Abstract

We present a high-sensitivity near-infrared optical imaging system for noninvasive cancer detection and localization based on molecularly labeled fluorescent contrast agents. This frequency-domain system utilizes the interferencelike pattern of diffuse photon density waves to achieve high detection sensitivity and localization accuracy for the fluorescent heterogeneity embedded inside the scattering media. A two-dimensional localization map is obtained through reflectance probe geometry and goniometric reconstruction. In vivo measurements with a tumor-bearing mouse model by use of the novel Cypate-mono-2-deoxy-glucose fluorescent contrast agent, which targets the enhanced tumor glycolysis, demonstrate the feasibility of detection of a 2-cm-deep subsurface tumor in the tissuelike medium, with a localization accuracy within 2–3 mm.

© 2003 Optical Society of America

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  1. V. Ntziachristos, A. G. Yodh, M. Schnall, and B. Chance, Proc. Natl. Acad. Sci. USA 97, 2767 (2000).
    [CrossRef]
  2. T. O. McBride, B. W. Pogue, S. D. Jiang, U. L. Osterberg, K. D. Paulsen, and S. P. Poplack, Opt. Lett. 26, 822 (2001).
    [CrossRef]
  3. X. Intes, J. Ripoll, Y. Chen, S. Nioka, A. G. Yodh, and B. Chance, Med. Phys. 30, 1039 (2003).
    [CrossRef] [PubMed]
  4. R. Weissleder and U. Mahmood, Radiology 219, 316 (2001).
    [CrossRef] [PubMed]
  5. S. Achilefu, R. B. Dorshow, J. E. Bugaj, and R. Rajagopalan, Invest. Radiol. 35, 479 (2000).
    [CrossRef] [PubMed]
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    [CrossRef]
  7. M. Zhang, Z. H. Zhang, D. Blessington, H. Li, T. M. Busch, V. Madrak, J. Miles, J. D. Glickson, and G. Zheng, Bioconjugate Chem. 14, 709 (2003).
    [CrossRef]
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    [CrossRef] [PubMed]
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    [CrossRef]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef]
  13. M. A. O’Leary, D. A. Boas, X. D. Li, B. Chance, and A. G. Yodh, Opt. Lett. 21, 158 (1996).
    [CrossRef] [PubMed]
  14. X. Intes, Y. Chen, X. Li, and B. Chance, Appl. Opt. 41, 3999 (2002).
    [CrossRef] [PubMed]
  15. Y. Chen, C. P. Mu, X. Intes, D. Blessington, and B. Chance, Rev. Sci. Instrum. 74, 3466 (2003).
    [CrossRef]

2003

X. Intes, J. Ripoll, Y. Chen, S. Nioka, A. G. Yodh, and B. Chance, Med. Phys. 30, 1039 (2003).
[CrossRef] [PubMed]

M. Zhang, Z. H. Zhang, D. Blessington, H. Li, T. M. Busch, V. Madrak, J. Miles, J. D. Glickson, and G. Zheng, Bioconjugate Chem. 14, 709 (2003).
[CrossRef]

Y. Chen, C. P. Mu, X. Intes, D. Blessington, and B. Chance, Rev. Sci. Instrum. 74, 3466 (2003).
[CrossRef]

2002

X. Intes, Y. Chen, X. Li, and B. Chance, Appl. Opt. 41, 3999 (2002).
[CrossRef] [PubMed]

V. Ntziachristos, C. H. Tung, C. Bremer, and R. Weissleder, Nat. Med. 8, 757 (2002).
[CrossRef] [PubMed]

M. J. Eppstein, D. J. Hawrysz, A. Godavarty, and E. M. Sevick-Muraca, Proc. Natl. Acad. Sci. USA 99, 9619 (2002).
[CrossRef]

A. Eidsath, V. Chernomordik, A. Gandjbakhche, P. Smith, and A. Russo, Phys. Med. Biol. 47, 4079 (2002).
[CrossRef] [PubMed]

2001

2000

V. Ntziachristos, A. G. Yodh, M. Schnall, and B. Chance, Proc. Natl. Acad. Sci. USA 97, 2767 (2000).
[CrossRef]

S. Achilefu, R. B. Dorshow, J. E. Bugaj, and R. Rajagopalan, Invest. Radiol. 35, 479 (2000).
[CrossRef] [PubMed]

M. E. Phelps, Proc. Natl. Acad. Sci. USA 97, 9226 (2000).
[CrossRef]

1996

1993

B. Chance, K. Kang, L. He, J. Weng, and E. Sevick, Proc. Natl. Acad. Sci. USA 90, 3423 (1993).
[CrossRef]

1992

J. M. Schmitt, A. Knuttel, and J. R. Knutson, J. Opt. Soc. Am. A 9, 1832 (1992).
[CrossRef] [PubMed]

Achilefu, S.

