Improved Intraoperative Detection of Ovarian Cancer by Folate Receptor Alpha Targeted Dual-Modality Imaging.

Abstract

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.

• Authors: Marlène C H Hekman, Otto C Boerman, Desirée L Bos, Leon F A G Massuger, Susan Weil, Luigi Grasso, Katherine A Rybinski, Egbert Oosterwijk, Peter F A Mulders, Mark Rijpkema
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 14 Issue 10 Pg. 3457-3463 (10 02 2017) ISSN: 1543-8392 [Electronic] United States
• PMID: 28826214 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal, Humanized
• Benzenesulfonates
• FOLR1 protein, human
• Fluorescent Dyes
• Folate Receptor 1
• IRDye 800CW
• Indium Radioisotopes
• Indoles
• farletuzumab
• Indium-111

Topics

• Animals
• Antibodies, Monoclonal, Humanized (chemistry, pharmacology)
• Benzenesulfonates (administration & dosage, chemistry)
• Cell Line, Tumor
• Feasibility Studies
• Female
• Fluorescent Dyes (administration & dosage, chemistry)
• Folate Receptor 1 (antagonists & inhibitors, immunology)
• Humans
• Indium Radioisotopes (administration & dosage, chemistry)
• Indoles (administration & dosage, chemistry)
• Intraoperative Care (methods)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Imaging (methods)
• Optical Imaging (methods)
• Ovarian Neoplasms (diagnostic imaging, pathology, surgery)
• Surgery, Computer-Assisted (methods)
• Tissue Distribution
• Tomography, Emission-Computed, Single-Photon (methods)
• Xenograft Model Antitumor Assays