Abstract

Fluorescence lifetime imaging is playing an increasing role in drug development by providing a sensitive method to monitor drug delivery and receptor-ligand interactions. However, the wide dynamic range of fluorescence intensity emitted by ex vivo and in vivo samples presents challenges in retrieving information over the whole subject accurately and quantitatively. To overcome this challenge, we developed an active wide-field illumination (AWFI) strategy based on a spatial light modulator that acquires optimal fluorescence signals by enhancing the dynamic range, signal to noise ratio, and estimation of lifetime-based parameters. We demonstrate the ability of AWFI to estimate Förster resonance energy transfer (FRET) donor fraction from dissected organs with high accuracy (standard deviation <6%) over the whole field of view, in contrast with the homogenous wide-field illumination. We further report its successful application to quantitative FRET imaging in a live mouse. AWFI allows improved detection of weak signals and enhanced quantitative accuracy in ex vivo and in vivo molecular fluorescence quantitative imaging. The technique allows for robust quantitative estimation of the bio-distribution of molecular probes and lifetime-based parameters over an extended imaging field exhibiting a large range of fluorescence intensities and at a high acquisition speed (less than 1 min).

© 2014 Optical Society of America

Full Article  |  PDF Article

References

  • View by:
  • |
  • |
  • |

  1. A. J. Fischman, N. M. Alpert, and R. H. Rubin, “Pharmacokinetic imaging: a noninvasive method for determining drug distribution and action,” Clin. Pharmacokinet.41(8), 581–602 (2002).
    [CrossRef] [PubMed]
  2. D. J. Bornhop, C. H. Contag, K. Licha, and C. J. Murphy, “Advance in contrast agents, reporters, and detection,” J. Biomed. Opt.6(2), 106–110 (2001).
    [CrossRef] [PubMed]
  3. T. F. Massoud, A. Singh, and S. S. Gambhir, “Noninvasive molecular neuroimaging using reporter genes: part II, experimental, current, and future applications,” AJNR Am. J. Neuroradiol.29(3), 409–418 (2008).
    [CrossRef] [PubMed]
  4. H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
    [CrossRef] [PubMed]
  5. N. Kosaka, M. Ogawa, N. Sato, P. L. Choyke, and H. Kobayashi, “In vivo real-time, multicolor, quantum dot lymphatic imaging,” J. Invest. Dermatol.129(12), 2818–2822 (2009).
    [CrossRef] [PubMed]
  6. M. Y. Berezin and S. Achilefu, “Fluorescence lifetime measurements and biological imaging,” Chem. Rev.110(5), 2641–2684 (2010).
    [CrossRef] [PubMed]
  7. H. Wallrabe and A. Periasamy, “Imaging protein molecules using FRET and FLIM microscopy,” Curr. Opin. Biotechnol.16(1), 19–27 (2005).
    [CrossRef] [PubMed]
  8. S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
    [CrossRef] [PubMed]
  9. V. Venugopal, J. Chen, M. Barroso, and X. Intes, “Quantitative tomographic imaging of intermolecular FRET in small animals,” Biomed. Opt. Express3(12), 3161–3175 (2012).
    [CrossRef] [PubMed]
  10. S. A. Hilderbrand and R. Weissleder, “Near-infrared fluorescence: application to in vivo molecular imaging,” Curr. Opin. Chem. Biol.14(1), 71–79 (2010).
    [CrossRef] [PubMed]
  11. L. Zhao, K. Abe, M. Barroso, and X. Intes, “Active wide-field illumination for high-throughput fluorescence lifetime imaging,” Opt. Lett.38(19), 3976–3979 (2013).
    [CrossRef] [PubMed]
  12. V. Venugopal, J. Chen, and X. Intes, “Development of an optical imaging platform for functional imaging of small animals using wide-field excitation,” Biomed. Opt. Express1(1), 143–156 (2010).
    [CrossRef] [PubMed]
  13. D. W. Bartlett, H. Su, I. J. Hildebrandt, W. A. Weber, and M. E. Davis, “Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging,” Proc. Natl. Acad. Sci. U.S.A.104(39), 15549–15554 (2007).
    [CrossRef] [PubMed]
  14. V. Venugopal and X. Intes, “Adaptive wide-field optical tomography,” J. Biomed. Opt.18(3), 036006 (2013).
    [CrossRef] [PubMed]
  15. V. Venugopal, “A small animal time-resolved optical tomography platform using wide-field excitation,” Doctoral Dissertation Rensselaer Polytechnic Institute, 47–49 (2011).
  16. K. Abe, L. Zhao, A. Periasamy, X. Intes, and M. Barroso, “Non-Invasive In Vivo Imaging of Near Infrared-labeled Transferrin in Breast Cancer Cells and Tumors Using Fluorescence Lifetime FRET,” PLoS ONE8(11), e80269 (2013).
    [CrossRef] [PubMed]
  17. M. Kollner and J. Wolfrum, “How Many Photons Are Necessary for Fluorescence-Lifetime Measurements,” Chem. Phys. Lett.200(1-2), 199–204 (1992).
    [CrossRef]
  18. H. Wallrabe, M. Elangovan, A. Burchard, A. Periasamy, and M. Barroso, “Confocal FRET microscopy to measure clustering of ligand-receptor complexes in endocytic membranes,” Biophys. J.85(1), 559–571 (2003).
    [CrossRef] [PubMed]
  19. H. Wallrabe, M. Stanley, A. Periasamy, and M. Barroso, “One- and two-photon fluorescence resonance energy transfer microscopy to establish a clustered distribution of receptor-ligand complexes in endocytic membranes,” J. Biomed. Opt.8(3), 339–346 (2003).
    [CrossRef] [PubMed]
  20. Transferrin-Vivo 750 Fluorescent Imaging Agent. Available at http://www.perkinelmer.com/Catalog/Product/ID/10091) ,” (2013).
  21. C. Alric, I. Miladi, D. Kryza, J. Taleb, F. Lux, R. Bazzi, C. Billotey, M. Janier, P. Perriat, S. Roux, and O. Tillement, “The biodistribution of gold nanoparticles designed for renal clearance,” Nanoscale5(13), 5930–5939 (2013).
    [CrossRef] [PubMed]
  22. C. R. Berry, P. Fisher, P. D. Koblik, W. G. Guilford, and W. H. Hornof, “Scintigraphic biodistribution and plasma kinetics of indium 111-labeled transferrin in dogs,” Am. J. Vet. Res.58(11), 1188–1192 (1997).
    [PubMed]
  23. A. L. Vavere and M. J. Welch, “Preparation, biodistribution, and small animal PET of 45Ti-transferrin,” J. Nucl. Med.46(4), 683–690 (2005).
    [PubMed]
  24. J. Meek and E. D. Adamson, “Transferrin in foetal and adult mouse tissues: synthesis, storage and secretion,” J. Embryol. Exp. Morphol.86, 205–218 (1985).
    [PubMed]
  25. M. K. Kuimova, G. Yahioglu, J. A. Levitt, and K. Suhling, “Molecular rotor measures viscosity of live cells via fluorescence lifetime imaging,” J. Am. Chem. Soc.130(21), 6672–6673 (2008).
    [CrossRef] [PubMed]
  26. M. Hassan, J. Riley, V. Chernomordik, P. Smith, R. Pursley, S. B. Lee, J. Capala, and A. H. Gandjbakhche, “Fluorescence lifetime imaging system for in vivo studies,” Mol. Imaging6(4), 229–236 (2007).
    [PubMed]
  27. M. Pimpalkhare, J. Chen, V. Venugopal, and X. Intes, “Ex vivo fluorescence molecular tomography of the spine,” Int. J. Biomed. Imaging2012, 942326 (2012).
    [CrossRef] [PubMed]