S. Achilefu, R. B. Dorshow, J. E. Bugaj, and R. Rajagopalan, Invest. Radiol. 35, 479 (2000).
[CrossRef] [PubMed]

Blessington, D.

M. Zhang, Z. H. Zhang, D. Blessington, H. Li, T. M. Busch, V. Madrak, J. Miles, J. D. Glickson, and G. Zheng, Bioconjugate Chem. 14, 709 (2003).
[CrossRef]

Y. Chen, C. P. Mu, X. Intes, D. Blessington, and B. Chance, Rev. Sci. Instrum. 74, 3466 (2003).
[CrossRef]

Boas, D. A.

Bremer, C.

V. Ntziachristos, C. H. Tung, C. Bremer, and R. Weissleder, Nat. Med. 8, 757 (2002).
[CrossRef] [PubMed]

Bugaj, J. E.

S. Achilefu, R. B. Dorshow, J. E. Bugaj, and R. Rajagopalan, Invest. Radiol. 35, 479 (2000).
[CrossRef] [PubMed]

Busch, T. M.

M. Zhang, Z. H. Zhang, D. Blessington, H. Li, T. M. Busch, V. Madrak, J. Miles, J. D. Glickson, and G. Zheng, Bioconjugate Chem. 14, 709 (2003).
[CrossRef]

Chance, B.

X. Intes, J. Ripoll, Y. Chen, S. Nioka, A. G. Yodh, and B. Chance, Med. Phys. 30, 1039 (2003).
[CrossRef] [PubMed]

Y. Chen, C. P. Mu, X. Intes, D. Blessington, and B. Chance, Rev. Sci. Instrum. 74, 3466 (2003).
[CrossRef]

X. Intes, Y. Chen, X. Li, and B. Chance, Appl. Opt. 41, 3999 (2002).
[CrossRef] [PubMed]

V. Ntziachristos, A. G. Yodh, M. Schnall, and B. Chance, Proc. Natl. Acad. Sci. USA 97, 2767 (2000).
[CrossRef]

M. A. O’Leary, D. A. Boas, X. D. Li, B. Chance, and A. G. Yodh, Opt. Lett. 21, 158 (1996).
[CrossRef] [PubMed]

B. Chance, K. Kang, L. He, J. Weng, and E. Sevick, Proc. Natl. Acad. Sci. USA 90, 3423 (1993).
[CrossRef]

Chen, Y.

Y. Chen, C. P. Mu, X. Intes, D. Blessington, and B. Chance, Rev. Sci. Instrum. 74, 3466 (2003).
[CrossRef]

X. Intes, J. Ripoll, Y. Chen, S. Nioka, A. G. Yodh, and B. Chance, Med. Phys. 30, 1039 (2003).
[CrossRef] [PubMed]

X. Intes, Y. Chen, X. Li, and B. Chance, Appl. Opt. 41, 3999 (2002).
[CrossRef] [PubMed]

Chernomordik, V.

A. Eidsath, V. Chernomordik, A. Gandjbakhche, P. Smith, and A. Russo, Phys. Med. Biol. 47, 4079 (2002).
[CrossRef] [PubMed]

Dorshow, R. B.

S. Achilefu, R. B. Dorshow, J. E. Bugaj, and R. Rajagopalan, Invest. Radiol. 35, 479 (2000).
[CrossRef] [PubMed]

Eidsath, A.

A. Eidsath, V. Chernomordik, A. Gandjbakhche, P. Smith, and A. Russo, Phys. Med. Biol. 47, 4079 (2002).
[CrossRef] [PubMed]

Eppstein, M. J.

