Live cell in vitro and in vivo imaging applications: Accelerating drug discovery

Pharmaceutics

Volumn 3, Issue 2, 2011, Pages 141-170

  Isherwood, Beverley ^a   Timpson, Paul ^b   Mcghee, Ewan J ^b   Anderson, Kurt I ^b   Canel, Marta ^c   Serrels, Alan ^c   Brunton, Valerie G ^c   Carragher, Neil O ^c  

^a ASTRAZENECA   (United Kingdom)

^b BEATSON INSTITUTE FOR CANCER RESEARCH   (United Kingdom)

^c UNIVERSITY OF EDINBURGH   (United Kingdom)

Author keywords

Biomarkers; Drug discovery; Efficacy; Fluorescence; High content; Imaging; Intravital; Temporal; Translation

Indexed keywords

QUANTUM DOT;

ANALYTIC METHOD; AUTOMATION; BIMOLECULAR FLUORESCENT COMPLEMENTATION ASSAY; CANCER INVASION; CELL FATE; CELL INTERACTION; CELL KINETICS; CELL MIGRATION; COMPUTER PROGRAM; CONFOCAL MICROSCOPY; DRUG RESEARCH; DRUG SCREENING; FLUORESCENCE ANALYSIS; FLUORESCENCE RECOVERY AFTER PHOTOBLEACHING; FLUORESCENCE RESONANCE ENERGY TRANSFER; FLUORESCENT LIFETIME IMAGING MICROSCOPY; HUMAN; IMAGE ANALYSIS; IMAGE PROCESSING; IMAGE QUALITY; IN VITRO STUDY; IN VIVO STUDY; INTRAVITAL CONFOCAL MICROSCOPY; LIVE CELL IMAGING; MICROSCOPY; MOLECULAR DYNAMICS; MOLECULAR PROBE; MULTIPHOTON CONFOCAL MICROSCOPY; NON INVASIVE MEASUREMENT; NONHUMAN; OPTICAL BIOSENSOR; PHASE CONTRAST MICROSCOPY; PHENOTYPE; PHOTOACTIVATION; PHOTODYNAMICS; PHOTOINACTIVATION; PHOTOSWITCHING; PROTEIN PROTEIN INTERACTION; REVIEW;

EID: 79959852662     PISSN: None     EISSN: 19994923     Source Type: Journal    
DOI: 10.3390/pharmaceutics3020141     Document Type: Review

References (94)

