Abstract
Background: Peritoneal dissemination is common in advanced ovarian cancer. The completeness of cytoreduction is an independent prognostic factor. The intraoperative fluorescence imaging via tumor-specific near-infrared fluorophore might improve staging and surgical completeness. A promising target for ovarian cancer is the gonadotropin-releasing hormone receptor (GnRHR). This study aimed to develop a GnRHR-targeted near-infrared imaging probe for the detection of peritoneal metastases of ovarian cancer.Methods: Indocyanine green (ICG) was conjugated with GnRH antagonist peptide to develop an ovarian cancer-selective fluorescence probe GnRHa-ICG. GnRHR expression was detected in ovarian cancer tissues. The binding capacity of GnRHa-ICG and ICG was detected in both cancer cell lines and mouse models of peritoneal metastatic ovarian cancer using fluorescence microscopy, flow cytometry, and near-infrared fluorescence imaging.Results: Tissue microarray analysis revealed the overexpression of GnRHR in ovarian cancer. GnRH-ICG exhibited the binding capacity in a panel of cancer cell lines with different expression levels of GnRHR. In ovarian cancer mouse models, GnRHa-ICG signals were detected in peritoneal tumor lesions rather than normal peritoneal and intestines tissues. ICG showed intensive fluorescence signals in intestines. The tumor-to-muscle ratio and tumor-to-intestine ratio of GnRHa-ICG was 7.41 ± 2.82 and 4.37 ± 1.66, higher than that of ICG (4.60 ± 0.50 and 0.57 ± 0.06) at 2 h post administration. The fluorescence signal of peritoneal metastases peaked in intensity at 2 h and maintained for up to 48 h. ICG also showed a weak signal in the tumor lesions due to the enhanced permeability and retention effect, but the intensity decreased quickly within 48 h.Conclusions: The developed GnRHR-targeted imaging agent GnRHa-ICG could specifically detected peritoneal tumor lesions from normal peritoneal and intestines tissues because of the modification of GnRHa to ICG. The plateau period of GnRHa-ICG accumulation may be feasible for clinical applications in fluorescence-guided surgery. Our GnRHR imaging concept may be effective in other hormone-related tumors with upregulated GnRHR expression.
Highlights
Among all gynecologic malignancies, ovarian cancer is the most common cause of death worldwide [1]
We report the use of a molecular imaging probe using GnRH peptide, a specific and high-affinity gonadotropin-releasing hormone receptor (GnRHR) ligand, conjugated to the near-infrared fluorophore ICG
Transcriptome profiling data related to samples of ovarian cancer, breast cancer, endometrial cancer, and prostate cancer were downloaded from the the Cancer Genome Atlas (TCGA) data portal (2019)
Summary
Ovarian cancer is the most common cause of death worldwide [1]. The 10-year survival rate is only 15% for patients diagnosed with stage III-IV disease [2]. Cytoreductive surgery remains the cornerstone of treatment for advanced ovarian cancer. The completeness of cytoreduction is associated with local recurrence rates and clinical outcomes [3]. The median survival time of patients who undergo complete resection of all visible disease (R0) is 99.1 months, and the corresponding durations for patients with residuals of 0.1–1 cm or >1 cm are 36.2 or 29.6 months, respectively [4]. Successful cytoreduction relies on the accurate localization of cancerous lesions, especially minimal residual diseases, followed by their complete resection. Peritoneal dissemination is common in advanced ovarian cancer. This study aimed to develop a GnRHR-targeted near-infrared imaging probe for the detection of peritoneal metastases of ovarian cancer
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