M. J. Eppstein, D. J. Hawrysz, A. Godavarty, and E. M. Sevick-Muraca, Proc. Natl. Acad. Sci. USA 99, 9619 (2002).
[CrossRef]

Gandjbakhche, A.

A. Eidsath, V. Chernomordik, A. Gandjbakhche, P. Smith, and A. Russo, Phys. Med. Biol. 47, 4079 (2002).
[CrossRef] [PubMed]

Glickson, J. D.

M. Zhang, Z. H. Zhang, D. Blessington, H. Li, T. M. Busch, V. Madrak, J. Miles, J. D. Glickson, and G. Zheng, Bioconjugate Chem. 14, 709 (2003).
[CrossRef]

Godavarty, A.

M. J. Eppstein, D. J. Hawrysz, A. Godavarty, and E. M. Sevick-Muraca, Proc. Natl. Acad. Sci. USA 99, 9619 (2002).
[CrossRef]

Hawrysz, D. J.

M. J. Eppstein, D. J. Hawrysz, A. Godavarty, and E. M. Sevick-Muraca, Proc. Natl. Acad. Sci. USA 99, 9619 (2002).
[CrossRef]

He, L.

B. Chance, K. Kang, L. He, J. Weng, and E. Sevick, Proc. Natl. Acad. Sci. USA 90, 3423 (1993).
[CrossRef]

Intes, X.

Y. Chen, C. P. Mu, X. Intes, D. Blessington, and B. Chance, Rev. Sci. Instrum. 74, 3466 (2003).
[CrossRef]

X. Intes, J. Ripoll, Y. Chen, S. Nioka, A. G. Yodh, and B. Chance, Med. Phys. 30, 1039 (2003).
[CrossRef] [PubMed]

X. Intes, Y. Chen, X. Li, and B. Chance, Appl. Opt. 41, 3999 (2002).
[CrossRef] [PubMed]

Jiang, S. D.

Kang, K.

B. Chance, K. Kang, L. He, J. Weng, and E. Sevick, Proc. Natl. Acad. Sci. USA 90, 3423 (1993).
[CrossRef]

Knutson, J. R.

J. M. Schmitt, A. Knuttel, and J. R. Knutson, J. Opt. Soc. Am. A 9, 1832 (1992).
[CrossRef] [PubMed]

Knuttel, A.

J. M. Schmitt, A. Knuttel, and J. R. Knutson, J. Opt. Soc. Am. A 9, 1832 (1992).
[CrossRef] [PubMed]

Li, H.

M. Zhang, Z. H. Zhang, D. Blessington, H. Li, T. M. Busch, V. Madrak, J. Miles, J. D. Glickson, and G. Zheng, Bioconjugate Chem. 14, 709 (2003).
[CrossRef]

Li, X.

Li, X. D.

Madrak, V.

M. Zhang, Z. H. Zhang, D. Blessington, H. Li, T. M. Busch, V. Madrak, J. Miles, J. D. Glickson, and G. Zheng, Bioconjugate Chem. 14, 709 (2003).
[CrossRef]

Mahmood, U.

R. Weissleder and U. Mahmood, Radiology 219, 316 (2001).
[CrossRef] [PubMed]

McBride, T. O.

Miles, J.

M. Zhang, Z. H. Zhang, D. Blessington, H. Li, T. M. Busch, V. Madrak, J. Miles, J. D. Glickson, and G. Zheng, Bioconjugate Chem. 14, 709 (2003).
[CrossRef]

Mu, C. P.

Y. Chen, C. P. Mu, X. Intes, D. Blessington, and B. Chance, Rev. Sci. Instrum. 74, 3466 (2003).
[CrossRef]

Nioka, S.

X. Intes, J. Ripoll, Y. Chen, S. Nioka, A. G. Yodh, and B. Chance, Med. Phys. 30, 1039 (2003).
[CrossRef] [PubMed]

Ntziachristos, V.

V. Ntziachristos, C. H. Tung, C. Bremer, and R. Weissleder, Nat. Med. 8, 757 (2002).
[CrossRef] [PubMed]

V. Ntziachristos, A. G. Yodh, M. Schnall, and B. Chance, Proc. Natl. Acad. Sci. USA 97, 2767 (2000).
[CrossRef]

O'Leary, M. A.

