Abstract
Protease-susceptible peptides delivered by “nanoworms” create breakdown products that can be detected in urine in mouse models of colorectal cancer and liver fibrosis.
Using protease-susceptible peptides that result in breakdown products that can be measured in urine, researchers at Massachusetts Institute of Technology (MIT) in Cambridge, MA, believe they have created a way to detect cancer much earlier than is possible with current technologies that depend on blood tests, biopsies, or imaging.
Many types of cancer and a variety of other diseases, such as atherosclerosis, could be found with this new detection method, says Gabriel Kwong, PhD, a researcher in the laboratory of Sangeeta Bhatia, MD, PhD, at MIT and lead author of an article describing the technique in mouse models of colorectal cancer and liver fibrosis (Nature Biotechnol 2013;31:63–70).
In this diagram, iron oxide “nanoworms” (brown) are coated with peptides (blue) that are cleaved by enzymes (green) found at the disease site. Accumulating in the urine, the peptides can be detected with mass spectrometry.
In this diagram, iron oxide “nanoworms” (brown) are coated with peptides (blue) that are cleaved by enzymes (green) found at the disease site. Accumulating in the urine, the peptides can be detected with mass spectrometry.
Early on, cancer and many other conditions produce abnormal protease activity that is not easily detectable by current means. Kwong and colleagues suggest, though, that peptides susceptible to the cleaving power of those proteases will yield fragments shed into the urine that can serve as indicators of nascent disease. Without “interrogating” cells in this way, notes Kwong, “you are really depending on what the disease cells give you.”
Kwong and his colleagues winnowed about 50 candidate peptides down to 10 by testing their response to recombinant versions of proteases commonly expressed by diseased cells. They used strings of iron oxide nanoparticles, or “nanoworms,” to ferry the sacrificial peptides to the diseased tissue in mice.
However, because the peptides can be sliced and diced in any number of ways, Kwong attached D isomer–rich derivatives of glutamate-fibrinopeptide B to the peptides so they cleave in a regular way. This allowed them to be measured with mass spectrometry and interpreted as signals of disease-associated protease activity. He also developed a coding system for classifying those peptide fragments into the 10 easily identifiable types.
In the colorectal cancer model, Kwong and his team tested the synthetically generated peptide fragments against carcinoembryonic antigen (CEA), a blood biomarker of colorectal cancer. Tumors that produced measurable amounts of the synthetic biomarkers were 60% smaller than those that produced measurable amounts of CEA.
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