和治疗靶标。此外，CD30在临床肺癌样品中显示出高表达。在这项研究中，开发了89种Zr放射性标记的brentuximab vedotin（BV），可通过与去铁胺（Df）结合在体内追踪BV并在肺癌模型中对CD30表达进行成像。通过蛋白质印迹定量三种肺癌细胞系（H460，H358和A549）中的CD30表达。流式细胞术和饱和结合法被用来评价示踪剂的结合能力在体外。在进行纵向正电子发射断层扫描（PET）成像和定量分析后，离体生物分布和组织学研究用于验证PET结果。最后，进行了鼠类数据对人的剂量学外推。在细胞水平上，发现CD30分别在具有最高和最低表达水平的H460和A549细胞上表达。Df-BV和89 Zr-Df-BV均显示出对H460细胞的高结合亲和力。PET图像及其定量验证表明，H460肿瘤模型中的BV积累最高（注射后24 h为9.93±2.70％ID / g；n = 4），其水平最高，其次是H358和A549肿瘤（8.05±2.43和5.00±1.56） ％ID / g；n＝ 4）。对于H460模型，非特异性89 Zr标记的IgG的肿瘤摄取率低，为5.2±1.0％ID / g。离体生物分布和荧光免疫组织化学也证实了这些发现。剂量学结果显示安全剂量估算。因此，89 Zr-Df-BV为潜在地评估肺癌中CD30的表达提供了一种潜在的药物，同时也为brentuximab vedotin的成像提供了更好的了解其药代动力学的方法。
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