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NIR-II fluorescence-guided liver cancer surgery by a small molecular HDAC6 targeting probe

文献类型：期刊论文

作者Wang, Bo1,2; Tang, Chu5; Lin, En1,2; Jia, Xiaohua2,3; Xie, Ganyuan1; Li, Peiping1; Li, Decheng1; Yang, Qiyue6; Guo, Xiaoyong2,7; Cao, Caiguang2,3
刊名EBIOMEDICINE
出版日期2023-12-01
卷号98页码:18
ISSN号2352-3964
关键词Hepatocellular carcinoma Second near-infrared window Molecular imaging HDAC6 Fluorescence guided surgery
DOI10.1016/j.ebiom.2023.104880
通讯作者Tian, Jie(jie.tian@ia.ac.cn) ; Hu, Zhenhua(zhenhua.hu@ia.ac.cn) ; Li, Jian(lijian5@mail.sysu.edu.cn)
英文摘要Background Hepatocellular carcinoma (HCC) is the sixth most common malignancy globally and ranks third in terms of both mortality and incidence rates. Surgical resection holds potential as a curative approach for HCC. However, the residual disease contributes to a high 5-year recurrence rate of 70%. Due to their excellent specificity and optical properties, fluorescence-targeted probes are deemed effective auxiliary tools for addressing residual lesions, enabling precise surgical diagnosis and treatment. Research indicates histone deacetylase 6 (HDAC6) overexpression in HCC cells, making it a potential imaging biomarker. This study designed a targeted small molecule fluorescent probe, SeCF3-IRDye800cw (SeCF3-IRD800), operating within the Second near-infrared window (NIR-II, 1000-1700 nm). The study confirms the biocompatibility of SeCF3-IRD800 and proceeds to demonstrate its applications in imaging in vivo, fluorescence-guided surgery (FGS) for liver cancer, liver fibrosis imaging, and clinical samples incubation, thereby preliminarily validating its utility in liver cancer. Methods SeCF3-IRD800 was synthesized by combining the near-infrared fluorescent dye IRDye800cw-NHS with an improved HDAC6 inhibitor. Initially, a HepG2-Luc subcutaneous tumor model (n = 12) was constructed to investigate the metabolic differences between SeCF3-IRD800 and ICG in vivo. Subsequently, HepG2-Luc (n = 12) and HCCLM3-Luc (n = 6) subcutaneous xenograft mouse models were used to assess in vivo targeting by SeCF3- IRD800. The HepG2-Luc orthotopic liver cancer model (n = 6) was employed to showcase the application of SeCF3-IRD800 in FGS. Liver fibrosis (n = 6) and HepG2-Luc orthotopic (n = 6) model imaging results were used to evaluate the impact of different pathological backgrounds on SeCF3-IRD800 imaging. Three groups of fresh HCC and normal liver samples from patients with liver cancer were utilized for SeCF3-IRD800 incubation ex vivo, while preclinical experiments illustrated its potential for clinical application. Findings The HDAC6 inhibitor 6 (SeCF3) modified with trifluoromethyl was labeled with IRDy800CW-NHS to synthesize the small-molecule targeted probe SeCF3-IRD800, with NIR-II fluorescence signals. SeCF3-IRD800 was rapidly metabolized by the kidneys and exhibited excellent biocompatibility. In vivo validation demonstrated that SeCF3-IRD800 achieved optimal imaging within 8 h, displaying high tumor fluorescence intensity (7658.41 +/- 933.34) and high tumor-to-background ratio (5.20 +/- 1.04). Imaging experiments with various expression levels revealed its capacity for HDAC6-specific targeting across multiple HCC tumor models, suitable for NIR-II intraoperative imaging. Fluorescence-guided surgery experiments were found feasible and capable of detecting sub-visible 2 mm tumor lesions under white light, aiding surgical decision-making. Further imaging of liver fibrosis mice showed that SeCF3-IRD800's imaging efficacy remained unaffected by