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化学进展 2020, Vol. 32 Issue (2/3): 204-218 DOI: 10.7536/PC190513 前一篇   后一篇

• •

监测细胞微环境及活性分子的有机小分子荧光探针

王阳, 黄楚森**(), 贾能勤**()   

  1. 上海师范大学化学与材料科学学院 上海市稀土功能材料重点实验室 资源化学教育部重点实验室 上海 200234
  • 收稿日期:2019-05-13 出版日期:2020-02-15 发布日期:2019-12-19
  • 通讯作者: 黄楚森, 贾能勤
  • 基金资助:
    国家自然科学基金项目(21672150); 国家自然科学基金项目(21302125); 德国洪堡基金会、上海科技启明星(19QA1406400); 教育部博士点新教师项目(20133127120005); 上海市科学技术委员会(18DZ2254200); 上海市科学技术委员会(17070503000); 教育部创新团队(IRT_16R49); 上海市稀土功能材料重点实验室和上海绿色能源化工工程技术研究中心资助()
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Molecular Fluorescent Probe for Monitoring Cellular Microenvironment and Active Molecules

Yang Wang, Chusen Huang**(), Nengqin Jia**()   

  1. Key Laboratory of Resource Chemistry of Ministry of Education, Shanghai Key Laboratory of Rare Earth Functional Material, College of Chemistry and Materials Science, Shanghai Normal University, Shanghai 200234, China
  • Received:2019-05-13 Online:2020-02-15 Published:2019-12-19
  • Contact: Chusen Huang, Nengqin Jia
  • About author:
    ** e-mail: (Chusen Huang);
    (Nengqin Jia)
  • Supported by:
    National Natural Science Foundation of China(21672150); National Natural Science Foundation of China(21302125); Alexander von Humboldt Foundation (AvH) the Shanghai Rising-Star Program(19QA1406400); Doctoral Fund of Ministry of Education of China(20133127120005); Shanghai Science and Technology Committee(18DZ2254200); Shanghai Science and Technology Committee(17070503000); Program for Changjiang Scholars and Innovative(IRT_16R49); Shanghai Key Laboratory of Rare Earth Functional Material, and the Shanghai Engineering Research Center of Green Energy Chemical Engineering.()

有机分子荧光探针因其灵敏度高,特异性强,对生物大分子和微环境扰动较少,同时可实现实时动态跟踪监测生物体中微环境的变化以及活性分子,已成为生物传感和生物成像领域的强大工具。本文总结了生物体微环境中常见的活性分子以及用于监测这些活性分子的有机分子荧光探针设计策略,并列举了近几年用于监测生物体中微环境变化以及活性分子的有机分子荧光探针,同时对这些荧光探针灵敏地监测与人类疾病相关的活性分子及其潜在应用价值做了讨论。

关键词： 细胞微环境, 活性分子, 生物成像, 有机小分子荧光探针

Small molecular fluorescent probe technology has become a potential tool for biosensing and bioimaging since it can realize real-time dynamic tracking and monitoring of active molecules and microenvironment changes in living organisms with advantages of less disturbance to biological samples, extremely high sensitivity and specificity. In this review, we summarize some characteristics of cellular microenvironment and related bioactive molecules commonly found in them. The design strategies of the molecular fluorescent probes utilized to monitor changes of cellular microenvironments and active molecules are also discussed. Some recently developed molecular fluorescent probes used to monitor microenvironmental changes and active molecules in organisms have also been listed in this review. Additionally, sensing behavior and potential application of these fluorescent probes have also been discussed.