1. Paul, S.M.; Mytelka, D.S.; Dunwiddie, C.T.; Persinger, C.C.; Munos, B.H.; Lindborg, S.R.; Schacht, A.L. How to improve R&D productivity: The pharmaceutical industry's grand challenge. Nat. Rev. Drug Discov. 2010, 9, 203-214.
2. Sams-Dodd, F. Target-based drug discovery: Is something wrong? Drug Discov. Today 2005, 10, 139-147.
3. Butcher, E.C. Can cell systems biology rescue drug discovery? Nat. Rev. Drug Discov. 2005, 4, 461-467.
4. Zock, J.M. Applications of high content screening in life science research. Comb. Chem. High Throughput Scr. 2009, 12, 870-876.
5. Bickle, M. The beautiful cell: High-content screening in drug discovery. Anal. Bioanal. Chem. 2010, 398, 219-226.
6. Bickle, M. High-content screening: A new primary screening tool? IDrugs 2008, 11, 822-826.
7. Perlman, Z.E.; Slack, M.D.; Feng, Y.; Mitchison, T.J.; Wu, L.F.; Altschuler, S.J. Multidimensional drug profiling by automated microscopy. Science 2004, 306, 1194-1198.
8. Tanaka, M.; Bateman, R.; Rauh, D.; Vaisberg, E.; Ramachandani, S.; Zhang, C.; Hansen, K.C.; Burlingame, A.L.; Trautman, J.K.; Shokat, K.M.; Adams, C.L. An unbiased cell morphology-based screen for new, biologically active small molecules. PLoS Biol. 2005, 3, e128.
9. Young, D.W.; Bender, A.; Hoyt, J.; McWhinnie, E.; Chirn, G.W.; Tao, C.Y.; Tallarico, J.A.; Labow, M.; Jenkins, J.L.; Mitchison, T.J.; Feng, Y. Integrating high-content screening and ligand-target prediction to identify mechanism of action. Nat. Chem. Biol. 2008, 4, 59-68.
10. Caie, P.D.; Walls, R.E.; Ingleston-Orme, A.; Daya, S.; Houslay, T.; Eagle, R.; Roberts, M.E.; Carragher, N.O. High-content phenotypic profiling of drug response signatures across distinct cancer cells. Mol. Cancer Ther. 2010, 9, 1913-1926.
11. Hassoun, A.T.; Erdelyi, F.; Szabo, G.; Davis, M.I. A rapid screening method for population-specific neuronal motogens, substrates and associated signaling pathways. J. Neurosci. Methods 2007, 166, 178-194.
12. Yarrow, J.C.; Perlman, Z.E.; Westwood, N.J.; Mitchison, T.J. A high-throughput cell migration assay using scratch wound healing, a comparison of image-based readout methods. BMC Biotechnol. 2004, 4, 21.
13. Huttenlocher, A.; Palecek, S.P.; Lu, Q.; Zhang, W.; Mellgren, R.L.; Lauffenburger, D.A.; Ginsberg, M.H.; Horwitz, A.F. Regulation of cell migration by the calcium-dependent protease calpain. J. Biol. Chem. 1997, 272, 32719-32722.
14. Friedl, P.; Wolf, K. Plasticity of cell migration: A multiscale tuning model. J. Cell Biol. 2010, 188, 11-19.
15. Wolf, K.; Mazo, I.; Leung, H.; Engelke, K.; von Andrian, U.H.; Deryugina, E.I.; Strongin, A.Y.; Brocker, E.B.; Friedl, P. Compensation mechanism in tumor cell migration: Mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J. Cell Biol. 2003, 160, 267-277.
16. Sahai, E.; Marshall, C.J. Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nat. Cell Biol. 2003, 5, 711-719.
17. Wolf, K.; Friedl, P. Molecular mechanisms of cancer cell invasion and plasticity. Br. J. Dermatol. 2006, 154 (Suppl. 1), 11-15.
18. Wyckoff, J.B.; Pinner, S.E.; Gschmeissner, S.; Condeelis, J.S.; Sahai, E. ROCK- and myosin-dependent matrix deformation enables protease-independent tumor-cell invasion in vivo. Curr. Biol. 2006, 16, 1515-1523.
