Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
Immunomedics, Morris Plains, New Jersey.
Cancer Res. 2014 Nov 1;74(21):6216-23. doi: 10.1158/0008-5472.CAN-14-0594. Epub 2014 Sep 24.
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 ± 3.7% ID/g at 2 hours postinjection), comparable with (111)In-IMP288 (9.1 ± 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 image-guided surgery using intraoperative NIRF imaging, showing the preclinical feasibility of pretargeted dual-modality imaging approach in prostate cancer.
使用包含放射性示踪剂和荧光标记物的肿瘤靶向双模态探针可以改善恶性病变的根治性切除，从而增强肿瘤切除边界的术中描绘。由于预靶向策略可产生高的信号背景比，我们评估了使用抗 TROP-2 x 抗 HSG 双特异性抗体（TF12）与双标记的 diHSG 肽（RDC018）结合，用于前列腺癌术中成像的预靶向策略的可行性，该肽具有用于放射性标记的 DOTA 螯合剂和荧光团（IRdye800CW），以允许近红外光学成像。皮下植入表达 TROP-2 的 PC3 人前列腺肿瘤细胞或肩胛骨和肾上腺区域 PC3 转移的裸鼠静脉内注射 1mg TF12，在肿瘤积累和血液清除 16 小时后，随后分别注射 10MBq、0.2nmol/只的（111）In-RDC018 或（111）In-IMP288 作为对照。注射后 2 小时，分别在肿瘤结节切除前后采集 microSPECT/CT 和荧光图像。图像采集后，测定（111）In-RDC018 和（111）In-IMP288 的生物分布，并进行免疫组织化学分析。双标记 RDC018 的生物分布显示在表达 TROP-2 的 PC3 肿瘤中有特异性积累（注射后 2 小时 12.4 ± 3.7% ID/g），与（111）In-IMP288 相似（注射后 2 小时 9.1 ± 2.8% ID/g）。microSPECT/CT 和近红外荧光（NIRF）成像证实了双标记（111）In-RDC018 在皮下和转移性生长肿瘤模型中的这种 TROP-2 特异性摄取。此外，SPECT/CT 可以在术前检测到 PC3 转移，然后可以使用术中 NIRF 成像进行图像引导手术切除，表明前列腺癌预靶向双模态成像方法的临床前可行性。
