Dual-Modality Image-Guided Surgery of Prostate Cancer with a Radiolabeled Fluorescent Anti-PSMA Monoclonal Antibody.
Both radionuclide imaging and near-infrared fluorescent (NIRF) imaging have a high sensitivity to detect tumors in vivo. The combination of these modalities using dual-labeled antibodies may allow both preoperative and intraoperative tumor localization and may be used in image-guided surgery to ensure complete resection of tumor tissue. Here, we evaluated the potential of dual-modality imaging of prostate cancer with the monoclonal antibody D2B, directed against an extracellular domain of prostate-specific membrane antigen (PSMA). For these studies, D2B was labeled both with (111)In and with the NIRF dye IRDye800CW.


METHODS
D2B was conjugated with N-hydroxysuccinimide-IRDye800CW and p-isothiocyanatobenzyl-diethylenetriaminepentaacetic acid (ITC-DTPA) and subsequently radiolabeled with (111)In. For biodistribution and NIRF imaging, (111)In-DTPA-D2B-IRDye800CW (2 μg, 0.55 MBq/mouse) was injected intravenously into BALB/c nude mice with subcutaneous PSMA-expressing LNCaP tumors (right flank) and PSMA-negative PC3 tumors (left flank). The biodistribution was determined at 1, 2, 3, and 7 d after injection. In addition, micro-SPECT/CT and NIRF imaging with (111)In-DTPA-D2B-IRDye800CW (3 μg, 8.5 MBq/mouse) was performed on mice with intraperitoneally growing LS174T-PSMA tumors.


RESULTS
(111)In-DTPA-D2B-IRDye800CW specifically accumulated in subcutaneous PSMA-positive LNCaP tumors (45.8 ± 8.0 percentage injected dose per gram at 168 h after injection), whereas uptake in subcutaneous PSMA-negative PC3 tumors was significantly lower (6.6 ± 1.3 percentage injected dose per gram at 168 h after injection). Intraperitoneal LS174T-PSMA tumors could be visualized specifically with both micro-SPECT/CT and NIRF imaging at 2 d after injection, and the feasibility of image-guided resection of intraperitoneal tumors was demonstrated in this model.


CONCLUSIONS
Dual-labeled (111)In-DTPA-D2B-IRDye800CW enables specific and sensitive detection of prostate cancer lesions in vivo with micro-SPECT/CT and NIRF imaging. In addition to preoperative micro-SPECT/CT imaging to detect tumors, NIRF imaging enables image-guided surgical resection. These preclinical findings warrant clinical studies with (111)In-DTPA-D2B-IRDye800CW to improve tumor detection and resection in prostate cancer patients.
Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands susanne.lutje@radboudumc.nl.
Susanne
S
Lütje
Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Mark
M
Rijpkema
Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Gerben M
GM
Franssen
Department of Pathology and Diagnostics, University of Verona, Verona, Italy; and.
Giulio
G
Fracasso
Department of Surgery, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
Wijnand
W
Helfrich
Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Annemarie
A
Eek
Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Wim J
WJ
Oyen
Department of Pathology and Diagnostics, University of Verona, Verona, Italy; and.
Marco
M
Colombatti
Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Otto C
OC
Boerman
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology / Q000493:pharmacokinetics; D000954:Antigens, Surface / Q000276:immunology*; D001557:Benzenesulfonates / Q000737:chemistry*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005456:Fluorescent Dyes / Q000737:chemistry; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D006801:Humans; D007205:Indium Radioisotopes; D007211:Indoles / Q000737:chemistry*; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D061848:Optical Imaging; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000473:pathology / Q000601:surgery*; D025321:Surgery, Computer-Assisted / Q000379:methods*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D001557:Benzenesulfonates; D005456:Fluorescent Dyes; C562366:IRDye 800CW; D007205:Indium Radioisotopes; D007211:Indoles; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
D2B IgG; IRDye800CW; PSMA; dual-modality imaging; fluorescence imaging; prostate cancer