Key words: cellular microenvironment, bioactive molecule, bioimaging, molecular fluorescent probe
()
图1 半胱氨酸(Cys)、高半胱氨酸(Hcy)、谷胱甘肽(GSH)的结构
Fig.1 Structures of cysteine(Cys), homocysteine(Hcy), and glutathione(GSH)
图2 荧光探针的结构[64]
Fig.2 Structures of the fluorescence probe[64]
图3 常见荧光团的结构[65]
Fig.3 Structures of common fluorophores[65]
图4 光诱导电子转移过程[67]
Fig.4 Mechanism of PET process[67]
图5 分子内电荷转移(ICT)机理[69]
Fig.5 Mechanism of ICT[69]
图6 ESIPT 过程原理[72]
Fig.6 Mechanism of ESIPT process[72]
图7 能量共振转移过程[82]
Fig.7 Mechanism of FRET process[82]
图8 (a)探针1监测线粒体中pH值变化的响应机理;(b)探针1的结构;(c)缺乏营养细胞的时间跟踪图像,记录时间点为0、 90、 180、 270和360 s[84]
Fig.8 (a)Proposed mitochondrion-specific pH sensing mechanism for probe 1.(b)The structure of probe 1.(c)nutrient-deprived cells. The images were recorded at time points consisting of t=0, 90, 180, 270 and 360 s[84]. Reprinted with permission from ref 84. Copyright 2014, American Chemical Society
图9 (a)探针2(CN-pH)的设计策略;(b)探针2(CN-pH)的响应机理和365 nm下5 μM探针2(CN-pH)在pH=4.5、6.5和8.5的荧光照片;(c)探针2(CN-pH)的结构和探针的共聚焦成像[85]
Fig.9 (a)Design strategies of fluorescent probes 2(CN-pH). (b)Proposed sensing mechanism and the fluorescence photographs of 5 μM probes 2(CN-pH) at pH 4.5, 6.5, and 8.5 under 365 nm.(c)The structure of fluorescent probe 2(CN-pH) and Confocal fluorescence images of probe 2(CN-pH)[85]. Reprinted with permission from ref 85. copyright 2016, American Chemical Society
图10 探针3(CPH)检测pH值的机理及其荧光/比色双模态成像[29]
Fig.10 The mechanism of probe 3(CPH) to pH and dual-modal colorimetric/fluorescence images[29]. Reprinted with permission from ref 29. copyright 2016, American Chemical Society
图11 (a)探针4 (CPY)检测pH值的机理;(b)探针4 CYP对不同pH值的荧光响应;(c)HeLa细胞在热休克状态下溶酶体pH值变化[86]
Fig.11 (a) The mechanism of probe 4(CPY) to pH.(b) The fluorescence response of probe 4(CPY) towards different pH values.(c) Relationship between lysosomal pH changes and heat stroke in HeLa cells[86]. Reprinted with permission from ref 86. copyright 2018, the Royal Society of Chemistry
图12 (a)Cys代谢双位点荧光探针5的设计;(b)探针5对5天斑马鱼对外源性Cys和S O 3 2 - 和内源性硫醇共聚焦成像;(c)探针对A549细胞就进行Cys代谢成像[20]
Fig.12 (a) Design of the dual-site fluorescent probe 5 for Cys metabolism.(b) Confocal images of probe 5 responding to exogenous Cys and S O 3 2 - and endogenous thiols in 5-day-old zebrafish.(c) Cys metabolism imaging with probe 5 in A549 cells[20]. Reprinted with permission from ref 20. copyright 2017, American Chemical Society
图13 探针6肝细胞靶向示意图[87]
Fig.13 Schematic representation of hepatocyte targeted imaging of probe 6[87]. Reprinted with permission from ref 87. copyright 2012, American Chemical Society
图14 探针7(VTAF)检测VDPs的机理及其比值荧光成像[88]
Fig.14 The mechanism of probe 7(VTAF) to VDPs and ratiometric fluorescence images[88]. Reprinted with permission from ref 88. copyright 2014, American Chemical Society
图15 (a)探针8(C7H)和对照探针9(Con-C7H)的原理图;(b)探针8(C7H)对斑马鱼幼体实时荧光成像[89]
Fig.15 (a) Schematic of probe 8(C7H) and control probe 9(Con-C7H).(b) Time-dependent fluorescence imaging in larval zebrafish with probe 8(C7H)[89]. Reprinted with permission from ref 89. copyright 2019, the Royal Society of Chemistry
图16 (a)探针10(PTZ-Cy2)的响应机理;(b)加入·OH后探针10(PTZ-Cy2)吸收光谱和荧光光谱的变化;(c)加入ClO-后探针10(PTZ-Cy2)吸收光谱和荧光光谱的变化;(d) 探针10(PTZ-Cy2)的共聚焦荧光图像[14]
