Near-infrared fluorescence-guided resection of micrometastases derived from esophageal squamous cell carcinoma using a c-Met-targeted probe in a preclinical xenograft model

• Published in: Journal of controlled release Vol. 332; pp. 171 - 183
• Main Authors: Liang, Mingzhu, Yang, Meilin, Wang, Fen, Wang, Xiaojin, He, Bailiang, Mei, Chaoming, He, Jianzhong, Lin, Yujing, Cao, Qingdong, Li, Dan, Shan, Hong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10-04-2021
• Subjects: Cellular mesenchymal-epithelial transition factor; Esophageal squamous cell carcinoma; Lymph node metastasis; Near-infrared fluorescence; Surgical navigation; Lymph node metastasis; Esophageal squamous cell carcinoma; Cellular mesenchymal-epithelial transition factor; Surgical navigation; Near-infrared fluorescence
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2021.02.019

The postoperative survival of esophageal squamous cell carcinoma (eSCC) is notably hindered by cancer recurrence due to difficulty in identifying occult metastases. Cellular mesenchymal-epithelial transition factor (c-Met), which is highly expressed in different cancers, including eSCC, has become a target for the development of imaging probes and therapeutic antibodies. In this study, we synthesized an optical probe (SHRmAb-IR800) containing a near-infrared fluorescence (NIRF) dye and c-Met antibody, which may help in NIRF-guided resection of micrometastases derived from eSCC. Cellular uptake of SHRmAb-IR800 was assessed by flow cytometry and confocal microscopy. In vivo accumulation of SHRmAb-IR800 and the potential application of NIRF-guided surgery were evaluated in eSCC xenograft tumor models. c-Met expression in human eSCC samples and lymph node metastases (LNMs) was analyzed via immunohistochemistry (IHC). Cellular accumulation of SHRmAb-IR800 was higher in c-Met-positive EC109 eSCC cells than in c-Met-negative A2780 cells. Infusion of SHRmAb-IR800 produced higher fluorescence intensity and a higher tumor-to-background ratio (TBR) than the control probe in EC109 subcutaneous tumors (P < 0.05). The TBRs of orthotopic EC109 tumors and LNMs were 3.01 ± 0.17 and 2.77 ± 0.56, respectively. The sensitivity and specificity of NIRF-guided resection of metastases derived from orthotopic cancers were 92.00% and 89.74%, respectively. IHC results demonstrated positive staining in 97.64% (124/127) of eSCC samples and 91.67% (55/60) of LNMs. Notably, increased c-Met expression was observed in LNMs compared to normal lymph nodes (P < 0.0001). Taken together, the results of this study indicated that SHRmAb-IR800 facilitated the resection of micrometastases of eSCC in the xenograft tumor model. This c-Met-targeted probe possesses translational potential in NIRF-guided surgery due to the high positive rate of c-Met protein in human eSCCs.
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•A near infrared fluorescent (NIRF) probe based on a c-Met antibody was synthesized.•In vivo NIRF imaging revealed specific accumulation of this probe in c-Met-positive esophageal squamous cell carcinomas (eSCCs).•This probe facilitated NIRF-guided resection of eSCC metastases in a preclinical model.•The c-Met positive rates were 97.64% in human primary eSCCs and 91.67% in the corresponding lymph node metastases.