Matching the decay half-life with the biological half-life: ImmunoPET imaging with (44)Sc-labeled cetuximab Fab fragment.
Matching the decay half-life with the biological half-life: ImmunoPET imaging with (44)Sc-labeled cetuximab Fab fragment.
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DOI：
10.1021/bc500415x
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发表时间：
2014-12-17
影响因子：
4.7
通讯作者：
Cai, Weibo
中科院分区：
文献类型：
--
作者：
Chakravarty, Rubel;Goel, Shreya;Valdovinos, Hector F.;Hernandez, Reinier;Hong, Hao;Nickles, Robert J.;Cai, Weibo
Sc-44(T1/2=3.9h)是一种相对较新的放射性同位素，在临床正电子发射断层扫描(PET)中具有潜在的应用价值。在此，我们首次报道了在活体PET成像中用44Sc对蛋白质进行室温放射性标记。为此，制备了与表皮生长因子受体具有高亲和力的单抗西妥昔单抗Fab片段，并将其与N-[(R)-2-amino-3-(para-isothiocyanato-phenyl)propyl]-trans-(S，(S)-环己烷-1，2-二胺-N，N，N‘，N“，N”-五乙酸(CHX-A“-DTPA)偶联。经SDS-PAGE和MS分析证实西妥昔单抗的纯度较高。研究了44Sc标记生物偶联物对人胶质母细胞瘤(U87 MG)荷瘤小鼠的EGFR表达进行PET成像的可能性。PET显像显示44Sc-CHX-A“-DTPA-西妥昔单抗-Fab对肿瘤的摄取迅速(注射后4h最大摄取量为12%ID/g)，具有良好的肿瘤-背景比，这可能为将来的临床研究提供同一天的∼显像。免疫荧光染色检测肿瘤组织和正常组织中示踪剂摄取与EGFR表达的关系。这一成功的利用44Sc-CHX-A“-DTPA-西妥昔单抗-Fab对EGFR表达进行免疫PET成像的策略可以在临床上取得可翻译的进展，以选择合适的患者群体进行EGFR靶向治疗，并监测抗EGFR治疗的治疗效果。
Scandium-44 (t1/2 = 3.9 h) is a relatively new radioisotope of potential interest for use in clinical positron emission tomography (PET). Herein, we report, for the first time, the room-temperature radiolabeling of proteins with 44Sc for in vivo PET imaging. For this purpose, the Fab fragment of Cetuximab, a monoclonal antibody that binds with high affinity to epidermal growth factor receptor (EGFR), was generated and conjugated with N-[(R)-2-amino-3-(para-isothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N′,N″,N″-pentaacetic acid (CHX-A″-DTPA). The high purity of Cetuximab-Fab was confirmed by SDS-PAGE and mass spectrometry. The potential of the bioconjugate for PET imaging of EGFR expression in human glioblastoma (U87MG) tumor-bearing mice was investigated after 44Sc labeling. PET imaging revealed rapid tumor uptake (maximum uptake of ∼12% ID/g at 4 h postinjection) of 44Sc–CHX-A″-DTPA–Cetuximab-Fab with excellent tumor-to-background ratio, which might allow for same day PET imaging in future clinical studies. Immunofluorescence staining was conducted to correlate tracer uptake in the tumor and normal tissues with EGFR expression. This successful strategy for immunoPET imaging of EGFR expression using 44Sc–CHX-A″-DTPA–Cetuximab-Fab can make clinically translatable advances to select the right population of patients for EGFR-targeted therapy and also to monitor the therapeutic efficacy of anti-EGFR treatments.
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