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化学进展 2021, Vol. 33 Issue (1): 52-65 DOI: 10.7536/PC201014 前一篇   后一篇

• 特邀评论 •

手术导航用荧光探针

徐云雪1,2, 刘仁发1, 徐坤1, 戴志飞1,*()   

  1. 1 北京大学工学院生物医学工程系 北京 100871
    2 北京大学前沿交叉学科研究院 北京 100871
  • 收稿日期:2020-10-14 修回日期:2020-11-30 出版日期:2021-01-24 发布日期:2020-12-09
  • 通讯作者: 戴志飞
  • 作者简介:
    * Corresponding author e-mail:
    † The authors contributed equally to this work.
  • 基金资助:
    北京市自然科学基金-海淀原始创新联合基金(17L20170); 国家重点研发计划纳米科技专项(2016YFA0201400); 国家自然科学基金重点项目(81930047); 国家重大科研仪器研制项目(81727803); 国家自然科学基金创新研究群体科学基金(81421004)
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Fluorescent Probes for Intraoperative Navigation

Yunxue Xu1,2, Renfu Liu1, Kun xu1, Zhifei Dai1,*()   

  1. 1 Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China
    2 Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
  • Received:2020-10-14 Revised:2020-11-30 Online:2021-01-24 Published:2020-12-09
  • Contact: Zhifei Dai
  • Supported by:
    the Beijing Natural Science Foundation & Haidian Original Innovation Joint Fund(17L20170); the National Key Research and Development Program of China(No. 2016YFA0201400) , the State Key Program of National Natural Science of China(81930047); the National Project for Research and Development of Major Scientific Instruments(81727803); and the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(81421004); the Projects of International Cooperation and Exchanges NSFC-PSF(31961143003)

荧光成像技术因具有操作简便、分辨率高、安全性好且可实时成像等优势,在术中导航中具有广阔的应用前景。虽然目前还没有靶向荧光探针在临床上得到批准,但已经有相当一部分荧光探针进入了临床试验阶段。最早进入临床试验的是一些偶联肿瘤靶向配体的荧光染料,例如近红外菁染料(IRDye800CW)标记的肿瘤特异抗体,叶酸标记的异硫氰酸荧光素(EC17)等。近来,结构更复杂的荧光探针如酶反应激活型探针和PET/荧光双模态探针也逐步进入临床试验。本文依据近年来手术导航用荧光探针的最新研究进展,分别就受体介导的靶向荧光探针、可激活型靶向荧光探针、近红外二区(NIR-Ⅱ)荧光探针、多模态荧光探针和诊疗一体化探针进行了分类讨论,重点对正在进行临床研究及具有临床转化前景的荧光探针的分子设计原理进行了分析与总结,并对手术导航用荧光探针未来的发展进行了展望。

关键词： 荧光手术导航, 受体介导的靶向荧光探针, 可激活型靶向荧光探针, NIR-Ⅱ荧光成像, 多模态荧光探针, 诊疗一体化荧光探针, 临床转化

Fluorescence imaging has a promising application prospect in clinical tumor tracing and intraoperative navigation, by virtue of its simple operation, high resolution, safety and real-time imaging. Though there are no targeted fluorescent probes clinically approved yet, a great number of targeted fluorescent probes are indeed under clinical trials. The very first ones are fluorescent dyes conjugated with tumor-targeting ligands, such as tumor-specific antibodies labeled with near-infrared(NIR) cyanine dye(IRDye800CW) and fluorescein isothiocyanate labeled with folic acid(EC17). In recent years, more complicated fluorescent probes, such as activatable probes and PET/fluorescent dual-modal imaging probes, have gradually entered clinical trials. Based on the latest research progress of fluorescent probes for intraoperative navigation, this review discusses receptor-mediated targeted fluorescent probes, activatable targeted fluorescent probes, NIR-Ⅱ fluorescent probes, multimodal fluorescent probes and theranostic fluorescent probes, with an emphasis on analyzing and summarizing the molecular design principles of fluorescent probes which are undergoing clinical evaluation or with the potential of clinical translation. At last, the future perspectives of fluorescent probes for intraoperative navigation are prospected.