2013

V. Venugopal and X. Intes, “Adaptive wide-field optical tomography,” J. Biomed. Opt.18(3), 036006 (2013).
[CrossRef] [PubMed]

K. Abe, L. Zhao, A. Periasamy, X. Intes, and M. Barroso, “Non-Invasive In Vivo Imaging of Near Infrared-labeled Transferrin in Breast Cancer Cells and Tumors Using Fluorescence Lifetime FRET,” PLoS ONE8(11), e80269 (2013).
[CrossRef] [PubMed]

C. Alric, I. Miladi, D. Kryza, J. Taleb, F. Lux, R. Bazzi, C. Billotey, M. Janier, P. Perriat, S. Roux, and O. Tillement, “The biodistribution of gold nanoparticles designed for renal clearance,” Nanoscale5(13), 5930–5939 (2013).
[CrossRef] [PubMed]

L. Zhao, K. Abe, M. Barroso, and X. Intes, “Active wide-field illumination for high-throughput fluorescence lifetime imaging,” Opt. Lett.38(19), 3976–3979 (2013).
[CrossRef] [PubMed]

2012

V. Venugopal, J. Chen, M. Barroso, and X. Intes, “Quantitative tomographic imaging of intermolecular FRET in small animals,” Biomed. Opt. Express3(12), 3161–3175 (2012).
[CrossRef] [PubMed]

M. Pimpalkhare, J. Chen, V. Venugopal, and X. Intes, “Ex vivo fluorescence molecular tomography of the spine,” Int. J. Biomed. Imaging2012, 942326 (2012).
[CrossRef] [PubMed]

2011

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

2010

M. Y. Berezin and S. Achilefu, “Fluorescence lifetime measurements and biological imaging,” Chem. Rev.110(5), 2641–2684 (2010).
[CrossRef] [PubMed]

S. A. Hilderbrand and R. Weissleder, “Near-infrared fluorescence: application to in vivo molecular imaging,” Curr. Opin. Chem. Biol.14(1), 71–79 (2010).
[CrossRef] [PubMed]

V. Venugopal, J. Chen, and X. Intes, “Development of an optical imaging platform for functional imaging of small animals using wide-field excitation,” Biomed. Opt. Express1(1), 143–156 (2010).
[CrossRef] [PubMed]

2009

N. Kosaka, M. Ogawa, N. Sato, P. L. Choyke, and H. Kobayashi, “In vivo real-time, multicolor, quantum dot lymphatic imaging,” J. Invest. Dermatol.129(12), 2818–2822 (2009).
[CrossRef] [PubMed]

2008

M. K. Kuimova, G. Yahioglu, J. A. Levitt, and K. Suhling, “Molecular rotor measures viscosity of live cells via fluorescence lifetime imaging,” J. Am. Chem. Soc.130(21), 6672–6673 (2008).
[CrossRef] [PubMed]

T. F. Massoud, A. Singh, and S. S. Gambhir, “Noninvasive molecular neuroimaging using reporter genes: part II, experimental, current, and future applications,” AJNR Am. J. Neuroradiol.29(3), 409–418 (2008).
[CrossRef] [PubMed]

2007

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
[CrossRef] [PubMed]

D. W. Bartlett, H. Su, I. J. Hildebrandt, W. A. Weber, and M. E. Davis, “Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging,” Proc. Natl. Acad. Sci. U.S.A.104(39), 15549–15554 (2007).
[CrossRef] [PubMed]

M. Hassan, J. Riley, V. Chernomordik, P. Smith, R. Pursley, S. B. Lee, J. Capala, and A. H. Gandjbakhche, “Fluorescence lifetime imaging system for in vivo studies,” Mol. Imaging6(4), 229–236 (2007).
[PubMed]

2005

H. Wallrabe and A. Periasamy, “Imaging protein molecules using FRET and FLIM microscopy,” Curr. Opin. Biotechnol.16(1), 19–27 (2005).
[CrossRef] [PubMed]

A. L. Vavere and M. J. Welch, “Preparation, biodistribution, and small animal PET of 45Ti-transferrin,” J. Nucl. Med.46(4), 683–690 (2005).
[PubMed]

2003

H. Wallrabe, M. Elangovan, A. Burchard, A. Periasamy, and M. Barroso, “Confocal FRET microscopy to measure clustering of ligand-receptor complexes in endocytic membranes,” Biophys. J.85(1), 559–571 (2003).
[CrossRef] [PubMed]

H. Wallrabe, M. Stanley, A. Periasamy, and M. Barroso, “One- and two-photon fluorescence resonance energy transfer microscopy to establish a clustered distribution of receptor-ligand complexes in endocytic membranes,” J. Biomed. Opt.8(3), 339–346 (2003).
[CrossRef] [PubMed]

2002

A. J. Fischman, N. M. Alpert, and R. H. Rubin, “Pharmacokinetic imaging: a noninvasive method for determining drug distribution and action,” Clin. Pharmacokinet.41(8), 581–602 (2002).
[CrossRef] [PubMed]

2001

D. J. Bornhop, C. H. Contag, K. Licha, and C. J. Murphy, “Advance in contrast agents, reporters, and detection,” J. Biomed. Opt.6(2), 106–110 (2001).
[CrossRef] [PubMed]

1997

C. R. Berry, P. Fisher, P. D. Koblik, W. G. Guilford, and W. H. Hornof, “Scintigraphic biodistribution and plasma kinetics of indium 111-labeled transferrin in dogs,” Am. J. Vet. Res.58(11), 1188–1192 (1997).
[PubMed]

1992

M. Kollner and J. Wolfrum, “How Many Photons Are Necessary for Fluorescence-Lifetime Measurements,” Chem. Phys. Lett.200(1-2), 199–204 (1992).
[CrossRef]

1985

J. Meek and E. D. Adamson, “Transferrin in foetal and adult mouse tissues: synthesis, storage and secretion,” J. Embryol. Exp. Morphol.86, 205–218 (1985).
[PubMed]

Abe, K.

