Abstract

We demonstrate the in vivo reconstruction of all fluorescence resonance energy transfer (FRET) parameters, including the nanometer donor–acceptor distance, in a mouse. The FRET chemical targets cancer cells, and on internalization, the acceptor is released, in lieu of a targeted anticancer drug in chemotherapy. Our method provides a new vehicle for studying disease by imaging FRET parameters in deep tissue.

© 2010 Optical Society of America

Full Article  |  PDF Article

References

  • View by:
  • |
  • |
  • |

  1. T. Förster, Ann. Phys. 2, 55 (1948).
    [CrossRef]
  2. K. Truong and M. Ikura, Curr. Opin. Struct. Biol. 11, 573 (2001).
    [CrossRef]
  3. J. Mills, J. Stone, D. Rubin, D. Melon, D. Okonkwo, and A. P. G. Helm, J. Biomed. Opt. 8, 347 (2003).
    [CrossRef] [PubMed]
  4. D. Stockholm, M. Bartoli, G. Sillon, N. Bourg, J. Davoust, and I. Richard, J. Mol. Biol. 346, 215 (2005).
    [CrossRef] [PubMed]
  5. V. Gaind, K. J. Webb, S. Kularatne, and C. A. Bouman, J. Opt. Soc. Am. A 26, 1805 (2009).
    [CrossRef]
  6. J. McGinty, V. Y. Soloviev, K. B. Tahir, R. Laine, D. W. Stuckey, J. V. Hajnal, A. Sardini, P. M. W. French, and S. R. Arridge, Opt. Lett. 34, 2772 (2009).
    [CrossRef] [PubMed]
  7. J. Yang, H. Chen, I. Vlahov, J. X. Cheng, and P. S. Low, Proc. Natl. Acad. Sci. USA 103, 13872 (2006).
    [CrossRef] [PubMed]
  8. P. S. Low, W. A. Henne, and D. D. Doorneweerd, Acc. Chem. Res. 41, 120 (2008).
    [CrossRef]
  9. E. Haas, ChemPhysChem 6, 858 (2005).
    [CrossRef] [PubMed]
  10. G. Hale and M. Querry, Appl. Opt. 12, 555 (1973).
    [CrossRef] [PubMed]
  11. A. B. Milstein, S. Oh, J. S. Reynolds, K. J. Webb, C. A. Bouman, and R. P. Millane, Opt. Lett. 27, 95 (2002).
    [CrossRef]

2009 (2)

2008 (1)

P. S. Low, W. A. Henne, and D. D. Doorneweerd, Acc. Chem. Res. 41, 120 (2008).
[CrossRef]

2006 (1)

J. Yang, H. Chen, I. Vlahov, J. X. Cheng, and P. S. Low, Proc. Natl. Acad. Sci. USA 103, 13872 (2006).
[CrossRef] [PubMed]

2005 (2)

E. Haas, ChemPhysChem 6, 858 (2005).
[CrossRef] [PubMed]

D. Stockholm, M. Bartoli, G. Sillon, N. Bourg, J. Davoust, and I. Richard, J. Mol. Biol. 346, 215 (2005).
[CrossRef] [PubMed]

2003 (1)

J. Mills, J. Stone, D. Rubin, D. Melon, D. Okonkwo, and A. P. G. Helm, J. Biomed. Opt. 8, 347 (2003).
[CrossRef] [PubMed]

2002 (1)

2001 (1)

K. Truong and M. Ikura, Curr. Opin. Struct. Biol. 11, 573 (2001).
[CrossRef]

1973 (1)

1948 (1)

T. Förster, Ann. Phys. 2, 55 (1948).
[CrossRef]

Arridge, S. R.

Bartoli, M.

D. Stockholm, M. Bartoli, G. Sillon, N. Bourg, J. Davoust, and I. Richard, J. Mol. Biol. 346, 215 (2005).
[CrossRef] [PubMed]

Bouman, C. A.

Bourg, N.

D. Stockholm, M. Bartoli, G. Sillon, N. Bourg, J. Davoust, and I. Richard, J. Mol. Biol. 346, 215 (2005).
[CrossRef] [PubMed]

Chen, H.

J. Yang, H. Chen, I. Vlahov, J. X. Cheng, and P. S. Low, Proc. Natl. Acad. Sci. USA 103, 13872 (2006).
[CrossRef] [PubMed]

Cheng, J. X.

J. Yang, H. Chen, I. Vlahov, J. X. Cheng, and P. S. Low, Proc. Natl. Acad. Sci. USA 103, 13872 (2006).
[CrossRef] [PubMed]

Davoust, J.

