Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710126, Shaanxi, China.
CAS Key Laboratory of Molecular Imaging, The State Key Laboratory of Management and Control for Complex Systems, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China.
Mol Imaging Biol. 2020 Jun;22(3):476-485. doi: 10.1007/s11307-019-01389-4.
PURPOSE: 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. PROCEDURES: 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. RESULTS: 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. CONCLUSIONS: Our results indicate that IRDye800CW-SAHA is a clinical translatable probe for HCC detection and resection.
目的：肝细胞癌（HCC）是一种常见的全球癌症，对病变组织进行完全手术切除是治疗癌症的可靠策略。荧光图像引导手术是外科医生识别和切除恶性病变的一种很有前途的工具。虽然已经使用非靶向荧光染料来诊断和切除 HCC，但由于炎症组织的特异性不足和假阳性摄取，导致复发率高或过度切除健康的肝组织。为了解决这些问题，我们专注于开发新型肿瘤特异性靶向探针，以便在手术期间选择性地照亮癌症区域。鉴于组蛋白去乙酰化酶（HDACs）在 HCC 和许多其他癌症中的过度表达，HDAC 靶向成像已成为肿瘤检测的一种很有前途的工具。
程序：最近，在 HCC 患者的肿瘤样本中观察到 HDACs，特别是 HDAC6 的高表达，并且一些 HDAC 抑制剂，包括 FDA 批准的丁酸钠（SAHA），对 HCC 显示出强大的抗肿瘤作用。相应地，在这项研究中，我们利用具有高 HDAC 结合亲和力的小分子 SAHA 作为 HCC 特异性靶向配体，开发用于 HCC 检测和荧光图像引导切除的 HDAC 靶向荧光探针。
结果：在体外成像中，SAHA 用异硫氰酸荧光素（FITC）标记以评估靶向特性，成像结果表明 FITC-SAHA 被 HCC Bel-7402 细胞特异性摄取。在体内成像中，近红外荧光染料 IRDye800CW 标记的 SAHA（NIR 探针 IRDye800CW-SAHA）在皮下和原位 HCC 小鼠肿瘤模型中均显示出快速肿瘤积累，并具有高肿瘤与背景的对比度。此外，通过 IRDye800CW-SAHA 荧光图像引导手术成功切除了原位 HCC。此外，IRDye800CW-SAHA 对健康组织没有毒性。
结论：我们的结果表明，IRDye800CW-SAHA 是一种可用于 HCC 检测和切除的临床转化探针。
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