Abstract
Precise measurement of enzyme activity in living systems with molecular imaging probes is becoming an important technique to unravel the functional roles of different enzymes in biological processes. Recent progress has been made in the development of a myriad of molecular imaging probes featuring different imaging modalities, including optical imaging, magnetic resonance imaging, nuclear imaging, and photoacoustic imaging, allowing for non-invasive detection of various enzyme activities in vivo with high sensitivity and high spatial resolution. Among these imaging probes, activatable or “smart” probes, whose imaging signal can be specifically switched from the “off” to “on” state upon interaction with a target enzyme, are particularly attractive due to their improved sensitivity and specificity. Here, recent advances in the development of activatable probes capable of imaging different enzyme activities in vivo are summarized based on different imaging modalities, and current challenges and future perspectives are discussed.
摘要
利用分子影像探针在活体上进行酶活性的无损、精确检测对研究酶的活性与功能具有重要意义。近年来,不同模态的分子影像探针,包括光学成像、核磁共振成像、核素成像和光声成像探针等被广泛报道,并成功应用于活体内高灵敏、高分辨的检测各种酶活性。本文主要综述了激活型分子影像探针及其在活体内可视化检测酶活性的研究进展,并讨论了这一研究领域目前面临的挑战和未来的发展方向。
This is a preview of subscription content, access via your institution.




References
Baruch A, Jeffery DA, Bogyo M (2004) Enzyme activity—it’s all about image. Trends Cell Biol 14:29–35
Deryugina EI, Quigley JP (2010) Pleiotropic roles of matrix metalloproteinases in tumor angiogenesis: contrasting, overlapping and compensatory functions. Biochim Biophys Acta 1803:103–120
Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastas Rev 25:9–34
Dimri GP, Lee X, Basile G et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367
Gu K, Xu Y, Li H et al (2016) Real-time tracking and in vivo visualization of beta-galactosidase activity in colorectal tumor with a ratiometric near-infrared fluorescent probe. J Am Chem Soc 138:5334–5340
Cai W, Rao J, Gambhir SS et al (2006) How molecular imaging is speeding up antiangiogenic drug development. Mol Cancer Ther 5:2624–2633
Weissleder R, Pittet MJ (2008) Imaging in the era of molecular oncology. Nature 452:580–589
Razgulin A, Ma N, Rao J (2011) Strategies for in vivo imaging of enzyme activity: an overview and recent advances. Chem Soc Rev 40:4186–4216
Kobayashi H, Choyke PL (2011) Target-cancer-cell-specific activatable fluorescence imaging probes: rational design and in vivo applications. Acc Chem Res 44:83–90
Zhang W, Gao C (2015) Recent advances in cell imaging and cytotoxicity of intracellular stimuli-responsive nanomaterials. Sci Bull 60:1973–1979
Lee S, Park K, Kim K et al (2008) Activatable imaging probes with amplified fluorescent signals. Chem Commun 36:4250–4260
Licha K, Resch-Genger U (2011) Probes for optical imaging: new developments. Drug Discov Today Technol 8:e87–e94
Thomas JA (2015) Optical imaging probes for biomolecules: an introductory perspective. Chem Soc Rev 44:4494–4500
He X, Wang K, Cheng Z (2010) In vivo near-infrared fluorescence imaging of cancer with nanoparticle-based probes. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2:349–366
Drake CR, Miller DC, Jones EF (2011) Activatable optical probes for the detection of enzymes. Curr Org Synth 8:498–520
Cheng Y, Xie H, Sule P et al (2014) Fluorogenic probes with substitutions at the 2 and 7 positions of cephalosporin are highly BlaC-specific for rapid Mycobacterium tuberculosis detection. Angew Chem Int Ed 53:9360–9364
Zheng M, Huang H, Zhou M et al (2015) Cysteine-mediated intracellular building of luciferin to enhance probe retention and fluorescence turn-on. Chem Eur J 21:10506–10512
Xue H, Xu X, Fu YV (2015) New insights in pre-replication complex formation with single-molecule visualization. Sci Bull 60:1133–1135