19. Carragher, N.O. Profiling distinct mechanisms of tumour invasion for drug discovery: Imaging adhesion, signalling and matrix turnover. Clin. Exp. Metastasis 2009, 26, 381-397.
20. Gaggioli, C.; Hooper, S.; Hidalgo-Carcedo, C.; Grosse, R.; Marshall, J.F.; Harrington, K.; Sahai, E. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 2007, 9, 1392-1400.
21. Lukyanov, K.A.; Chudakov, D.M.; Lukyanov, S.; Verkhusha, V.V. Innovation: Photoactivatable fluorescent proteins. Nat. Rev. Mol. Cell Biol. 2005, 6, 885-891.
22. Gurskaya, N.G.; Verkhusha, V.V.; Shcheglov, A.S.; Staroverov, D.B.; Chepurnykh, T.V.; Fradkov, A.F.; Lukyanov, S.; Lukyanov, K.A. Engineering of a monomeric green-to-red photoactivatable fluorescent protein induced by blue light. Nat. Biotechnol. 2006, 24, 461-465.
23. Kedrin, D.; Gligorijevic, B.; Wyckoff, J.; Verkhusha, V.V.; Condeelis, J.; Segall, J.E.; van Rheenen, J. Intravital imaging of metastatic behavior through a mammary imaging window. Nat. Methods 2008, 5, 1019-1021.
24. Brown, E.; McKee, T.; diTomaso, E.; Pluen, A.; Seed, B.; Boucher, Y.; Jain, R.K. Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation. Nat. Med. 2003, 9, 796-800.
25. Perentes, J.Y.; McKee, T.D.; Ley, C.D.; Mathiew, H.; Dawson, M.; Padera, T.P.; Munn, L.L.; Jain, R.K.; Boucher, Y. In vivo imaging of extracellular matrix remodeling by tumor-associated fibroblasts. Nat. Methods 2009, 6, 143-145.
26. Canel, M.; Serrels, A.; Anderson, K.I.; Frame, M.C.; Brunton, V.G. Use of photoactivation and photobleaching to monitor the dynamic regulation of E-cadherin at the plasma membrane. Cell Adh. Migr. 2010, 4, 491-501.
27. Serrels, A.; Timpson, P.; Canel, M.; Schwarz, J.P.; Carragher, N.O.; Frame, M.C.; Brunton, V.G.; Anderson, K.I. Real-time study of E-cadherin and membrane dynamics in living animals: Implications for disease modeling and drug development. Cancer Res. 2009, 69, 2714-2719.
28. Welman, A.; Serrels, A.; Brunton, V.G.; Ditzel, M.; Frame, M.C. Two-color photoactivatable probe for selective tracking of proteins and cells. J. Biol. Chem. 2010, 285, 11607-11616.
29. Ballestrem, C.; Geiger, B. Application of microscope-based FRET to study molecular interactions in focal adhesions of live cells. Methods Mol. Biol. 2005, 294, 321-334.
30. Wu, Y.I.; Frey, D.; Lungu, O.I.; Jaehrig, A.; Schlichting, I.; Kuhlman, B.; Hahn, K.M. A genetically encoded photoactivatable Rac controls the motility of living cells. Nature 2009, 461, 104-108.
31. Wang, X.; He, L.; Wu, Y.I.; Hahn, K.M.; Montell, D.J. Light-mediated activation reveals a key role for Rac in collective guidance of cell movement in vivo. Nat. Cell Biol. 2010, 12, 591-597.
32. Levskaya, A.; Weiner, O.D.; Lim, W.A.; Voigt, C.A. Spatiotemporal control of cell signalling using a light-switchable protein interaction. Nature 2009, 461, 997-1001.
33. Rajfur, Z.; Roy, P.; Otey, C.; Romer, L.; Jacobson, K. Dissecting the link between stress fibres and focal adhesions by CALI with EGFP fusion proteins. Nat. Cell Biol. 2002, 4, 286-293.
34. Wallrabe, H.; Periasamy, A. Imaging protein molecules using FRET and FLIM microscopy. Curr. Opin. Biotechnol. 2005, 16, 19-27.