K. Abe, L. Zhao, A. Periasamy, X. Intes, and M. Barroso, “Non-Invasive In Vivo Imaging of Near Infrared-labeled Transferrin in Breast Cancer Cells and Tumors Using Fluorescence Lifetime FRET,” PLoS ONE8(11), e80269 (2013).
[CrossRef] [PubMed]

L. Zhao, K. Abe, M. Barroso, and X. Intes, “Active wide-field illumination for high-throughput fluorescence lifetime imaging,” Opt. Lett.38(19), 3976–3979 (2013).
[CrossRef] [PubMed]

Achilefu, S.

M. Y. Berezin and S. Achilefu, “Fluorescence lifetime measurements and biological imaging,” Chem. Rev.110(5), 2641–2684 (2010).
[CrossRef] [PubMed]

Adamson, E. D.

J. Meek and E. D. Adamson, “Transferrin in foetal and adult mouse tissues: synthesis, storage and secretion,” J. Embryol. Exp. Morphol.86, 205–218 (1985).
[PubMed]

Alexandrov, Y.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Alibhai, D.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Alpert, N. M.

A. J. Fischman, N. M. Alpert, and R. H. Rubin, “Pharmacokinetic imaging: a noninvasive method for determining drug distribution and action,” Clin. Pharmacokinet.41(8), 581–602 (2002).
[CrossRef] [PubMed]

Alric, C.

C. Alric, I. Miladi, D. Kryza, J. Taleb, F. Lux, R. Bazzi, C. Billotey, M. Janier, P. Perriat, S. Roux, and O. Tillement, “The biodistribution of gold nanoparticles designed for renal clearance,” Nanoscale5(13), 5930–5939 (2013).
[CrossRef] [PubMed]

Barrett, T.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
[CrossRef] [PubMed]

Barroso, M.

K. Abe, L. Zhao, A. Periasamy, X. Intes, and M. Barroso, “Non-Invasive In Vivo Imaging of Near Infrared-labeled Transferrin in Breast Cancer Cells and Tumors Using Fluorescence Lifetime FRET,” PLoS ONE8(11), e80269 (2013).
[CrossRef] [PubMed]

L. Zhao, K. Abe, M. Barroso, and X. Intes, “Active wide-field illumination for high-throughput fluorescence lifetime imaging,” Opt. Lett.38(19), 3976–3979 (2013).
[CrossRef] [PubMed]

V. Venugopal, J. Chen, M. Barroso, and X. Intes, “Quantitative tomographic imaging of intermolecular FRET in small animals,” Biomed. Opt. Express3(12), 3161–3175 (2012).
[CrossRef] [PubMed]

H. Wallrabe, M. Elangovan, A. Burchard, A. Periasamy, and M. Barroso, “Confocal FRET microscopy to measure clustering of ligand-receptor complexes in endocytic membranes,” Biophys. J.85(1), 559–571 (2003).
[CrossRef] [PubMed]

H. Wallrabe, M. Stanley, A. Periasamy, and M. Barroso, “One- and two-photon fluorescence resonance energy transfer microscopy to establish a clustered distribution of receptor-ligand complexes in endocytic membranes,” J. Biomed. Opt.8(3), 339–346 (2003).
[CrossRef] [PubMed]

Bartlett, D. W.

D. W. Bartlett, H. Su, I. J. Hildebrandt, W. A. Weber, and M. E. Davis, “Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging,” Proc. Natl. Acad. Sci. U.S.A.104(39), 15549–15554 (2007).
[CrossRef] [PubMed]

Bazzi, R.

C. Alric, I. Miladi, D. Kryza, J. Taleb, F. Lux, R. Bazzi, C. Billotey, M. Janier, P. Perriat, S. Roux, and O. Tillement, “The biodistribution of gold nanoparticles designed for renal clearance,” Nanoscale5(13), 5930–5939 (2013).
[CrossRef] [PubMed]

Berezin, M. Y.

M. Y. Berezin and S. Achilefu, “Fluorescence lifetime measurements and biological imaging,” Chem. Rev.110(5), 2641–2684 (2010).
[CrossRef] [PubMed]

Berry, C. R.

C. R. Berry, P. Fisher, P. D. Koblik, W. G. Guilford, and W. H. Hornof, “Scintigraphic biodistribution and plasma kinetics of indium 111-labeled transferrin in dogs,” Am. J. Vet. Res.58(11), 1188–1192 (1997).
[PubMed]

Billotey, C.

C. Alric, I. Miladi, D. Kryza, J. Taleb, F. Lux, R. Bazzi, C. Billotey, M. Janier, P. Perriat, S. Roux, and O. Tillement, “The biodistribution of gold nanoparticles designed for renal clearance,” Nanoscale5(13), 5930–5939 (2013).
[CrossRef] [PubMed]

Bornhop, D. J.

D. J. Bornhop, C. H. Contag, K. Licha, and C. J. Murphy, “Advance in contrast agents, reporters, and detection,” J. Biomed. Opt.6(2), 106–110 (2001).
[CrossRef] [PubMed]

Burchard, A.

H. Wallrabe, M. Elangovan, A. Burchard, A. Periasamy, and M. Barroso, “Confocal FRET microscopy to measure clustering of ligand-receptor complexes in endocytic membranes,” Biophys. J.85(1), 559–571 (2003).
[CrossRef] [PubMed]

Capala, J.

