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Two-photon fluorescence correlation microscopy reveals the two-phase nature of transport in tumors

Nature Medicine volume 10, pages 203–207 (2004)Cite this article

Abstract

Transport parameters determine the access of drugs to tumors. However, technical difficulties preclude the measurement of these parameters deep inside living tissues. To this end, we adapted and further optimized two-photon fluorescence correlation microscopy (TPFCM) for in vivo measurement of transport parameters in tumors. TPFCM extends the detectable range of diffusion coefficients in tumors by one order of magnitude, and reveals both a fast and a slow component of diffusion. The ratio of these two components depends on molecular size and can be altered in vivo with hyaluronidase and collagenase. These studies indicate that TPFCM is a promising tool to dissect the barriers to drug delivery in tumors.

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Figure 1: Key steps in TPFCM.
Figure 2: Effect of tracer size on diffusion.
Figure 3: Tumor matrix components.
Figure 4: Effect of matrix modification on diffusion.

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Acknowledgements

We thank J. Kahn for dorsal skinfold chamber preparations; S. Roberge and R. Delgiacco for histological preparations; W. Zipfel for discussion and help with software analysis; and Z. Demou and M. Booth for comments on the manuscript. This work was supported by National Cancer Institute fellowships to G.A. (T32CA73479 and F32CA97818) and E.B.B. (F32CA88490), a National Science Foundation Graduate Research Fellowship to R.T.T., a Biotechnology Fellowship (T32GM08334) to T.D.M., and a Bioengineering Research Partnership Grant (R24 CA85140) and Program Project Grant (P01CA80124) to R.K.J.

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Author notes

  1. Edward B Brown and Ricky T Tong: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Radiation Oncology, Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, Massachusetts, USA

    George Alexandrakis, Edward B Brown, Ricky T Tong, Trevor D McKee, Yves Boucher & Rakesh K Jain

  2. Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Ricky T Tong

  3. Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Trevor D McKee

  4. Department of Pharmaceutical Sciences, Northeastern University, Bouvé College of Health Sciences, 02115, Massachusetts, USA

    Robert B Campbell

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Correspondence to Rakesh K Jain.

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Alexandrakis, G., Brown, E., Tong, R. et al. Two-photon fluorescence correlation microscopy reveals the two-phase nature of transport in tumors. Nat Med 10, 203–207 (2004). https://doi.org/10.1038/nm981

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