Pretargeted Dual-Modality Immuno-SPECT and Near-Infrared Fluorescence Imaging for Image-Guided Surgery of Prostate Cancer

Abstract

Radical removal of malignant lesions may be improved using tumor-targeted dual-modality probes that contain both a radiotracer and a fluorescent label to allow for enhanced intraoperative delineation of tumor resection margins. Because pretargeting strategies yield high signal-to-background ratios, we evaluated the feasibility of a pretargeting strategy for intraoperative imaging in prostate cancer using an anti-TROP-2 x anti-HSG bispecific antibody (TF12) in conjunction with the dual-labeled diHSG peptide (RDC018) equipped with both a DOTA chelate for radiolabeling purposes and a fluorophore (IRdye800CW) to allow near-infrared optical imaging. Nude mice implanted s.c. with TROP-2-expressing PC3 human prostate tumor cells or with PC3 metastases in the scapular and suprarenal region were injected i.v. with 1 mg of TF12 and, after 16 hours of tumor accumulation and blood clearance, were subsequently injected with 10 MBq, 0.2 nmol/mouse of either 111 In-RDC018 or 111 In-IMP288 as a control. Two hours after injection, both microSPECT/CT and fluorescence images were acquired, both before and after resection of the tumor nodules. After image acquisition, the biodistribution of 111 In-RDC018 and 111 In-IMP288 was determined and tumors were analyzed immunohistochemically. The biodistribution of the dual-label RDC018 showed specific accumulation in the TROP-2-expressing PC3 tumors (12.4 AE 3.7% ID/g at 2 hours postinjection), comparable with 111 In-IMP288 (9.1 AE 2.8% ID/g at 2 hours postinjection). MicroSPECT/CT and near-infrared fluorescence (NIRF) imaging confirmed this TROP-2-specific uptake of the dual-label 111 In-RDC018 in both the s.c. and metastatic growing tumor model. In addition, PC3 metastases could be visualized preoperatively with SPECT/CT and could subsequently be resected by imageguided surgery using intraoperative NIRF imaging, showing the preclinical feasibility of pretargeted dualmodality imaging approach in prostate cancer. Cancer Res; 74(21); 6216-23. Ó2014 AACR.

Review on near-infrared heptamethine cyanine dyes as theranostic agents for tumor imaging, targeting, and photodynamic therapy

“…In a RANKL-overexpressing LNCaP metastatic prostate tumor xenograft model, NIRF imaging detected two superficial tumors in the mouse after PC-1001 injection, while PC-1001-coupled PET revealed an extra tumor in a deep location in the same mouse, 30 indicating the enhanced sensitivity of NIRF nuclear imaging. To date, several PET tracers have been applied for NIRF nuclear imaging of experimental tumor models, including 18 F, 11 C, 99m Tc, 64 Cu, and 111 In. 31,[62][63][64] Recent studies have reported on a PET/NIRF probe, PC-1001∕ 64 Cu, conjugating NIRF dye PC-1001 with 64 Cu for breast cancer PET and fluorescence imaging.…”

“…To date, several PET tracers have been applied for NIRF nuclear imaging of experimental tumor models, including 18 F, 11 C, 99m Tc, 64 Cu, and 111 In. 31,[62][63][64] Recent studies have reported on a PET/NIRF probe, PC-1001∕ 64 Cu, conjugating NIRF dye PC-1001 with 64 Cu for breast cancer PET and fluorescence imaging. This PC-1001∕ 64 Cu compound has been validated in both breast cancer cells and a breast cancer xenograft model.…”

“…31,[62][63][64] Recent studies have reported on a PET/NIRF probe, PC-1001∕ 64 Cu, conjugating NIRF dye PC-1001 with 64 Cu for breast cancer PET and fluorescence imaging. This PC-1001∕ 64 Cu compound has been validated in both breast cancer cells and a breast cancer xenograft model. 31 It showed a much higher rate of uptake and accumulation in tumors compared to normal organs, such as the heart, liver, lung, and spleen, which further exhibited a decrease in the uptake rate with time.…”

“…31 It showed a much higher rate of uptake and accumulation in tumors compared to normal organs, such as the heart, liver, lung, and spleen, which further exhibited a decrease in the uptake rate with time. However, developing the PET application with this probe in both the research and clinical settings was costly, due to the limited supply of cyclotron-produced 64 Cu radioisotope. By contrast, the cancer-targeting SPECT/NIRF dual-modality imaging probe PC-1007∕ 99m Tc has been successfully synthesized in a low-cost scheme and also exhibited cancer-specific targeting and accumulation properties in cancer cells and tumor xenograft models.…”

New Dioxaborolane Chemistry Enables [18F]-Positron-Emitting, Fluorescent [18F]-Multimodality Biomolecule Generation from the Solid Phase

“…25–27 The reported boronate chemistry is generally applicable to other biomolecules including other [ 18 F]-PET/NIRF-mAbs that can be used additionally in other nonsystemically delivered applications, like lymphatic mapping and drug delivery. 28,29 …”