Contents

1 Introduction

2 Receptor-mediated targeted fluorescent probe

3 Activatable targeted fluorescent probe

4 NIR-Ⅱ fluorescent probe

5 Multimodal fluorescent probe

6 Theranostic fluorescent probe

7 Conclusion and outlook

Key words: fluorescent intraoperative navigation, receptor-mediated targeted fluorescent probes, activatable targeted fluorescent probes, NIR-Ⅱ imaging, multimodal fluorescent probes, theranostic fluorescent probes, clinical translation
()
图1 受体介导的靶向荧光探针的结构: (a)IRDye800CW标记抗体;(b)cRGD-ZW800-1;(c)EC-17;(d)OTL38;(e)C dots 的结构与(f)C dots荧光团Cy5的吸收光谱[49]
Fig. 1 Chemical structures of some affinity-based probes. (a)IRDye800CW-Antibody;(b)cRGD-ZW800-1;(c)EC-17;(d)OTL38;(e)C dots and (f)the absorbance spectra of its fluorophore Cy5[49]
图2 可激活型小分子靶向探针的化学结构及激活机理。 (a)BMV109;(b)GCP-001;(c)LUM105;(d)Lipidated Probe 3;(e)6QCNIR
Fig. 2 Chemical structures and activation mechanisms of reaction-activatable probes. (a)BMV109; (b)GCP-001; (c)LUM105; (d)Lipidated Probe 3; (e)6QCNIR
图3 (a)PINS纳米荧光探针对肿瘤酸性pH(转变pH=6.9)的响应机理;(b)在头颈癌、乳腺癌和腹膜转移瘤等多种模型中,PINS具有广泛的肿瘤检测特异性[16]
Fig. 3 (a) The response mechanism of PINS nanoprobes to tumor acidic pH(transition pH=6.9);(b) In a variety of tumor models(head and neck, breast, peritoneal metastasis, etc.), PINS nanoprobes exhibited broad tumor imaging efficacy[16]
图4 (a)NIR-Ⅱ荧光探针CH1055的结构;(b)IR-FEP的结构;(c)IR-FEP用于活体肿瘤的NIR-Ⅱ成像[82] ;(d)FD-1080的结构及其近红外吸收/荧光发射光谱[85] ;(e)靶向NIR-Ⅱ纳米荧光探针5H5 NPs及其用于活体肿瘤的NIR-Ⅱ和NIR-Ⅱa成像[86]
Fig. 4 (a) Chemical structure of CH1055 and (b) IR-FEP; (c) The NIR-Ⅱ imaging of tumor based on IR-FEP[82] ; (d) Chemical structure and absorbance/fluorescent emission spectra of FD-1080[85] ; (e) 5H5-based nanoprobe(5H5 NPs) for NIR-Ⅱ and NIR-Ⅱa imaging of tumor[86]
图5 (a)DiI-DiD纳米泡的构建及其荧光/超声双模态成像机理;(b)鲁米诺联合DiI-DiD纳米泡用于4T1肿瘤的荧光和超声成像[89] ;(c)荧光/光声/拉曼三模态成像探针OTPA-TQ3的结构;(d)OTPA-TQ3术前荧光/光声成像获取肿瘤全面信息,术中荧光/拉曼成像描绘肿瘤边界[91]
Fig. 5 (a) Schematic illustration of DiI-DiD NBs and the mechanism of its fluorescent/ultrasound dual-modal imaging; (b) Fluorescent and contrast-enhanced ultrasound imaging of the 4T1-luc xenograft tumor with luminal & DiI-DiD NBs[89] ; (c) The chemical structure of OTPA-TQ3; (d) The preoperative fluorescent/photoacoustic imaging obtained extensive tumor information and intraoperative fluorescent/Raman imaging accurately delineate tumor margin[91]
图6 (a)MMP-2和GSH双响应活化的前药囊泡(EAPV)示意图;(b)EAPV介导的光动力免疫治疗的机制[103]
Fig. 6 (a) Schematic of the MMP-2 and GSH activatable prodrug vesicle; (b) Schematic illustration of EAPV-mediated photodynamic immunotherapy of cancer[103]
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