M. Hassan, J. Riley, V. Chernomordik, P. Smith, R. Pursley, S. B. Lee, J. Capala, and A. H. Gandjbakhche, “Fluorescence lifetime imaging system for in vivo studies,” Mol. Imaging6(4), 229–236 (2007).
[PubMed]

Chen, J.

Chernomordik, V.

M. Hassan, J. Riley, V. Chernomordik, P. Smith, R. Pursley, S. B. Lee, J. Capala, and A. H. Gandjbakhche, “Fluorescence lifetime imaging system for in vivo studies,” Mol. Imaging6(4), 229–236 (2007).
[PubMed]

Choyke, P. L.

N. Kosaka, M. Ogawa, N. Sato, P. L. Choyke, and H. Kobayashi, “In vivo real-time, multicolor, quantum dot lymphatic imaging,” J. Invest. Dermatol.129(12), 2818–2822 (2009).
[CrossRef] [PubMed]

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
[CrossRef] [PubMed]

Contag, C. H.

D. J. Bornhop, C. H. Contag, K. Licha, and C. J. Murphy, “Advance in contrast agents, reporters, and detection,” J. Biomed. Opt.6(2), 106–110 (2001).
[CrossRef] [PubMed]

Dallman, M. J.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Davis, M. E.

D. W. Bartlett, H. Su, I. J. Hildebrandt, W. A. Weber, and M. E. Davis, “Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging,” Proc. Natl. Acad. Sci. U.S.A.104(39), 15549–15554 (2007).
[CrossRef] [PubMed]

Dunsby, C.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Elangovan, M.

H. Wallrabe, M. Elangovan, A. Burchard, A. Periasamy, and M. Barroso, “Confocal FRET microscopy to measure clustering of ligand-receptor complexes in endocytic membranes,” Biophys. J.85(1), 559–571 (2003).
[CrossRef] [PubMed]

Elson, D. S.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Fischman, A. J.

A. J. Fischman, N. M. Alpert, and R. H. Rubin, “Pharmacokinetic imaging: a noninvasive method for determining drug distribution and action,” Clin. Pharmacokinet.41(8), 581–602 (2002).
[CrossRef] [PubMed]

Fisher, P.

C. R. Berry, P. Fisher, P. D. Koblik, W. G. Guilford, and W. H. Hornof, “Scintigraphic biodistribution and plasma kinetics of indium 111-labeled transferrin in dogs,” Am. J. Vet. Res.58(11), 1188–1192 (1997).
[PubMed]

French, P. M.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Gambhir, S. S.

T. F. Massoud, A. Singh, and S. S. Gambhir, “Noninvasive molecular neuroimaging using reporter genes: part II, experimental, current, and future applications,” AJNR Am. J. Neuroradiol.29(3), 409–418 (2008).
[CrossRef] [PubMed]

Gandjbakhche, A. H.

M. Hassan, J. Riley, V. Chernomordik, P. Smith, R. Pursley, S. B. Lee, J. Capala, and A. H. Gandjbakhche, “Fluorescence lifetime imaging system for in vivo studies,” Mol. Imaging6(4), 229–236 (2007).
[PubMed]

Guilford, W. G.

C. R. Berry, P. Fisher, P. D. Koblik, W. G. Guilford, and W. H. Hornof, “Scintigraphic biodistribution and plasma kinetics of indium 111-labeled transferrin in dogs,” Am. J. Vet. Res.58(11), 1188–1192 (1997).
[PubMed]

Hama, Y.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
[CrossRef] [PubMed]

Hassan, M.

M. Hassan, J. Riley, V. Chernomordik, P. Smith, R. Pursley, S. B. Lee, J. Capala, and A. H. Gandjbakhche, “Fluorescence lifetime imaging system for in vivo studies,” Mol. Imaging6(4), 229–236 (2007).
[PubMed]

Hildebrandt, I. J.

D. W. Bartlett, H. Su, I. J. Hildebrandt, W. A. Weber, and M. E. Davis, “Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging,” Proc. Natl. Acad. Sci. U.S.A.104(39), 15549–15554 (2007).
[CrossRef] [PubMed]

Hilderbrand, S. A.

S. A. Hilderbrand and R. Weissleder, “Near-infrared fluorescence: application to in vivo molecular imaging,” Curr. Opin. Chem. Biol.14(1), 71–79 (2010).
[CrossRef] [PubMed]

Hornof, W. H.

C. R. Berry, P. Fisher, P. D. Koblik, W. G. Guilford, and W. H. Hornof, “Scintigraphic biodistribution and plasma kinetics of indium 111-labeled transferrin in dogs,” Am. J. Vet. Res.58(11), 1188–1192 (1997).
[PubMed]

Intes, X.

L. Zhao, K. Abe, M. Barroso, and X. Intes, “Active wide-field illumination for high-throughput fluorescence lifetime imaging,” Opt. Lett.38(19), 3976–3979 (2013).
[CrossRef] [PubMed]

V. Venugopal and X. Intes, “Adaptive wide-field optical tomography,” J. Biomed. Opt.18(3), 036006 (2013).
[CrossRef] [PubMed]

K. Abe, L. Zhao, A. Periasamy, X. Intes, and M. Barroso, “Non-Invasive In Vivo Imaging of Near Infrared-labeled Transferrin in Breast Cancer Cells and Tumors Using Fluorescence Lifetime FRET,” PLoS ONE8(11), e80269 (2013).
[CrossRef] [PubMed]

V. Venugopal, J. Chen, M. Barroso, and X. Intes, “Quantitative tomographic imaging of intermolecular FRET in small animals,” Biomed. Opt. Express3(12), 3161–3175 (2012).
[CrossRef] [PubMed]

M. Pimpalkhare, J. Chen, V. Venugopal, and X. Intes, “Ex vivo fluorescence molecular tomography of the spine,” Int. J. Biomed. Imaging2012, 942326 (2012).
[CrossRef] [PubMed]

V. Venugopal, J. Chen, and X. Intes, “Development of an optical imaging platform for functional imaging of small animals using wide-field excitation,” Biomed. Opt. Express1(1), 143–156 (2010).
[CrossRef] [PubMed]

Janier, M.

C. Alric, I. Miladi, D. Kryza, J. Taleb, F. Lux, R. Bazzi, C. Billotey, M. Janier, P. Perriat, S. Roux, and O. Tillement, “The biodistribution of gold nanoparticles designed for renal clearance,” Nanoscale5(13), 5930–5939 (2013).
[CrossRef] [PubMed]

Katan, M.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Kelly, D.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Kennedy, G.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Kimberly, C.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Kobayashi, H.