liver pathological conditions. Correlations were observed between HDAC6 expression levels and corresponding fluorescence intensity (R2 = 0.8124) among normal liver, liver fibrosis, and HCC tissues. SeCF3-IRD800 identified HDAC6positive samples from patients with HCC, holding advantages for perspective intraoperative identification in liver cancer. Thus, the rapidly metabolized HDAC6-targeted small-molecule NIR-II fluorescence probe SeCF3-IRD800 holds significant clinical translational value. Interpretation The successful application of NIR-II fluorescence-guided surgery in liver cancer indicates that SeCF3- IRD800 has great potential to improve the clinical diagnosis and treatment of liver cancer, and could be used as an auxiliary tool for surgical treatment of liver cancer without being affected by liver pathology. Copyright (c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
WOS关键词HISTONE DEACETYLASE INHIBITOR ; INDOCYANINE GREEN ; HEPATOCELLULAR-CARCINOMA ; INTRAOPERATIVE ASSESSMENT ; TUMOR-SUPPRESSOR ; HYDROXAMIC ACID ; PHASE-I ; TRANSPLANTATION ; PROGRESSION
资助项目National Natural Science Foundation of China (NSFC)[92,059,207] ; National Natural Science Foundation of China (NSFC)[62,027,901] ; National Natural Science Foundation of China (NSFC)[81,930,053] ; National Natural Science Foundation of China (NSFC)[81,227,901] ; National Natural Science Foundation of China (NSFC)[82,272,105] ; National Natural Science Foundation of China (NSFC)[U21A20386] ; National Natural Science Foundation of China (NSFC)[81,971,773] ; CAS Youth Interdisciplinary Team[JCTD-2021-08] ; Zhuhai High-level Health Personnel Team Project[Zhuhai HLHPTP201703] ; Guangdong Basic and Applied Basic Research Foundation[2022A1515011244]
WOS研究方向General & Internal Medicine ; Research & Experimental Medicine
语种英语
出版者ELSEVIER
WOS记录号WOS:001129935100001
资助机构National Natural Science Foundation of China (NSFC) ; CAS Youth Interdisciplinary Team ; Zhuhai High-level Health Personnel Team Project ; Guangdong Basic and Applied Basic Research Foundation
源URL[http://ir.ia.ac.cn/handle/173211/54934]  
专题自动化研究所_中国科学院分子影像重点实验室
通讯作者Tian, Jie; Hu, Zhenhua; Li, Jian
作者单位1.Sun Yat Sen Univ, Affiliated Hosp 5, Dept Hepatobiliary Surg & Liver Transplantat, Zhuhai 519000, Peoples R China
2.Chinese Acad Sci, Inst Automat, CAS Key Lab Mol Imaging, Beijing Key Lab Mol Imaging, Beijing 100190, Peoples R China
3.Univ Chinese Acad Sci, Sch Artificial Intelligence, Beijing 100049, Peoples R China
4.Beihang Univ, Beijing Adv Innovat Ctr Big Data Based Precis Med, Sch Engn Med, Beijing 100191, Peoples R China
5.Xidian Univ, Sch Life Sci & Technol, Engn Res Ctr Mol & Neuro Imaging, Minist Educ, Xian 710071, Peoples R China
6.Chinese PLA, PLA, Key Lab Digital Hepatobiliary Surg, Inst Hepatobiliary Surg, Beijing 100048, Peoples R China
7.Anhui Med Univ, Chinese PLA Gen Hosp, Armed Police Gen Hosp, Clin Coll,Dept Gastroenterol,Med Ctr 3, Beijing 100039, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Bo,Tang, Chu,Lin, En,et al. NIR-II fluorescence-guided liver cancer surgery by a small molecular HDAC6 targeting probe[J]. EBIOMEDICINE,2023,98:18.
APA Wang, Bo.,Tang, Chu.,Lin, En.,Jia, Xiaohua.,Xie, Ganyuan.,...&Li, Jian.(2023).NIR-II fluorescence-guided liver cancer surgery by a small molecular HDAC6 targeting probe.EBIOMEDICINE,98,18.
MLA Wang, Bo,et al."NIR-II fluorescence-guided liver cancer surgery by a small molecular HDAC6 targeting probe".EBIOMEDICINE 98(2023):18.

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来源：自动化研究所

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