Fig.16 (a)Proposed sensing mechanisms of probe 10(PTZ-Cy2). (b)Changes in fluorescence and adsorption spectra of probe 10(PTZ-Cy2) upon addition of ·OH.(c)Changes in fluorescence and adsorption spectra of probe 10(PTZ-Cy2) upon addition of ClO-. (d)Confocal fluorescence images of probe 10(PTZ-Cy2)[14]. Reprinted with permission from ref 14. copyright 2013, the Royal Society of Chemistry
图17 (a)探针11(MitoClO) 的响应机理;(b) 探针11(MitoClO) 的共聚焦荧光图像[93]
Fig.17 (a)Proposed sensing mechanisms of probe 11(MitoClO).(b)Confocal fluorescence images of probe 11(MitoClO)[93]. Reprinted with permission from ref 93. copyright 2013, the Royal Society of Chemistry
图18 溶酶体靶向探针12用于过氧化氢检测的结构[94]
Fig.18 The structure of lysosome-targetable H2O2 probe 12[94]. Reprinted with permission from ref 94. copyright 2015, scientific reports
图19 探针13结构及其对ONOO-的响应机理[95]
Fig.19 Structure of probe 13 and the mechanism of its response to ONO O - [ 95 ] . Reprinted with permission from ref 95. copyright 2014, the Royal Society of Chemistry
图20 线粒体靶向探针14用于过氧化氢和黏度检测的结构[96]
Fig.20 The structure of mito-targetable H2O2 and viscosity probe 14[96]. Reprinted with permission from ref 96. copyright 2017, American Chemical Society
图21 探针15(EIN) 合成以及原理示意图[97]
Fig.21 Schematic representation of the synthesis procedures of probe 15(EIN) and its working principle[97]. Reprinted with permission from ref 97. copyright 2016, the Royal Society of Chemistry
图22 溶酶体黏度探针16(Lyso-V)的工作原理图[23]
Fig.22 Working principle of lysosomal viscosity probe 16(Lyso-V)[23]. Reprinted with permission from ref 23. copyright 2013, American Chemical Society
图23 (a)溶酶体黏度探针17(Lys-V)的设计过程;(b)探针17(Lys-V)随着黏度变化的荧光光谱;(c)不同黏度下不同pH缓冲溶液中探针17(Lys-V)最大荧光强度;(d)探针17(Lys-V)对MCF-7细胞中溶酶体的靶向;(e)地塞米松处理后,探针17(Lys-V)对MCF-7细胞中溶酶体黏度改变的实时监测[98]
Fig.23 (a) Design procedures for the viscosity probe 17(Lys-V); (b) Fluorescence spectrum of probe 17(Lys-V) with increasing solvent viscosity;(c) Maximum fluorescence intensity of probe 17(Lys-V) in the different pH buffer solutions at various viscosities;(d) The lysosome-targeting properties of probe 17(Lys-V) in live MCF-7 cells;(e) Real-time monitoring of fluorescence changes in probe 17(Lys-V) labelled live MCF-7 after the cells were treated with dexamethasone[98]. Reprinted with permission from ref 98. copyright 2018, the Royal Society of Chemistry
图24 荧光探针18~21的结构[102,103,104,105]
Fig.24 Structures of fluorescent probe 18~21[102,103,104,105]
图25 探针22结构以及与NTR、ATP和NTP/ATP的反应[106]
Fig.25 Structures of fluorescent probe 22 and its reaction with NTP, ATP and NTP/ATP[106]. Reprinted with permission from ref 106. copyright 2018, the Royal Society of Chemistry
图26 ESIPT探针23用于区别活细胞和死细胞[113]
Fig.26 ESIPT probe 23 for discrimination between live and dead cells[113]. Reprinted with permission from ref 113. copyright 2018, American Chemical Society
图27 (a)探针24的结构;(b)在不同浓度ATP下,探针24的荧光发射光谱;(c)加入apyrase从0到60 min HeLa细胞成像[114]
Fig.27 (a)Chemical structure of probe 24. (b)The fluorescence spectra of probe 24 in the presence of different concentrations of ATP. (c)Images of HeLa cell treated with apyrase from 0 to 60 min[114]. Reprinted with permission from ref 114. copyright 2014, the Royal Society of Chemistry
图28 (a)探针25对ATP响应机理;(b)探针25与商业线粒体共定位成像[115]
Fig.28 (a)Proposed response mechanism of probe 25 to ATP.(b)Colocation imaging of HeLa cells staining with probe 25 and Mtio-Tracker Green[115]. Reprinted with permission from ref 115. copyright 2017, American Chemical Society
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