D. Stockholm, M. Bartoli, G. Sillon, N. Bourg, J. Davoust, and I. Richard, J. Mol. Biol. 346, 215 (2005).
[CrossRef] [PubMed]

Doorneweerd, D. D.

P. S. Low, W. A. Henne, and D. D. Doorneweerd, Acc. Chem. Res. 41, 120 (2008).
[CrossRef]

Förster, T.

T. Förster, Ann. Phys. 2, 55 (1948).
[CrossRef]

French, P. M. W.

Gaind, V.

Haas, E.

E. Haas, ChemPhysChem 6, 858 (2005).
[CrossRef] [PubMed]

Hajnal, J. V.

Hale, G.

Helm, A. P. G.

J. Mills, J. Stone, D. Rubin, D. Melon, D. Okonkwo, and A. P. G. Helm, J. Biomed. Opt. 8, 347 (2003).
[CrossRef] [PubMed]

Henne, W. A.

P. S. Low, W. A. Henne, and D. D. Doorneweerd, Acc. Chem. Res. 41, 120 (2008).
[CrossRef]

Ikura, M.

K. Truong and M. Ikura, Curr. Opin. Struct. Biol. 11, 573 (2001).
[CrossRef]

Kularatne, S.

Laine, R.

Low, P. S.

P. S. Low, W. A. Henne, and D. D. Doorneweerd, Acc. Chem. Res. 41, 120 (2008).
[CrossRef]

J. Yang, H. Chen, I. Vlahov, J. X. Cheng, and P. S. Low, Proc. Natl. Acad. Sci. USA 103, 13872 (2006).
[CrossRef] [PubMed]

McGinty, J.

Melon, D.

J. Mills, J. Stone, D. Rubin, D. Melon, D. Okonkwo, and A. P. G. Helm, J. Biomed. Opt. 8, 347 (2003).
[CrossRef] [PubMed]

Millane, R. P.

Mills, J.

J. Mills, J. Stone, D. Rubin, D. Melon, D. Okonkwo, and A. P. G. Helm, J. Biomed. Opt. 8, 347 (2003).
[CrossRef] [PubMed]

Milstein, A. B.

Oh, S.

Okonkwo, D.

J. Mills, J. Stone, D. Rubin, D. Melon, D. Okonkwo, and A. P. G. Helm, J. Biomed. Opt. 8, 347 (2003).
[CrossRef] [PubMed]

Querry, M.

Reynolds, J. S.

Richard, I.

D. Stockholm, M. Bartoli, G. Sillon, N. Bourg, J. Davoust, and I. Richard, J. Mol. Biol. 346, 215 (2005).
[CrossRef] [PubMed]

Rubin, D.

J. Mills, J. Stone, D. Rubin, D. Melon, D. Okonkwo, and A. P. G. Helm, J. Biomed. Opt. 8, 347 (2003).
[CrossRef] [PubMed]

Sardini, A.

Sillon, G.

D. Stockholm, M. Bartoli, G. Sillon, N. Bourg, J. Davoust, and I. Richard, J. Mol. Biol. 346, 215 (2005).
[CrossRef] [PubMed]

Soloviev, V. Y.

Stockholm, D.

D. Stockholm, M. Bartoli, G. Sillon, N. Bourg, J. Davoust, and I. Richard, J. Mol. Biol. 346, 215 (2005).
[CrossRef] [PubMed]

Stone, J.

J. Mills, J. Stone, D. Rubin, D. Melon, D. Okonkwo, and A. P. G. Helm, J. Biomed. Opt. 8, 347 (2003).
[CrossRef] [PubMed]

Stuckey, D. W.

Tahir, K. B.

Truong, K.

K. Truong and M. Ikura, Curr. Opin. Struct. Biol. 11, 573 (2001).
[CrossRef]

Vlahov, I.

J. Yang, H. Chen, I. Vlahov, J. X. Cheng, and P. S. Low, Proc. Natl. Acad. Sci. USA 103, 13872 (2006).
[CrossRef] [PubMed]

Webb, K. J.

Yang, J.