N. Kosaka, M. Ogawa, N. Sato, P. L. Choyke, and H. Kobayashi, “In vivo real-time, multicolor, quantum dot lymphatic imaging,” J. Invest. Dermatol.129(12), 2818–2822 (2009).
[CrossRef] [PubMed]

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
[CrossRef] [PubMed]

Koblik, P. D.

C. R. Berry, P. Fisher, P. D. Koblik, W. G. Guilford, and W. H. Hornof, “Scintigraphic biodistribution and plasma kinetics of indium 111-labeled transferrin in dogs,” Am. J. Vet. Res.58(11), 1188–1192 (1997).
[PubMed]

Kollner, M.

M. Kollner and J. Wolfrum, “How Many Photons Are Necessary for Fluorescence-Lifetime Measurements,” Chem. Phys. Lett.200(1-2), 199–204 (1992).
[CrossRef]

Kosaka, N.

N. Kosaka, M. Ogawa, N. Sato, P. L. Choyke, and H. Kobayashi, “In vivo real-time, multicolor, quantum dot lymphatic imaging,” J. Invest. Dermatol.129(12), 2818–2822 (2009).
[CrossRef] [PubMed]

Koyama, Y.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
[CrossRef] [PubMed]

Kryza, D.

C. Alric, I. Miladi, D. Kryza, J. Taleb, F. Lux, R. Bazzi, C. Billotey, M. Janier, P. Perriat, S. Roux, and O. Tillement, “The biodistribution of gold nanoparticles designed for renal clearance,” Nanoscale5(13), 5930–5939 (2013).
[CrossRef] [PubMed]

Kuimova, M. K.

M. K. Kuimova, G. Yahioglu, J. A. Levitt, and K. Suhling, “Molecular rotor measures viscosity of live cells via fluorescence lifetime imaging,” J. Am. Chem. Soc.130(21), 6672–6673 (2008).
[CrossRef] [PubMed]

Kumar, S.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Lacombe, F.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Laine, R.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Lam, E. W.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Lee, S. B.

M. Hassan, J. Riley, V. Chernomordik, P. Smith, R. Pursley, S. B. Lee, J. Capala, and A. H. Gandjbakhche, “Fluorescence lifetime imaging system for in vivo studies,” Mol. Imaging6(4), 229–236 (2007).
[PubMed]

Levitt, J. A.

M. K. Kuimova, G. Yahioglu, J. A. Levitt, and K. Suhling, “Molecular rotor measures viscosity of live cells via fluorescence lifetime imaging,” J. Am. Chem. Soc.130(21), 6672–6673 (2008).
[CrossRef] [PubMed]

Licha, K.

D. J. Bornhop, C. H. Contag, K. Licha, and C. J. Murphy, “Advance in contrast agents, reporters, and detection,” J. Biomed. Opt.6(2), 106–110 (2001).
[CrossRef] [PubMed]

Lux, F.

C. Alric, I. Miladi, D. Kryza, J. Taleb, F. Lux, R. Bazzi, C. Billotey, M. Janier, P. Perriat, S. Roux, and O. Tillement, “The biodistribution of gold nanoparticles designed for renal clearance,” Nanoscale5(13), 5930–5939 (2013).
[CrossRef] [PubMed]

Margineanu, A.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Massoud, T. F.

T. F. Massoud, A. Singh, and S. S. Gambhir, “Noninvasive molecular neuroimaging using reporter genes: part II, experimental, current, and future applications,” AJNR Am. J. Neuroradiol.29(3), 409–418 (2008).
[CrossRef] [PubMed]

McGinty, J.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Meek, J.

J. Meek and E. D. Adamson, “Transferrin in foetal and adult mouse tissues: synthesis, storage and secretion,” J. Embryol. Exp. Morphol.86, 205–218 (1985).
[PubMed]

Miladi, I.

C. Alric, I. Miladi, D. Kryza, J. Taleb, F. Lux, R. Bazzi, C. Billotey, M. Janier, P. Perriat, S. Roux, and O. Tillement, “The biodistribution of gold nanoparticles designed for renal clearance,” Nanoscale5(13), 5930–5939 (2013).
[CrossRef] [PubMed]

Munro, I.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Murphy, C. J.

D. J. Bornhop, C. H. Contag, K. Licha, and C. J. Murphy, “Advance in contrast agents, reporters, and detection,” J. Biomed. Opt.6(2), 106–110 (2001).
[CrossRef] [PubMed]

Murray, E. J.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Neil, M. A.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Ogawa, M.

N. Kosaka, M. Ogawa, N. Sato, P. L. Choyke, and H. Kobayashi, “In vivo real-time, multicolor, quantum dot lymphatic imaging,” J. Invest. Dermatol.129(12), 2818–2822 (2009).
[CrossRef] [PubMed]

Periasamy, A.

K. Abe, L. Zhao, A. Periasamy, X. Intes, and M. Barroso, “Non-Invasive In Vivo Imaging of Near Infrared-labeled Transferrin in Breast Cancer Cells and Tumors Using Fluorescence Lifetime FRET,” PLoS ONE8(11), e80269 (2013).
[CrossRef] [PubMed]

H. Wallrabe and A. Periasamy, “Imaging protein molecules using FRET and FLIM microscopy,” Curr. Opin. Biotechnol.16(1), 19–27 (2005).
[CrossRef] [PubMed]

H. Wallrabe, M. Stanley, A. Periasamy, and M. Barroso, “One- and two-photon fluorescence resonance energy transfer microscopy to establish a clustered distribution of receptor-ligand complexes in endocytic membranes,” J. Biomed. Opt.8(3), 339–346 (2003).
[CrossRef] [PubMed]

H. Wallrabe, M. Elangovan, A. Burchard, A. Periasamy, and M. Barroso, “Confocal FRET microscopy to measure clustering of ligand-receptor complexes in endocytic membranes,” Biophys. J.85(1), 559–571 (2003).
[CrossRef] [PubMed]

Perriat, P.

C. Alric, I. Miladi, D. Kryza, J. Taleb, F. Lux, R. Bazzi, C. Billotey, M. Janier, P. Perriat, S. Roux, and O. Tillement, “The biodistribution of gold nanoparticles designed for renal clearance,” Nanoscale5(13), 5930–5939 (2013).
[CrossRef] [PubMed]

Pimpalkhare, M.