Osterberg, U. L.

Paulsen, K. D.

Phelps, M. E.

M. E. Phelps, Proc. Natl. Acad. Sci. USA 97, 9226 (2000).
[CrossRef]

Pogue, B. W.

Poplack, S. P.

Rajagopalan, R.

S. Achilefu, R. B. Dorshow, J. E. Bugaj, and R. Rajagopalan, Invest. Radiol. 35, 479 (2000).
[CrossRef] [PubMed]

Ripoll, J.

X. Intes, J. Ripoll, Y. Chen, S. Nioka, A. G. Yodh, and B. Chance, Med. Phys. 30, 1039 (2003).
[CrossRef] [PubMed]

Russo, A.

A. Eidsath, V. Chernomordik, A. Gandjbakhche, P. Smith, and A. Russo, Phys. Med. Biol. 47, 4079 (2002).
[CrossRef] [PubMed]

Schmitt, J. M.

J. M. Schmitt, A. Knuttel, and J. R. Knutson, J. Opt. Soc. Am. A 9, 1832 (1992).
[CrossRef] [PubMed]

Schnall, M.

V. Ntziachristos, A. G. Yodh, M. Schnall, and B. Chance, Proc. Natl. Acad. Sci. USA 97, 2767 (2000).
[CrossRef]

Sevick, E.

B. Chance, K. Kang, L. He, J. Weng, and E. Sevick, Proc. Natl. Acad. Sci. USA 90, 3423 (1993).
[CrossRef]

Sevick-Muraca, E. M.

M. J. Eppstein, D. J. Hawrysz, A. Godavarty, and E. M. Sevick-Muraca, Proc. Natl. Acad. Sci. USA 99, 9619 (2002).
[CrossRef]

Smith, P.

A. Eidsath, V. Chernomordik, A. Gandjbakhche, P. Smith, and A. Russo, Phys. Med. Biol. 47, 4079 (2002).
[CrossRef] [PubMed]

Tung, C. H.

V. Ntziachristos, C. H. Tung, C. Bremer, and R. Weissleder, Nat. Med. 8, 757 (2002).
[CrossRef] [PubMed]

Weissleder, R.

V. Ntziachristos, C. H. Tung, C. Bremer, and R. Weissleder, Nat. Med. 8, 757 (2002).
[CrossRef] [PubMed]

R. Weissleder and U. Mahmood, Radiology 219, 316 (2001).
[CrossRef] [PubMed]

Weng, J.

B. Chance, K. Kang, L. He, J. Weng, and E. Sevick, Proc. Natl. Acad. Sci. USA 90, 3423 (1993).
[CrossRef]

Yodh, A. G.

X. Intes, J. Ripoll, Y. Chen, S. Nioka, A. G. Yodh, and B. Chance, Med. Phys. 30, 1039 (2003).
[CrossRef] [PubMed]

V. Ntziachristos, A. G. Yodh, M. Schnall, and B. Chance, Proc. Natl. Acad. Sci. USA 97, 2767 (2000).
[CrossRef]

M. A. O’Leary, D. A. Boas, X. D. Li, B. Chance, and A. G. Yodh, Opt. Lett. 21, 158 (1996).
[CrossRef] [PubMed]

Zhang, M.

M. Zhang, Z. H. Zhang, D. Blessington, H. Li, T. M. Busch, V. Madrak, J. Miles, J. D. Glickson, and G. Zheng, Bioconjugate Chem. 14, 709 (2003).
[CrossRef]

Zhang, Z. H.

M. Zhang, Z. H. Zhang, D. Blessington, H. Li, T. M. Busch, V. Madrak, J. Miles, J. D. Glickson, and G. Zheng, Bioconjugate Chem. 14, 709 (2003).
[CrossRef]

Zheng, G.

M. Zhang, Z. H. Zhang, D. Blessington, H. Li, T. M. Busch, V. Madrak, J. Miles, J. D. Glickson, and G. Zheng, Bioconjugate Chem. 14, 709 (2003).
[CrossRef]

Appl. Opt.

Bioconjugate Chem.