J. Yang, H. Chen, I. Vlahov, J. X. Cheng, and P. S. Low, Proc. Natl. Acad. Sci. USA 103, 13872 (2006).
[CrossRef] [PubMed]

Acc. Chem. Res. (1)

P. S. Low, W. A. Henne, and D. D. Doorneweerd, Acc. Chem. Res. 41, 120 (2008).
[CrossRef]

Ann. Phys. (1)

T. Förster, Ann. Phys. 2, 55 (1948).
[CrossRef]

Appl. Opt. (1)

ChemPhysChem (1)

E. Haas, ChemPhysChem 6, 858 (2005).
[CrossRef] [PubMed]

Curr. Opin. Struct. Biol. (1)

K. Truong and M. Ikura, Curr. Opin. Struct. Biol. 11, 573 (2001).
[CrossRef]

J. Biomed. Opt. (1)

J. Mills, J. Stone, D. Rubin, D. Melon, D. Okonkwo, and A. P. G. Helm, J. Biomed. Opt. 8, 347 (2003).
[CrossRef] [PubMed]

J. Mol. Biol. (1)

D. Stockholm, M. Bartoli, G. Sillon, N. Bourg, J. Davoust, and I. Richard, J. Mol. Biol. 346, 215 (2005).
[CrossRef] [PubMed]

J. Opt. Soc. Am. A (1)

Opt. Lett. (2)

Proc. Natl. Acad. Sci. USA (1)

J. Yang, H. Chen, I. Vlahov, J. X. Cheng, and P. S. Low, Proc. Natl. Acad. Sci. USA 103, 13872 (2006).
[CrossRef] [PubMed]

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 (4)

Fig. 1
Fig. 1

(a) Folate-FRET conjugate ( FA + linker + DA ) , bound to FR, is internalized by the cell by forming an endosome via invagination of the surrounding plasma membrane. After internalization of the folate-FRET conjugate, the disulfide ( S S ) bond is reduced. This detaches the acceptor (red ellipse) from the folate-FRET conjugate containing the donor (yellow ellipse), thus inhibiting DA FRET, leading to an increase in donor emission. (b) Experimental setup: a 3 mW 488 nm argon-ion laser, an x y scanning mirror system, a Plexiglas box of size 6 cm ( L ) × 6 cm ( H ) × 2.5 cm ( W ) , a 520 nm narrow bandpass filter, and a lens to focus the 5.4 cm × 5.4 cm image of the scattering medium onto a 512 × 512  pixel cooled CCD camera.

Fig. 2
Fig. 2

Images reconstructed from measurement set 1 data showing spatial localization of the FRET parameters within the mouse tumor. (a) Absorption ( μ a cm 1 ) image approximately bisecting the mouse. Note that there is no update near the boundaries; hence the apparent truncation at the top of the mouse. (b), (c) Simultaneously, reconstructed η and C for the euthanized mouse calculated using r F = 3.6 nm . (d) Reconstructed μ a and η image superimposed on the mouse.

Fig. 3
Fig. 3

Images from measurement set 2. Compared with Fig. 2, the mouse was moved slightly towards the center. (a) Reconstructed μ a , for the same mouse in a different position inside the scattering medium. (b) Reconstructed FRET DA distance ( r F ) , using η and C from Figs. 2b, 2c. (c) μ a image superimposed on the mouse image.

Fig. 4
Fig. 4

Calculation of the normalized rms error (NRMSE), defined as NRMSE = ( { i = 1 N [ x ( i ) x ̂ ( i ) ] 2 } { i = 1 N x 2 ( i ) } ) 0.5 , for η and C. Here, x ( i ) and x ̂ ( i ) represent the true and reconstructed image, respectively, N is the number of voxels and the spherical region is the support for the NRMSE calculation. (a) Superposition of the normalized true μ a of a cylinder representing a mouse and the normalized true η for a spherical region. The normalized μ a image was scaled with the multipliers μ a 1 = 0.1 , μ a 2 = 1.2 , μ a 3 = 10 . For each μ a j , we used η = 3.5 × 10 4 , 6.5 × 10 4 , and C = 0.3 , 0.45 , 0.6 , 0.75 . The reconstructed μ a NRMSE was 0.29 for μ a 1 = 0.1 , 0.51 for μ a 2 = 1.2 , and 0.91 for μ a 3 = 10 . (b) Superposition of the normalized reconstructed μ a for the cylinder and the normalized reconstructed η obtained using simulated data. (c) and (d) NRMSE for η and C at η = 3.5 × 10 4 . (e), (f) NRMSE for η and C at η = 6.5 × 10 4 . Here, μ a j and μ a j r represent the true and reconstructed μ a image.

Equations (2)

Equations on this page are rendered with MathJax. Learn more.

[ D j ( r ) ( μ a j ( r ) i ω c ) ] ϕ j ( r ; ω ) = S j ( r ; ω ) ,
S D ( r ; ω ) = r min r max [ 1 C ( r ) ] ζ [ r F ( r ) ] p [ r F ( r ) ] d r F ( r ) + C ( r ) η ( r ) 1 i ω τ D ,

Metrics