Ogawa M, Kosaka N, Choyke PL et al (2009) H-type dimer formation of fluorophores: a mechanism for activatable, in vivo optical molecular imaging. ACS Chem Biol 4:535–546
Ofori LO, Withana NP, Prestwood TR et al (2015) Design of protease activated optical contrast agents that exploit a latent lysosomotropic effect for use in fluorescence-guided surgery. ACS Chem Biol 10:1977–1988
Bremer C, Bredow S, Mahmood U et al (2001) Optical imaging of matrix metalloproteinase-2 activity in tumors: feasibility study in a mouse model. Radiology 221:523–529
Lee S, Choi KY, Chung H et al (2011) Real time, high resolution video imaging of apoptosis in single cells with a polymeric nanoprobe. Bioconjugate Chem 22:125–131
Kong Y, Yao H, Ren H et al (2010) Imaging tuberculosis with endogenous beta-lactamase reporter enzyme fluorescence in live mice. Proc Natl Acad Sci USA 107:12239–12244
Versluis F, van Esch JH, Eelkema R (2016) Synthetic self-assembled materials in biological environments. Adv Mater 28:4576–4592
Gao Y, Shi J, Yuan D et al (2012) Imaging enzyme-triggered self-assembly of small molecules inside live cells. Nat Commun 3:1033
Ye D, Liang G, Ma ML et al (2011) Controlling intracellular macrocyclization for the imaging of protease activity. Angew Chem Int Ed 50:2275–2279
Ye D, Shuhendler AJ, Cui L et al (2014) Bioorthogonal cyclization-mediated in situ self-assembly of small-molecule probes for imaging caspase activity in vivo. Nat Chem 6:519–526
Shen B, Jeon J, Palner M et al (2013) Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-triggered nanoaggregation probe. Angew Chem Int Ed 52:10511–10514
Witney TH, Hoehne A, Reeves RE et al (2015) A systematic comparison of 18F-C-SNAT to established radiotracer imaging agents for the detection of tumor response to treatment. Clin Cancer Res 21:3896–3905
Ye D, Shuhendler AJ, Pandit P et al (2014) Caspase-responsive smart gadolinium-based contrast agent for magnetic resonance imaging of drug-induced apoptosis. Chem Sci 4:3845–3852
Nejadnik H, Ye D, Lenkov OD et al (2015) Magnetic resonance imaging of stem cell apoptosis in arthritic joints with a caspase activatable contrast agent. ACS Nano 9:1150–1160
Shuhendler AJ, Ye D, Brewer KD et al (2015) Molecular magnetic resonance imaging of tumor response to therapy. Sci Rep 5:14759
Terreno E, Castelli DD, Viale A et al (2010) Challenges for molecular magnetic resonance imaging. Chem Rev 110:3019–3042
Tu C, Osborne EA, Louie AY (2011) Activatable T(1) and T(2) magnetic resonance imaging contrast agents. Ann Biomed Eng 39:1335–1348
Shen C, New EJ (2013) Promising strategies for Gd-based responsive magnetic resonance imaging contrast agents. Curr Opin Chem Biol 17:158–166
Davies GL, Kramberger I, Davis JJ (2013) Environmentally responsive MRI contrast agents. Chem Commun 49:9704–9721
Do QN, Ratnakar JS, Kovacs Z et al (2014) Redox- and hypoxia-responsive MRI contrast agents. ChemMedChem 9:1116–1129
De Leon-Rodriguez LM, Martins AF, Pinho MC et al (2015) Basic MR relaxation mechanisms and contrast agent design. J Magn Reson Imaging 42:545–565
Louie AY, Huber MM, Ahrens ET et al (2000) In vivo visualization of gene expression using magnetic resonance imaging. Nat Biotechnol 18:321–325
Hanaoka K, Kikuchi K, Terai T et al (2008) A Gd3+-based magnetic resonance imaging contrast agent sensitive to beta-galactosidase activity utilizing a receptor-induced magnetization enhancement (RIME) phenomenon. Chem Eur J 14:987–995
Nivorozhkin AL, Kolodziej AF, Caravan P et al (2001) Enzyme-activated Gd(3+) magnetic resonance imaging contrast agents with a prominent receptor-induced magnetization enhancement. Angew Chem Int Ed 40:2903–2906