35. Sato, M.; Ozawa, T.; Inukai, K.; Asano, T.; Umezawa, Y. Fluorescent indicators for imaging protein phosphorylation in single living cells. Nat. Biotechnol. 2002, 20, 287-294.
36. Ting, A.Y.; Kain, K.H.; Klemke, R.L.; Tsien, R.Y. Genetically encoded fluorescent reporters of protein tyrosine kinase activities in living cells. Proc. Natl. Acad. Sci. USA 2001, 98, 15003-15008.
37. Vanderklish, P.W.; Krushel, L.A.; Holst, B.H.; Gally, J.A.; Crossin, K.L.; Edelman, G.M. Marking synaptic activity in dendritic spines with a calpain substrate exhibiting fluorescence resonance energy transfer. Proc. Natl. Acad. Sci. USA 2000, 97, 2253-2258.
38. Miyawaki, A.; Llopis, J.; Heim, R.; McCaffery, J.M.; Adams, J.A.; Ikura, M.; Tsien, R.Y. Fluorescent indicators for Ca2+ based on green fluorescent proteins and calmodulin. Nature 1997, 388, 882-887.
39. Mank, M.; Reiff, D.F.; Heim, N.; Friedrich, M.W.; Borst, A.; Griesbeck, O. A FRET-based calcium biosensor with fast signal kinetics and high fluorescence change. Biophys. J. 2006, 90, 1790-1796.
40. Li, I.T.; Chiang, J.J.; Truong, K. FRET evidence that an isoform of caspase-7 binds but does not cleave its substrate. In Proceedings of IEEE Engineering in Medicine and Biology Society, NewYork, NY, USA, 30 August-3 September 2006.
41. Grant, D.M.; McGinty, J.; McGhee, E.J.; Bunney, T.D.; Owen, D.M.; Talbot, C.B.; Zhang, W.; Kumar, S.; Munro, I.; Lanigan, P.M.; Kennedy, G.T.; Dunsby, C.; Magee, A.I.; Courtney, P.; Katan, M.; Neil, M.A.; French, P.M. High speed optically sectioned fluorescence lifetime imaging permits study of live cell signaling events. Opt. Express 2007, 15, 15656-15673.
42. Talbot, C.B.; McGinty, J.; Grant, D.M.; McGhee, E.J.; Owen, D.M.; Zhang, W.; Bunney, T.D.; Munro, I.; Isherwood, B.; Eagle, R.; Hargreaves, A.; Dunsby, C.; Neil, M.A.; French, P.M. High speed unsupervised fluorescence lifetime imaging confocal multiwell plate reader for high content analysis. J. Biophotonics 2008, 1, 514-521.
43. Machacek, M.; Hodgson, L.; Welch, C.; Elliott, H.; Pertz, O.; Nalbant, P.; Abell, A.; Johnson, G.L.; Hahn, K.M.; Danuser, G. Coordination of Rho GTPase activities during cell protrusion. Nature 2009, 461, 99-103.
44. Grecco, H.E.; Roda-Navarro, P.; Girod, A.; Hou, J.; Frahm, T.; Truxius, D.C.; Pepperkok, R.; Squire, A.; Bastiaens, P.I. In situ analysis of tyrosine phosphorylation networks by FLIM on cell arrays. Nat. Methods 2010, 7, 467-472.
45. Elson, D.; Requejo-Isidro, J.; Munro, I.; Reavell, F.; Siegel, J.; Suhling, K.; Tadrous, P.; Benninger, R.; Lanigan, P.; McGinty, J.; Talbot, C.; Treanor, B.; Webb, S.; Sandison, A.; Wallace, A.; Davis, D.; Lever, J.; Neil, M.; Phillips, D.; Stamp, G.; French, P. Time-domain fluorescence lifetime imaging applied to biological tissue. Photochem. Photobiol. Sci. 2004, 3, 795-801.
46. Galletly, N.P.; McGinty, J.; Dunsby, C.; Teixeira, F.; Requejo-Isidro, J.; Munro, I.; Elson, D.S.; Neil, M.A.; Chu, A.C.; French, P.M.; Stamp, G.W. Fluorescence lifetime imaging distinguishes basal cell carcinoma from surrounding uninvolved skin. Br. J. Dermatol. 2008, 159, 152-161.
47. Kelleher, M.T.; Fruhwirth, G.; Patel, G.; Ofo, E.; Festy, F.; Barber, P.R.; Ameer-Beg, S.M.; Vojnovic, B.; Gillett, C.; Coolen, A.; Keri, G.; Ellis, P.A.; Ng, T. The potential of optical proteomic technologies to individualize prognosis and guide rational treatment for cancer patients. Target Oncol. 2009, 4, 235-252.