M. Pimpalkhare, J. Chen, V. Venugopal, and X. Intes, “Ex vivo fluorescence molecular tomography of the spine,” Int. J. Biomed. Imaging2012, 942326 (2012).
[CrossRef] [PubMed]

Pursley, R.

M. Hassan, J. Riley, V. Chernomordik, P. Smith, R. Pursley, S. B. Lee, J. Capala, and A. H. Gandjbakhche, “Fluorescence lifetime imaging system for in vivo studies,” Mol. Imaging6(4), 229–236 (2007).
[PubMed]

Regino, C. A.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
[CrossRef] [PubMed]

Riley, J.

M. Hassan, J. Riley, V. Chernomordik, P. Smith, R. Pursley, S. B. Lee, J. Capala, and A. H. Gandjbakhche, “Fluorescence lifetime imaging system for in vivo studies,” Mol. Imaging6(4), 229–236 (2007).
[PubMed]

Roux, S.

C. Alric, I. Miladi, D. Kryza, J. Taleb, F. Lux, R. Bazzi, C. Billotey, M. Janier, P. Perriat, S. Roux, and O. Tillement, “The biodistribution of gold nanoparticles designed for renal clearance,” Nanoscale5(13), 5930–5939 (2013).
[CrossRef] [PubMed]

Rubin, R. H.

A. J. Fischman, N. M. Alpert, and R. H. Rubin, “Pharmacokinetic imaging: a noninvasive method for determining drug distribution and action,” Clin. Pharmacokinet.41(8), 581–602 (2002).
[CrossRef] [PubMed]

Sardini, A.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Sato, N.

N. Kosaka, M. Ogawa, N. Sato, P. L. Choyke, and H. Kobayashi, “In vivo real-time, multicolor, quantum dot lymphatic imaging,” J. Invest. Dermatol.129(12), 2818–2822 (2009).
[CrossRef] [PubMed]

Singh, A.

T. F. Massoud, A. Singh, and S. S. Gambhir, “Noninvasive molecular neuroimaging using reporter genes: part II, experimental, current, and future applications,” AJNR Am. J. Neuroradiol.29(3), 409–418 (2008).
[CrossRef] [PubMed]

Smith, P.

M. Hassan, J. Riley, V. Chernomordik, P. Smith, R. Pursley, S. B. Lee, J. Capala, and A. H. Gandjbakhche, “Fluorescence lifetime imaging system for in vivo studies,” Mol. Imaging6(4), 229–236 (2007).
[PubMed]

Stamp, G.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Stanley, M.

H. Wallrabe, M. Stanley, A. Periasamy, and M. Barroso, “One- and two-photon fluorescence resonance energy transfer microscopy to establish a clustered distribution of receptor-ligand complexes in endocytic membranes,” J. Biomed. Opt.8(3), 339–346 (2003).
[CrossRef] [PubMed]

Stuckey, D. W.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Stuhmeier, F.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Su, H.

D. W. Bartlett, H. Su, I. J. Hildebrandt, W. A. Weber, and M. E. Davis, “Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging,” Proc. Natl. Acad. Sci. U.S.A.104(39), 15549–15554 (2007).
[CrossRef] [PubMed]

Suhling, K.

M. K. Kuimova, G. Yahioglu, J. A. Levitt, and K. Suhling, “Molecular rotor measures viscosity of live cells via fluorescence lifetime imaging,” J. Am. Chem. Soc.130(21), 6672–6673 (2008).
[CrossRef] [PubMed]

Talbot, C.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Taleb, J.

C. Alric, I. Miladi, D. Kryza, J. Taleb, F. Lux, R. Bazzi, C. Billotey, M. Janier, P. Perriat, S. Roux, and O. Tillement, “The biodistribution of gold nanoparticles designed for renal clearance,” Nanoscale5(13), 5930–5939 (2013).
[CrossRef] [PubMed]

Taylor, H.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Tillement, O.

C. Alric, I. Miladi, D. Kryza, J. Taleb, F. Lux, R. Bazzi, C. Billotey, M. Janier, P. Perriat, S. Roux, and O. Tillement, “The biodistribution of gold nanoparticles designed for renal clearance,” Nanoscale5(13), 5930–5939 (2013).
[CrossRef] [PubMed]

Urano, Y.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
[CrossRef] [PubMed]

Vavere, A. L.

A. L. Vavere and M. J. Welch, “Preparation, biodistribution, and small animal PET of 45Ti-transferrin,” J. Nucl. Med.46(4), 683–690 (2005).
[PubMed]

Venugopal, V.

Viellerobe, B.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Wallrabe, H.

H. Wallrabe and A. Periasamy, “Imaging protein molecules using FRET and FLIM microscopy,” Curr. Opin. Biotechnol.16(1), 19–27 (2005).
[CrossRef] [PubMed]

H. Wallrabe, M. Elangovan, A. Burchard, A. Periasamy, and M. Barroso, “Confocal FRET microscopy to measure clustering of ligand-receptor complexes in endocytic membranes,” Biophys. J.85(1), 559–571 (2003).
[CrossRef] [PubMed]

H. Wallrabe, M. Stanley, A. Periasamy, and M. Barroso, “One- and two-photon fluorescence resonance energy transfer microscopy to establish a clustered distribution of receptor-ligand complexes in endocytic membranes,” J. Biomed. Opt.8(3), 339–346 (2003).
[CrossRef] [PubMed]

Warren, S.

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Weber, W. A.

D. W. Bartlett, H. Su, I. J. Hildebrandt, W. A. Weber, and M. E. Davis, “Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging,” Proc. Natl. Acad. Sci. U.S.A.104(39), 15549–15554 (2007).
[CrossRef] [PubMed]

Weissleder, R.

S. A. Hilderbrand and R. Weissleder, “Near-infrared fluorescence: application to in vivo molecular imaging,” Curr. Opin. Chem. Biol.14(1), 71–79 (2010).
[CrossRef] [PubMed]

Welch, M. J.

A. L. Vavere and M. J. Welch, “Preparation, biodistribution, and small animal PET of 45Ti-transferrin,” J. Nucl. Med.46(4), 683–690 (2005).
[PubMed]

Wolfrum, J.

M. Kollner and J. Wolfrum, “How Many Photons Are Necessary for Fluorescence-Lifetime Measurements,” Chem. Phys. Lett.200(1-2), 199–204 (1992).
[CrossRef]

Yahioglu, G.