M. Zhang, Z. H. Zhang, D. Blessington, H. Li, T. M. Busch, V. Madrak, J. Miles, J. D. Glickson, and G. Zheng, Bioconjugate Chem. 14, 709 (2003).
[CrossRef]

Invest. Radiol.

S. Achilefu, R. B. Dorshow, J. E. Bugaj, and R. Rajagopalan, Invest. Radiol. 35, 479 (2000).
[CrossRef] [PubMed]

J. Opt. Soc. Am. A

J. M. Schmitt, A. Knuttel, and J. R. Knutson, J. Opt. Soc. Am. A 9, 1832 (1992).
[CrossRef] [PubMed]

Med. Phys.

X. Intes, J. Ripoll, Y. Chen, S. Nioka, A. G. Yodh, and B. Chance, Med. Phys. 30, 1039 (2003).
[CrossRef] [PubMed]

Nat. Med.

V. Ntziachristos, C. H. Tung, C. Bremer, and R. Weissleder, Nat. Med. 8, 757 (2002).
[CrossRef] [PubMed]

Opt. Lett.

Phys. Med. Biol.

A. Eidsath, V. Chernomordik, A. Gandjbakhche, P. Smith, and A. Russo, Phys. Med. Biol. 47, 4079 (2002).
[CrossRef] [PubMed]

Proc. Natl. Acad. Sci. USA

B. Chance, K. Kang, L. He, J. Weng, and E. Sevick, Proc. Natl. Acad. Sci. USA 90, 3423 (1993).
[CrossRef]

V. Ntziachristos, A. G. Yodh, M. Schnall, and B. Chance, Proc. Natl. Acad. Sci. USA 97, 2767 (2000).
[CrossRef]

M. J. Eppstein, D. J. Hawrysz, A. Godavarty, and E. M. Sevick-Muraca, Proc. Natl. Acad. Sci. USA 99, 9619 (2002).
[CrossRef]

M. E. Phelps, Proc. Natl. Acad. Sci. USA 97, 9226 (2000).
[CrossRef]

Radiology

R. Weissleder and U. Mahmood, Radiology 219, 316 (2001).
[CrossRef] [PubMed]

Rev. Sci. Instrum.

Y. Chen, C. P. Mu, X. Intes, D. Blessington, and B. Chance, Rev. Sci. Instrum. 74, 3466 (2003).
[CrossRef]

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Figures (3)

Fig. 1
Fig. 1

Schematic of the fluorescent phase cancellation system. Inset, 2D goniometric probe. RF, radio frequency; IF, intermediate frequency; M, modulator; LD, laser diode; PMT, photomultiplier tube.

Fig. 2
Fig. 2

(a) 5-mm diameter sphere (shaded circle) filled with 1µM Cypate-2DG embedded 2.5 cm inside the scattering media. (b) 2D localization of the fluorescent object. (c) χ2 map of the fitting.

Fig. 3
Fig. 3

(a) Submerged tumor-bearing mouse with tail vein injection of 200µl 1-mg/ml Cypate-2DG. The tumor (shaded circle) is 8 mm×8 mm. (b) 2D localization of the tumor in (a) 3.5 h postinjection. The tumor is 1.5 cm deep. (c) 2D localization of the tumor in (a) 3.5 h postinjection. The tumor is 2.0 cm deep. (d) Submerged non-tumor-bearing mouse with tail vein injection of 200µl 1-mg/ml Cypate-2DG. (e) 2D localization of the mouse in (d) 3.5 h postinjection. The depth of the mouse is the same as in (a). (f) Submerged tumor-bearing mouse with tail vein injection of 200µl 1-mg/ml ICG. The tumor (shaded oval) is 8 mm×6 mm. (g) 2D localization of the tumor in (f) 3.5 h postinjection. The tumor is 1.5 cm deep. (h) Submerged tumor-bearing mouse without injection of any type of contrast agent. The tumor (shaded oval) is 8 mm×6 mm. (i) 2D localization of the tumor in (h). The tumor is 1.5 cm deep.

Equations (3)

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

Uflrd,rs=Uincr,rsησNtr1-iωτDflGflr,rddr,
χθ2ρ=12Ni=1NAθSIGi-AθPOFρ,iσA2+PθSIGi-PθPOFρ,iσP2,
Sx,y=1Ki=1K-lgχθi2ρ,

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