Kim J, Wu Y, Guo Y et al (2015) A review of optimization and quantification techniques for chemical exchange saturation transfer MRI toward sensitive in vivo imaging. Contrast Media Mol 10:163–178
Chen JW, Querol Sans M, Bogdanov A Jr et al (2006) Imaging of myeloperoxidase in mice by using novel amplifiable paramagnetic substrates. Radiology 240:473–481
Nahrendorf M, Sosnovik D, Chen JW et al (2008) Activatable magnetic resonance imaging agent reports myeloperoxidase activity in healing infarcts and noninvasively detects the antiinflammatory effects of atorvastatin on ischemia-reperfusion injury. Circulation 117:1153–1160
Cao CY, Shen YY, Wang JD et al (2013) Controlled intracellular self-assembly of gadolinium nanoparticles as smart molecular MR contrast agents. Sci Rep 3:1024
Loving GS, Caravan P (2014) Activation and retention: a magnetic resonance probe for the detection of acute thrombosis. Angew Chem Int Ed 53:1140–1143
Su JL, Wang B, Wilson KE et al (2010) Advances in clinical and biomedical applications of photoacoustic imaging. Exp Opin Med Diagn 4:497–510
Lu HD, Wilson BK, Heinmiller A et al (2016) Narrow absorption NIR wavelength organic nanoparticles enable multiplexed photoacoustic imaging. ACS Appl Mater Inter 8:14379–14388
Huang P, Gao Y, Lin J et al (2015) Tumor-specific formation of enzyme-instructed supramolecular self-assemblies as cancer theranostics. ACS Nano 9:9517–9527
Wang L, Yang PP, Zhao XX et al (2016) Self-assembled nanomaterials for photoacoustic imaging. Nanoscale 8:2488–2509
Wu D, Huang L, Jiang MS et al (2014) Contrast agents for photoacoustic and thermoacoustic imaging: a review. Int J Mol Sci 15:23616–23639
Dragulescu-Andrasi A, Kothapalli SR, Tikhomirov GA et al (2013) Activatable oligomerizable imaging agents for photoacoustic imaging of furin-like activity in living subjects. J Am Chem Soc 135:11015–11022
Zhang D, Qi GB, Zhao YX et al (2015) In situ formation of nanofibers from purpurin18-peptide conjugates and the assembly induced retention effect in tumor sites. Adv Mater 27:6125–6130
Yang K, Zhu L, Nie L et al (2014) Visualization of protease activity in vivo using an activatable photo-acoustic imaging probe based on CuS nanoparticles. Theranostics 4:134–141
van Duijnhoven SM, Robillard MS, Nicolay K et al (2015) Development of radiolabeled membrane type-1 matrix metalloproteinase activatable cell penetrating peptide imaging probes. Molecules 20:12076–12092
Oien NP, Nguyen LT, Jernigan FE et al (2014) Long-wavelength fluorescent reporters for monitoring protein kinase activity. Angew Chem Int Ed 53:3975–3978
Silvers WC, Prasai B, Burk DH et al (2013) Profluorogenic reductase substrate for rapid, selective, and sensitive visualization and detection of human cancer cells that overexpress NQO1. Angew Chem Int Ed 135:309–314
Prasai B, Silvers WC, McCarley RL (2015) Oxidoreductase-facilitated visualization and detection of human cancer cells. Anal Chem 87:6411–6418
Lee SY, Jeon SI, Jung S et al (2014) Targeted multimodal imaging modalities. Adv Drug Deliv Rev 76:60–78
Huang CW, Li Z, Conti PS (2012) Radioactive smart probe for potential corrected matrix metalloproteinase imaging. Bioconjugate Chem 23:2159–2167
Acknowledgments
This work was supported by the National Natural Science Foundation of China (21505070, 21632008) and Natural Foundation of Jiangsu Province (BK20150567).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
About this article
Cite this article
Yan, R., Ye, D. Molecular imaging of enzyme activity in vivo using activatable probes. Sci. Bull. 61, 1672–1679 (2016). https://doi.org/10.1007/s11434-016-1175-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11434-016-1175-y
Keywords
- Activatable probe
- Molecular imaging
- Enzyme
- In vivo
- Fluorescence
关键词
- 激活型探针
- 分子成像分析
- 酶
- 活体
- 荧光