48. van Zandvoort, M.A.; de Grauw, C.J.; Gerritsen, H.C.; Broers, J.L.; Oude Egbrink, M.G.; Ramaekers, F.C.; Slaaf, D.W. Discrimination of DNA and RNA in cells by a vital fluorescent probe: Lifetime imaging of SYTO13 in healthy and apoptotic cells. Cytometry 2002, 47, 226-235.
49. Cui, H.H.; Valdez, J.G.; Steinkamp, J.A.; Crissman, H.A. Fluorescence lifetime-based discrimination and quantification of cellular DNA and RNA with phase-sensitive flow cytometry. Cytometry A 2003, 52, 46-55.
50. Murata, S.; Herman, P.; Lakowicz, J.R. Texture analysis of fluorescence lifetime images of AT-and GC-rich regions in nuclei. J. Histochem. Cytochem. 2001, 49, 1443-1451.
51. Owen, D.M.; Lanigan, P.M.; Dunsby, C.; Munro, I.; Grant, D.; Neil, M.A.; French, P.M.; Magee, A.I. Fluorescence lifetime imaging provides enhanced contrast when imaging the phase-sensitive dye di-4-ANEPPDHQ in model membranes and live cells. Biophys. J. 2006, 90, L80-L82.
52. Magliery, T.J.; Regan, L. Reassembled GFP: Detecting protein-protein interactions and protein expression patterns. Methods Biochem. Anal. 2006, 47, 391-405.
53. Michnick, S.W.; MacDonald, M.L.; Westwick, J.K. Chemical genetic strategies to delineate MAP kinase signaling pathways using protein-fragment complementation assays (PCA). Methods 2006, 40, 287-293.
54. Ainscow, E.K.; Rutter, G.A. Glucose-stimulated oscillations in free cytosolic ATP concentration imaged in single islet beta-cells: Evidence for a Ca2+-dependent mechanism. Diabetes 2002, 51 (Suppl. 1), S162-S170.
55. Webb, D.J.; Donais, K.; Whitmore, L.A.; Thomas, S.M.; Turner, C.E.; Parsons, J.T.; Horwitz, A.F. FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly. Nat. Cell Biol. 2004, 6, 154-161.
56. Nelson, D.E.; Ihekwaba, A.E.; Elliott, M.; Johnson, J.R.; Gibney, C.A.; Foreman, B.E.; Nelson, G.; See, V.; Horton, C.A.; Spiller, D.G.; Edwards, S.W.; McDowell, H.P.; Unitt, J.F.; Sullivan, E.; Grimley, R.; Benson, N.; Broomhead, D.; Kell, D.B.; White, M.R. Oscillations in NF-kappaB signaling control the dynamics of gene expression. Science 2004, 306, 704-708.
57. Bains, M.; Heidenreich, K.A. Live-cell imaging of autophagy induction and autophagosome-lysosome fusion in primary cultured neurons. Methods Enzymol. 2009, 453, 145-158.
58. Rubin, M.A.; Zerkowski, M.P.; Camp, R.L.; Kuefer, R.; Hofer, M.D.; Chinnaiyan, A.M.; Rimm, D.L. Quantitative determination of expression of the prostate cancer protein alpha-methylacyl-CoA racemase using automated quantitative analysis (AQUA): A novel paradigm for automated and continuous biomarker measurements. Am. J. Pathol. 2004, 164, 831-840.
59. Weigert, R.; Sramkova, M.; Parente, L.; Amornphimoltham, P.; Masedunskas, A. Intravital microscopy: A novel tool to study cell biology in living animals. Histochem. Cell Biol. 2010, 133, 481-491.
60. Beerling, E.; Ritsma, L.; Vrisekoop, N.; Derksen, P.W.; van Rheenen, J. Intravital microscopy: New insights into metastasis of tumors. J. Cell Sci. 2011, 124, 299-310.
61. Levenson, R.M.; Mansfield, J.R. Multispectral imaging in biology and medicine: Slices of life. Cytometry A 2006, 69, 748-758.
