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In vivo molecular target assessment of matrix metalloproteinase inhibition

Nature Medicine volume 7, pages 743–748 (2001)Cite this article

Abstract

A number of different matrix metalloproteinase (MMP) inhibitors have been developed as cytostatic and anti-angiogenic agents and are currently in clinical testing. One major hurdle in assessing the efficacy of such drugs has been the inability to sense or image anti-proteinase activity directly and non-invasively in vivo. We show here that novel, biocompatible near-infrared fluorogenic MMP substrates can be used as activatable reporter probes to sense MMP activity in intact tumors in nude mice. Moreover, we show for the first time that the effect of MMP inhibition can be directly imaged using this approach within hours after initiation of treatment using the potent MMP inhibitor, prinomastat (AG3340). The developed probes, together with novel near-infrared fluorescence imaging technology will enable the detailed analysis of a number of proteinases critical for advancing the therapeutic use of clinical proteinase inhibitors.

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Figure 1: MMP-2–sensitive imaging probe.
Figure 2: Characterization of NIRF probe.
Figure 3: MMP-2 enzyme activity in tumor models.
Figure 4: In vivo imaging.
Figure 5: Histology.

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Acknowledgements

The authors would like to thank A. Bogdanov for providing the graft copolymer and U. Mahmood and A. Moore for technical assistance in imaging and animal preparation. The authors also gratefully acknowledge the assistance of S. Bredow for optimizing RT-PCR and zymography conditions. The authors would also like to thank Agouron Pharmaceuticals and Pfizer for providing prinomastat, and R. Feeley, S. Gregory and D. Shalinsky (Department of Research Pharmacology) for helpful discussions and critical review of the manuscript. This project is supported in part by NIH CA088365 and a RSNA seed grant. C.B. was supported by the Deutsche Forschungsgemeinschaft.

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  1. Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA

    Christoph Bremer, Ching-Hsuan Tung & Ralph Weissleder

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  1. Christoph Bremer
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Correspondence to Ching-Hsuan Tung or Ralph Weissleder.

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Bremer, C., Tung, CH. & Weissleder, R. In vivo molecular target assessment of matrix metalloproteinase inhibition. Nat Med 7, 743–748 (2001). https://doi.org/10.1038/89126

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