Near-infrared optical proteolytic beacons for in vivo imaging of matrix metalloproteinase activity.
The exuberant expression of proteinases by tumor cells has long been associated with the breakdown of the extracellular matrix, tumor invasion, and metastasis to distant organs. There are both epidemiological and experimental data that support a causative role for proteinases of the matrix metalloproteinase (MMP) family in tumor progression. Optical imaging techniques provide an extraordinary opportunity for non-invasive "molecular imaging" of tumor-associated proteolytic activity. The application of optical proteolytic beacons for the detection of specific proteinase activities associated with tumors has several potential purposes: (1) Detection of small, early-stage tumors with increased sensitivity due to the catalytic nature of the proteolytic activity, (2) diagnosis and prognosis to distinguish tumors that require particularly aggressive therapy or those that will not benefit from therapy, (3) identification of tumors appropriate for specific anti-proteinase therapeutics and optimization of drug and its dose based on determination of target modulation, and (4) as an indicator of the efficacy of proteolytically activated pro-drugs. This chapter describes the synthesis, characterization, and application of reagents that use visible and near-infrared fluorescence resonance energy transfer (FRET) fluorophore pairs to detect and measure MMP proteolytic activity in tumors in murine models of cancer.
McIntyre
J Oliver
JO
Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA. oliver.mcintyre@vanderbilt.edu
Scherer
Randy L
RL
Matrisian
Lynn M
LM
D000236:Adenoma / Q000473:pathology; D000818:Animals; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods*; D006801:Humans; D007259:Infrared Rays; D007414:Intestinal Neoplasms / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D015335:Molecular Probes / Q000138:chemical synthesis / Q000378:metabolism*; D055620:Optical Phenomena; D011499:Protein Processing, Post-Translational; D013050:Spectrometry, Fluorescence; D023041:Xenograft Model Antitumor Assays
D015335:Molecular Probes; D020782:Matrix Metalloproteinases