M. K. Kuimova, G. Yahioglu, J. A. Levitt, and K. Suhling, “Molecular rotor measures viscosity of live cells via fluorescence lifetime imaging,” J. Am. Chem. Soc.130(21), 6672–6673 (2008).
[CrossRef] [PubMed]

Zhao, L.

L. Zhao, K. Abe, M. Barroso, and X. Intes, “Active wide-field illumination for high-throughput fluorescence lifetime imaging,” Opt. Lett.38(19), 3976–3979 (2013).
[CrossRef] [PubMed]

K. Abe, L. Zhao, A. Periasamy, X. Intes, and M. Barroso, “Non-Invasive In Vivo Imaging of Near Infrared-labeled Transferrin in Breast Cancer Cells and Tumors Using Fluorescence Lifetime FRET,” PLoS ONE8(11), e80269 (2013).
[CrossRef] [PubMed]

AJNR Am. J. Neuroradiol.

T. F. Massoud, A. Singh, and S. S. Gambhir, “Noninvasive molecular neuroimaging using reporter genes: part II, experimental, current, and future applications,” AJNR Am. J. Neuroradiol.29(3), 409–418 (2008).
[CrossRef] [PubMed]

Am. J. Vet. Res.

C. R. Berry, P. Fisher, P. D. Koblik, W. G. Guilford, and W. H. Hornof, “Scintigraphic biodistribution and plasma kinetics of indium 111-labeled transferrin in dogs,” Am. J. Vet. Res.58(11), 1188–1192 (1997).
[PubMed]

Biomed. Opt. Express

Biophys. J.

H. Wallrabe, M. Elangovan, A. Burchard, A. Periasamy, and M. Barroso, “Confocal FRET microscopy to measure clustering of ligand-receptor complexes in endocytic membranes,” Biophys. J.85(1), 559–571 (2003).
[CrossRef] [PubMed]

Chem. Phys. Lett.

M. Kollner and J. Wolfrum, “How Many Photons Are Necessary for Fluorescence-Lifetime Measurements,” Chem. Phys. Lett.200(1-2), 199–204 (1992).
[CrossRef]

Chem. Rev.

M. Y. Berezin and S. Achilefu, “Fluorescence lifetime measurements and biological imaging,” Chem. Rev.110(5), 2641–2684 (2010).
[CrossRef] [PubMed]

ChemPhysChem

S. Kumar, D. Alibhai, A. Margineanu, R. Laine, G. Kennedy, J. McGinty, S. Warren, D. Kelly, Y. Alexandrov, I. Munro, C. Talbot, D. W. Stuckey, C. Kimberly, B. Viellerobe, F. Lacombe, E. W. Lam, H. Taylor, M. J. Dallman, G. Stamp, E. J. Murray, F. Stuhmeier, A. Sardini, M. Katan, D. S. Elson, M. A. Neil, C. Dunsby, and P. M. French, “FLIM FRET technology for drug discovery: automated multiwell-plate high-content analysis, multiplexed readouts and application in situ,” ChemPhysChem12(3), 609–626 (2011).
[CrossRef] [PubMed]

Clin. Pharmacokinet.

A. J. Fischman, N. M. Alpert, and R. H. Rubin, “Pharmacokinetic imaging: a noninvasive method for determining drug distribution and action,” Clin. Pharmacokinet.41(8), 581–602 (2002).
[CrossRef] [PubMed]

Curr. Opin. Biotechnol.

H. Wallrabe and A. Periasamy, “Imaging protein molecules using FRET and FLIM microscopy,” Curr. Opin. Biotechnol.16(1), 19–27 (2005).
[CrossRef] [PubMed]

Curr. Opin. Chem. Biol.

S. A. Hilderbrand and R. Weissleder, “Near-infrared fluorescence: application to in vivo molecular imaging,” Curr. Opin. Chem. Biol.14(1), 71–79 (2010).
[CrossRef] [PubMed]

Int. J. Biomed. Imaging

M. Pimpalkhare, J. Chen, V. Venugopal, and X. Intes, “Ex vivo fluorescence molecular tomography of the spine,” Int. J. Biomed. Imaging2012, 942326 (2012).
[CrossRef] [PubMed]

J. Am. Chem. Soc.

M. K. Kuimova, G. Yahioglu, J. A. Levitt, and K. Suhling, “Molecular rotor measures viscosity of live cells via fluorescence lifetime imaging,” J. Am. Chem. Soc.130(21), 6672–6673 (2008).
[CrossRef] [PubMed]

J. Biomed. Opt.

D. J. Bornhop, C. H. Contag, K. Licha, and C. J. Murphy, “Advance in contrast agents, reporters, and detection,” J. Biomed. Opt.6(2), 106–110 (2001).
[CrossRef] [PubMed]

H. Wallrabe, M. Stanley, A. Periasamy, and M. Barroso, “One- and two-photon fluorescence resonance energy transfer microscopy to establish a clustered distribution of receptor-ligand complexes in endocytic membranes,” J. Biomed. Opt.8(3), 339–346 (2003).
[CrossRef] [PubMed]

V. Venugopal and X. Intes, “Adaptive wide-field optical tomography,” J. Biomed. Opt.18(3), 036006 (2013).
[CrossRef] [PubMed]

J. Embryol. Exp. Morphol.

J. Meek and E. D. Adamson, “Transferrin in foetal and adult mouse tissues: synthesis, storage and secretion,” J. Embryol. Exp. Morphol.86, 205–218 (1985).
[PubMed]

J. Invest. Dermatol.

N. Kosaka, M. Ogawa, N. Sato, P. L. Choyke, and H. Kobayashi, “In vivo real-time, multicolor, quantum dot lymphatic imaging,” J. Invest. Dermatol.129(12), 2818–2822 (2009).
[CrossRef] [PubMed]

J. Nucl. Med.

A. L. Vavere and M. J. Welch, “Preparation, biodistribution, and small animal PET of 45Ti-transferrin,” J. Nucl. Med.46(4), 683–690 (2005).
[PubMed]

Mol. Imaging

M. Hassan, J. Riley, V. Chernomordik, P. Smith, R. Pursley, S. B. Lee, J. Capala, and A. H. Gandjbakhche, “Fluorescence lifetime imaging system for in vivo studies,” Mol. Imaging6(4), 229–236 (2007).
[PubMed]

Nano Lett.

