In vivo positron emission tomography imaging of protease activity by generation of a hydrophobic product from a noninhibitory protease substrate

Chih Hung Chuang, Kuo Hsiang Chuang, Hsin Ell Wang, Steve R. Roffler, Jen Taie Shiea, Shey Cherng Tzou, Ta Chun Cheng, Chien Han Kao, Shih Yen Wu, Wei Lung Tseng, Chiu Min Cheng, Ming Feng Hou, Ju Ming Wang, Tian Lu Cheng

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Abstract

Purpose: To develop an imaging technology for protease activities in patients that could help in prognosis prediction and in design of personalized, protease-based inhibitors and prodrugs for targeted therapy. Experimental Design: Polyethylene glycol (PEG) was covalently attached to the N-terminus of a hydrophilic peptide substrate (GPLGVR) for matrix metalloproteinase (MMP) to increase hydrophilicity. PEG-peptide was then linked to a hydrophobic tetramethylrhodamine (TMR) domain and labeled with 18F to form a PEG-peptide-18F-TMR probe. Specific cleavage of the probe by MMP2 was tested in vitro by matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF). In vivo imaging of MMP2-expressing tumors was evaluated by micro-PET. Results: The hydrophobic TMR fragment (948 Da) was specifically generated by MMP2 enzymes and MMP-expressing HT1080 cells but not control MCF-7 cells. MMP-expressing HT1080 cells and tumors selectively accumulated the hydrolyzed, hydrophobic TMR fragment at sites of protease activity. Importantly, we found that 18F-labeled probe (18F-TMR) preferentially localized in HT1080 tumors but not control MCF-7 tumors as shown by micro-PET. Uptake of the probe in HT1080 tumors was 18.4 ± 1.9-fold greater than in the MCF-7 tumors 30 minutes after injection. These results suggest that the PEG-peptide-18F-TMR probe displays high selectivity for imaging MMP activity. Conclusions: This strategy successfully images MMP expression in vivo and may be extended to other proteases to predict patient prognosis and to design personalized, protease-based inhibitors and prodrug-targeted therapies.

Original languageEnglish
Pages (from-to)238-247
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number1
DOIs
Publication statusPublished - 2012 Jan 1

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Chuang, C. H., Chuang, K. H., Wang, H. E., Roffler, S. R., Shiea, J. T., Tzou, S. C., Cheng, T. C., Kao, C. H., Wu, S. Y., Tseng, W. L., Cheng, C. M., Hou, M. F., Wang, J. M., & Cheng, T. L. (2012). In vivo positron emission tomography imaging of protease activity by generation of a hydrophobic product from a noninhibitory protease substrate. Clinical Cancer Research, 18(1), 238-247. https://doi.org/10.1158/1078-0432.CCR-11-0608