Optical proteolytic beacons for in vivo detection 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 noninvasive "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 proteolytic activity, (2) diagnosis and prognosis to distinguished tumors that require particularly aggressive therapy or those that will not benefit from therapy, (3) identification of tumors appropriate for specific antiproteinase therapeutics and optimization of drug and dose based on determination of target modulation, and (4) as an indicator of efficacy of proteolytically activated prodrugs. 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-referable proteolytic activity in tumors in mouse models of cancer.
Department of Cancer Biology, Box 6840, Vanderbilt University, Nashville, TN, USA.
J Oliver
JO
McIntyre
Lynn M
LM
Matrisian
D000818:Animals; D050091:Dendrimers; D005456:Fluorescent Dyes / Q000032:analysis* / Q000138:chemical synthesis / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000201:enzymology; D010455:Peptides / Q000032:analysis* / Q000138:chemical synthesis / Q000378:metabolism; D011073:Polyamines / Q000032:analysis* / Q000138:chemical synthesis / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D019265:Spectroscopy, Near-Infrared; D014183:Transplantation, Heterologous; D051598:Whole Body Imaging
D050091:Dendrimers; D005456:Fluorescent Dyes; C104700:PAMAM Starburst; D010455:Peptides; D011073:Polyamines; D020782:Matrix Metalloproteinases