H. Kobayashi, Y. Hama, Y. Koyama, T. Barrett, C. A. Regino, Y. Urano, and P. L. Choyke, “Simultaneous multicolor imaging of five different lymphatic basins using quantum dots,” Nano Lett.7(6), 1711–1716 (2007).
[CrossRef] [PubMed]

Nanoscale

C. Alric, I. Miladi, D. Kryza, J. Taleb, F. Lux, R. Bazzi, C. Billotey, M. Janier, P. Perriat, S. Roux, and O. Tillement, “The biodistribution of gold nanoparticles designed for renal clearance,” Nanoscale5(13), 5930–5939 (2013).
[CrossRef] [PubMed]

Opt. Lett.

PLoS ONE

K. Abe, L. Zhao, A. Periasamy, X. Intes, and M. Barroso, “Non-Invasive In Vivo Imaging of Near Infrared-labeled Transferrin in Breast Cancer Cells and Tumors Using Fluorescence Lifetime FRET,” PLoS ONE8(11), e80269 (2013).
[CrossRef] [PubMed]

Proc. Natl. Acad. Sci. U.S.A.

D. W. Bartlett, H. Su, I. J. Hildebrandt, W. A. Weber, and M. E. Davis, “Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging,” Proc. Natl. Acad. Sci. U.S.A.104(39), 15549–15554 (2007).
[CrossRef] [PubMed]

Other

V. Venugopal, “A small animal time-resolved optical tomography platform using wide-field excitation,” Doctoral Dissertation Rensselaer Polytechnic Institute, 47–49 (2011).

Transferrin-Vivo 750 Fluorescent Imaging Agent. Available at http://www.perkinelmer.com/Catalog/Product/ID/10091) ,” (2013).

Supplementary Material (4)

» Media 1: AVI (217 KB)     
» Media 2: AVI (217 KB)     
» Media 3: AVI (5128 KB)     
» Media 4: AVI (4860 KB)     

Cited By

OSA participates in CrossRef's Cited-By Linking service. Citing articles from OSA journals and other participating publishers are listed here.

Alert me when this article is cited.


Figures (10)

Fig. 1
Fig. 1

Wide-field fluorescence lifetime imaging system for ex vivo and in vivo imaging. (a) The schematics of the time-domain fluorescence lifetime imaging system based on a gated ICCD detection. (b) The actual wide-field fluorescence lifetime imaging system for in vivo imaging.

Fig. 2
Fig. 2

Calibration of the spatial fidelity and transmitted power efficiency of the DMD. (a) Grayscale test pattern (top). Detected grayscale pattern normalized to the uniformed detected pattern (bottom). (b) Comparison of detected grayscale levels versus expected grayscale levels. (c) The Calibration of transmitted power efficiency of DMD. The transmitted power efficiency of DMD was calculated over the 695nm-820nm spectral range by estimating the slope of the curve between input laser power and output laser power. TPE: transmitted power efficiency.

Fig. 3
Fig. 3

Calibration of temporal characteristics of the DMD. (a) Effect of gate-width settings on IRF. (b) Impact of gate-width settings on IRF characteristics t0 and FWHM. (c) IRF measured for various excitation wavelengths. (d) Impact of different excitation wavelengths on IRF characteristics t0 and FWHM. (e) t0 profile along the center of the uniform illumination pattern. (f) FWHM profile along the center of the uniform illumination pattern. IRF: instrument response function, t0: the initial time, FWHM: full width at half maximum.

Fig. 4
Fig. 4

(a) The imaging layout of five organs (Liver, kidney, spleen, brain and heart) distribution in one field of view (FOV, 35mm × 12mm). (b) Comparison between before and after AWFI using fluorescence intensity (FI) and FRET Donor fraction (FD %) from 6-hour and 24-hour injection at A:D = 0:1 and A:D = 2:1.

Fig. 5
Fig. 5

The comparison of the mean photon counts of five organs (Liver, kidney, spleen, brain and heart) versus different iteration numbers. (a) A:D = 0:1 with post 6-hour injection (Media 1). (b) A:D = 2:1 with post 6-hour injection (Media 1). (c) A:D = 0:1 with post 24-hour injection (Media 2). (d) A:D = 2:1 with post 24-hour injection (Media 2). A: D = acceptor to donor ratio.

Fig. 6
Fig. 6

Comparison of normalized fluorescence intensities of five organs (Liver, kidney, spleen, brain and heart) at post 6-hour injection. (a) Normalized fluorescence intensity images of the five organs at A:D = 0:1 and A:D = 2:1, including the fluorescence images before AWFI, the recovery image, and fluorescence image after AWFI. (b) Comparison of normalized photon counts from five organs at A:D = 0:1 and A:D = 2:1. A:D = acceptor to donor ratio.

Fig. 7
Fig. 7

Comparison of normalized fluorescence intensities of five organs (Liver, kidney, spleen, brain and heart) at post 24-hour injection. (a) Normalized fluorescence intensity images of the five organs at A:D = 0:1 and A:D = 2:1, including the fluorescence images before AWFI and the recovered image, and fluorescence image after AWFI. (b) Comparison of normalized photon counts from five organs at A:D = 0:1 and A:D = 2:1. A:D = acceptor to donor ratio.

Fig. 8
Fig. 8

Fluorescence intensity based analysis of ex vivo distribution. The photon counts were calculated for five organs (Liver, kidney, spleen, brain and heart) from the fluorescence images before AWFI and recovered images, and then the photon counts were corrected based on the laser powers used for each case: 6hr-AD01, 6hr-AD21, 24hr-AD01, 24hr-AD21.

Fig. 9
Fig. 9

AWFI for in vivo imaging using a live mouse injected with 6-hour post injection at A:D = 2:1. (a) The comparison of the mean photon counts of bladder and liver versus different iteration numbers (Media 3). (b) The comparison of the excitation normalized image before AWFI and the recovered image. The excitation normalized image before AWFI: the fluorescence image before AWFI was normalized to the excitation image of the mouse obtained from the corresponding illumination pattern. (d) The distribution of FRET donor fraction (FD %) at A:D = 2:1.

Fig. 10
Fig. 10

Excerpt from video showing the fluorescence images before AWFI and after AWFI at the corresponding delay time from the TPSF of the liver and bladder (Media 4).

Tables (1)

Tables Icon

Table 1 Comparison of FD% and CV% from 6-hour post injection

Metrics