62. Ntziachristos, V.; Bremer, C.; Weissleder, R. Fluorescence imaging with near-infrared light: New technological advances that enable in vivo molecular imaging. Eur. Radiol. 2003, 13, 195-208.
63. Bullen, A. Microscopic imaging techniques for drug discovery. Nat. Rev. Drug Discov. 2008, 7, 54-67.
64. Kennedy, G.T.; Manning, H.B.; Elson, D.S.; Neil, M.A.; Stamp, G.W.; Viellerobe, B.; Lacombe, F.; Dunsby, C.; French, P.M. A fluorescence lifetime imaging scanning confocal endomicroscope. J. Biophotonics 2010, 3, 103-107.
65. Brown, E.; Munn, L.L.; Fukumura, D.; Jain, R.K. In vivo imaging of tumors. Cold Spring Harb. Protoc. 2010, 2010, pdb prot5452.
66. Makale, M. Intravital imaging and cell invasion. Methods Enzymol. 2007, 426, 375-401.
67. Condeelis, J.; Segall, J.E. Intravital imaging of cell movement in tumours. Nat. Rev. Cancer 2003, 3, 921-930.
68. Xue, C.; Wyckoff, J.; Liang, F.; Sidani, M.; Violini, S.; Tsai, K.L.; Zhang, Z.Y.; Sahai, E.; Condeelis, J.; Segall, J.E. Epidermal growth factor receptor overexpression results in increased tumor cell motility in vivo coordinately with enhanced intravasation and metastasis. Cancer Res. 2006, 66, 192-197.
69. Yamaguchi, H.; Wyckoff, J.; Condeelis, J. Cell migration in tumors. Curr. Opin. Cell Biol. 2005, 17, 559-564.
70. Canel, M.; Serrels, A.; Miller, D.; Timpson, P.; Serrels, B.; Frame, M.C.; Brunton, V.G. Quantitative in vivo imaging of the effects of inhibiting integrin signaling via Src and FAK on cancer cell movement: Effects on E-cadherin dynamics. Cancer Res. 2010, 70, 9413-9422.
71. Canel, M.; Serrels, A.; Miller, D.; Timpson, P.; Serrels, B.; Frame, M.C.; Brunton, V.G. Quantitative in vivo imaging of the effects of inhibiting integrin signaling via Src and FAK on cancer cell movement: Effects on E-cadherin dynamics. Cancer Res. 2010, 70, 9413-9422.
72. Giampieri, S.; Manning, C.; Hooper, S.; Jones, L.; Hill, C.S.; Sahai, E. Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nat. Cell Biol. 2009, 11, 1287-1296.
73. Timpson, P.; McGhee, E.J.; Morton, J.P.; von Kriegsheim, A.; Schwarz, J.P.; Karim, S.A.; Doyle, B.; Quinn, J.A.; Carragher, N.O.; Edward, M.; Olson, M.F.; Frame, M.C.; Brunton, V.G.; Sansom, O.J.; Anderson, K.I. Spatial Regulation of RhoA Activity during Pancreatic Cancer Cell Invasion Driven by Mutant p53. Cancer Res. 2011, 71, 747-757.
74. Turner, S.M.; Hellerstein, M.K. Emerging applications of kinetic biomarkers in preclinical and clinical drug development. Curr. Opin. Drug Discov. Devel. 2005, 8, 115-126.
75. Morton, J.P.; Timpson, P.; Karim, S.A.; Ridgway, R.A.; Athineos, D.; Doyle, B.; Jamieson, N.B.; Oien, K.A.; Lowy, A.M.; Brunton, V.G.; Frame, M.C.; Evans, T.R.; Sansom, O.J. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc. Natl. Acad. Sci. USA 2010, 107, 246-251.
76. Ahmad, I.; Morton, J.P.; Singh, L.B.; Radulescu, S.M.; Ridgway, R.A.; Patel, S.; Woodgett, J.; Winton, D.J.; Taketo, M.M.; Wu, X.R.; Leung, H.Y.; Sansom, O.J. beta-Catenin activation synergizes with PTEN loss to cause bladder cancer formation. Oncogene 2011, 30, 178-189.
