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Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation

Abstract

The content and structure of collagen is essential in governing the delivery of therapeutic molecules in tumors. Thus, simple histological staining of tumor tissue biopsies for collagen could be used to assess the accessibility of molecular therapeutics in tumors. Here we show that it is possible to optically image fibrillar collagen in tumors growing in mice using second-harmonic generation (SHG). Using this noninvasive technique, we estimated relative diffusive hindrance, quantified the dynamics of collagen modification after pharmacologic intervention and provided mechanistic insight into improved diffusive transport induced by the hormone relaxin. This technology could offer basic scientists and clinicians an enhanced ability to estimate the relative penetrabilities of molecular therapeutics.

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Figure 1: SHG imaging of tumors in vivo.
Figure 2: SHG images of fibrillar collagen I in tumors.
Figure 3: Dependence of SHG signal on tumor type.
Figure 4: Effect of collagenase and relaxin on tumor collagen dynamics.

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Acknowledgements

We thank P. So and L. Hsu-Laiho for use of their spectrum analyzer; L. Munn and T. Padera for their comments on the manuscript; J. Kahn for dorsal skin-fold chamber preparations; E. Unemori (Connetics, San Francisco, California) for the relaxin; L. Fisher (National Institute of Dental Research, Bethesda, Maryland) for the antibody to collagen I and D. Berk for his contributions to this project. This work was supported by a Biotechnology Training Grant (T32GM08334) to T.M., and a Program Project Grant (P01CA80124) to R.K.J.

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Correspondence to Rakesh K. Jain.

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Brown, E., McKee, T., diTomaso, E. et al. Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation. Nat Med 9, 796–800 (2003). https://doi.org/10.1038/nm879

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