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*

*Corresponding author for this work

Research output: Contribution to journalArticle

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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 18 F to form a PEG-peptide- 18 F-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 18 F-labeled probe ( 18 F-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- 18 F-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
StatePublished - 1 Jan 2012

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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