Complete resection of tumor lesions in advanced stage ovarian cancer patients is of utmost importance, since the extent of residual disease after surgery strongly affects survival. Intraoperative imaging may be useful to improve surgery in these patients. Farletuzumab is a humanized IgG1 antibody that specifically recognizes the folate receptor alpha (FRα). Labeled with a radiolabel and a fluorescent dye, farletuzumab may be used for the intraoperative detection of ovarian cancer lesions. The current aim is to demonstrate the feasibility of FRα-targeted dual-modality imaging using ¹¹¹In-farletuzumab-IRDye800CW in an intraperitoneal ovarian cancer model. Biodistribution studies were performed 3 days after injection of 3, 10, 30, or 100 μg of ¹¹¹In-farletuzumab-IRDye800CW in mice with subcutaneous IGROV-1 tumors (5 mice per group). In mice with intraperitoneal IGROV-1 tumors the nonspecific uptake of ¹¹¹In-farletuzumab-IRDye800CW was determined by coinjecting an excess of unlabeled farletuzumab. MicroSPECT/CT and fluorescence imaging were performed 3 days after injection of 10 μg of ¹¹¹In-farletuzumab-IRDye800CW. FRα expression in tumors was determined immunohistochemically. Optimal tumor-to-blood-ratios (3.4–3.7) were obtained at protein doses up to 30 μg. Multiple intra-abdominal tumor lesions were clearly visualized by microSPECT/CT, while uptake in normal tissues was limited. Fluorescence imaging was used to visualize and guide resection of superficial tumors. Coinjection of an excess of unlabeled farletuzumab significantly decreased tumor uptake of ¹¹¹In-farletuzumab-IRDye800CW (69.4 ± 27.6 versus 18.3 ± 2.2% ID/g, p < 0.05). Immunohistochemical analyses demonstrated that the radioactive and fluorescent signal corresponded with FRα-expressing tumor lesions. FRα-targeted SPECT/fluorescence imaging using ¹¹¹In-farletuzumab-IRDye800CW can be used to detect ovarian cancer in vivo and could be a valuable tool for enhanced intraoperative tumor visualization in patients with intraperitoneal metastases of ovarian cancer.

中文翻译：

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叶酸受体α靶向双峰成像改善术中卵巢癌的检测

在晚期卵巢癌患者中完全切除肿瘤病变至关重要，因为手术后残留疾病的程度会严重影响生存率。术中影像检查可能对改善这些患者的手术有用。Farletuzumab是一种人源化IgG1抗体，可特异性识别叶酸受体α（FRα）。用放射性标记和荧光染料标记的法雷珠单抗可用于术中检测卵巢癌病变。当前的目的是证明在腹膜内卵巢癌模型中使用¹¹¹ In-farletuzumab-IRDye800CW进行FRα靶向的双模态成像的可行性。生物分布研究在注射3，10，30后3天进行，或100μg的¹¹¹法拉妥珠单抗-IRDye800CW在患有皮下IGROV-1肿瘤的小鼠中（每组5只小鼠）。在腹膜内IGROV-1肿瘤的小鼠中，通过共注射过量的未标记法雷珠单抗来确定¹¹¹ In-法雷珠单抗-IRDye800CW的非特异性摄取。注射10μg的¹¹¹后3天进行MicroSPECT / CT和荧光成像法拉珠单抗-IRDye800CW。免疫组织化学测定肿瘤中的FRα表达。最高30μg的蛋白质剂量可获得最佳的肿瘤与血液之比（3.4–3.7）。通过microSPECT / CT可以清晰地看到多个腹腔内肿瘤病变，而正常组织的摄取受到限制。荧光成像用于可视化并指导浅表肿瘤的切除。共注射过量的未标记法雷珠单抗可显着降低¹¹¹ In-法雷珠单抗-IRDye800CW的肿瘤吸收（69.4±27.6对18.3±2.2％ID / g，p <0.05）。免疫组织化学分析表明，放射性和荧光信号与表达FRα的肿瘤病变相对应。使用^111的FRα靶向SPECT /荧光成像法拉珠单抗-IRDye800CW可用于体内检测卵巢癌，并且对于增强腹膜内转移性卵巢癌患者的术中肿瘤可视化能力可能是一个有价值的工具。