Development of a Novel Histone Deacetylase-Targeted Near-Infrared Probe for Hepatocellular Carcinoma Imaging and Fluorescence Image-Guided Surgery.

Abstract

Hepatocellular carcinoma (HCC) is a common cancer worldwide, and complete surgical resection of diseased tissue is a reliable strategy to cure cancer. Fluorescence image-guided surgery is a promising tool for surgeons to identify and remove malignant lesions. While non-targeted fluorescent dyes have been used for HCC diagnosis and resection, insufficient specificity and false positive uptake from inflammatory tissue result in a high recurrence rate or excessive excision of healthy liver tissue. To circumvent these problems, we focused on developing novel tumor-specific targeting probe to selectively illuminate cancer region during surgery. Given overexpression of histone deacetylases (HDACs) in HCC and many other cancers, HDAC-targeted imaging has been emerged as a promising tool for tumor detection. Recently, high expression of HDACs, in particular HDAC6, has been observed in tumor samples of HCC patient, and a few HDAC inhibitors, including FDA-approved suberoylanilide hydroxamic acid (SAHA), display potent antitumor effect on HCC. Correspondingly, in this study, we utilized a small molecule SAHA with the high HDAC-binding affinity as the HCC-specific targeting ligand to develop HDAC-targeted fluorescence probe for HCC detection and fluorescence image-guided resection. In in vitro imaging, SAHA was labelled with fluorescein isothiocyanate (FITC) to evaluate targeting property, and the imaging results demonstrated that FITC-SAHA was specific uptake by HCC Bel-7402 cells. In in vivo imaging, near infrared fluorescence dye IRDye800CW-labelled SAHA (NIR probe IRDye800CW-SAHA) showed rapid tumor accumulation with high tumor-to-background contrast on both the subcutaneous and orthotopic HCC mouse tumor models. Furthermore, the orthotopic HCC was successfully resected by the IRDye800CW-SAHA fluorescence image-guided surgery. Moreover, IRDye800CW-SAHA showed no toxicity toward healthy tissues. Our results indicate that IRDye800CW-SAHA is a clinical translatable probe for HCC detection and resection.