77. Cole, A.M.; Ridgway, R.A.; Derkits, S.E.; Parry, L.; Barker, N.; Clevers, H.; Clarke, A.R.; Sansom, O.J. p21 loss blocks senescence following Apc loss and provokes tumourigenesis in the renal but not the intestinal epithelium. EMBO Mol. Med. 2010, 2, 472-486.
78. Doyle, B.; Morton, J.P.; Delaney, D.W.; Ridgway, R.A.; Wilkins, J.A.; Sansom, O.J. p53 mutation and loss have different effects on tumourigenesis in a novel mouse model of pleomorphic rhabdomyosarcoma. J. Pathol. 2010, 222, 129-137.
79. Zhang, J.; Campbell, R.E.; Ting, A.Y.; Tsien, R.Y. Creating new fluorescent probes for cell biology. Nat. Rev. Mol. Cell Biol. 2002, 3, 906-918.
80. Giepmans, B.N.; Adams, S.R.; Ellisman, M.H.; Tsien, R.Y. The fluorescent toolbox for assessing protein location and function. Science 2006, 312, 217-224.
81. Haney, S.A.; LaPan, P.; Pan, J.; Zhang, J. High-content screening moves to the front of the line. Drug Discov. Today 2006, 11, 889-894.
82. Lundholt, B.K.; Heydorn, A.; Bjorn, S.P.; Praestegaard, M. A simple cell-based HTS assay system to screen for inhibitors of p53-Hdm2 protein-protein interactions. Assay Drug Dev. Technol. 2006, 4, 679-688.
83. Heydorn, A.; Lundholt, B.K.; Praestegaard, M.; Pagliaro, L. Protein translocation assays: Key tools for accessing new biological information with high-throughput microscopy. Methods Enzymol. 2006, 414, 513-530.
84. Shcherbo, D.; Merzlyak, E.M.; Chepurnykh, T.V.; Fradkov, A.F.; Ermakova, G.V.; Solovieva, E.A.; Lukyanov, K.A.; Bogdanova, E.A.; Zaraisky, A.G.; Lukyanov, S.; Chudakov, D.M. Bright far-red fluorescent protein for whole-body imaging. Nat. Methods 2007, 4, 741-746.
85. Campbell, R.E.; Tour, O.; Palmer, A.E.; Steinbach, P.A.; Baird, G.S.; Zacharias, D.A.; Tsien, R.Y. A monomeric red fluorescent protein. Proc. Natl. Acad. Sci. USA 2002, 99, 7877-7882.
86. Shu, X.; Royant, A.; Lin, M.Z.; Aguilera, T.A.; Lev-Ram, V.; Steinbach, P.A.; Tsien, R.Y. Mammalian expression of infrared fluorescent proteins engineered from a bacterial phytochrome. Science 2009, 324, 804-807.
87. Panchuk-Voloshina, N.; Haugland, R.P.; Bishop-Stewart, J.; Bhalgat, M.K.; Millard, P.J.; Mao, F.; Leung, W.Y. Alexa dyes, a series of new fluorescent dyes that yield exceptionally bright, photostable conjugates. J. Histochem. Cytochem. 1999, 47, 1179-1188.
88. Escobedo, J.O.; Rusin, O.; Lim, S.; Strongin, R.M. NIR dyes for bioimaging applications. Curr. Opin. Chem. Biol. 2010, 14, 64-70.
89. Klohs, J.; Wunder, A.; Licha, K. Near-infrared fluorescent probes for imaging vascular pathophysiology. Basic Res. Cardiol. 2008, 103, 144-151.
90. Kasili, P.M.; Song, J.M.; Vo-Dinh, T. Optical sensor for the detection of caspase-9 activity in a single cell. J. Am. Chem. Soc. 2004, 126, 2799-2806.
91. Tung, C.H.; Mahmood, U.; Bredow, S.; Weissleder, R. In vivo imaging of proteolytic enzyme activity using a novel molecular reporter. Cancer Res. 2000, 60, 4953-4958.
92. Bremer, C.; Tung, C.H.; Weissleder, R. In vivo molecular target assessment of matrix metalloproteinase inhibition. Nat. Med. 2001, 7, 743-748.
93. Bruchez, M.P. Turning all the lights on: Quantum dots in cellular assays. Curr. Opin. Chem. Biol. 2005, 9, 533-537.
94. Bentolila, L.A.; Ebenstein, Y.; Weiss, S. Quantum dots for in vivo small-animal imaging. J. Nucl. Med. 2009, 50, 493-496.