Amplifying the signal

New nanoparticles can trigger cancer proteins to mass-produce biomarkers for easier, earlier detection

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CAMBRIDGE, Mass.—Biomarkers are one of the leading beaus inseveral therapeutic indications for their potential in determining the efficacyof treatments in patients, but some of the latest work to come out of theMassachusetts Institute of Technology (MIT) is focusing on how to increasebiomarker production to enable easier, earlier cancer diagnoses.
Diagnosis via biomarkers focuses on proteins secreted bycancer cells, but the cancer cells release so few of the biomarkers thatdetection is difficult. However, researchers at MIT led by Sangeeta Bhatia havedeveloped a new set of nanoparticles capable of homing in on a tumor andinteracting with cancer proteins, thereby stimulating the production ofthousands of biomarkers. The produced biomarkers allow for easy detection inurine samples.
"There's a desperate search for biomarkers, for earlydetection or disease prognosis, or looking at how the body responds totherapy," said Bhatia, the John and Dorothy Wilson Professor of Health Sciencesand Technology and Electrical Engineering and Computer Science at MIT, in apress release. In fact, Stanford University researchers published a recentstudy that revealed that even with the best technology and existing ovariancancer biomarkers, an ovarian tumor would not be found until eight to 10 yearsafter its formation.
The idea for this new technology came from an "a-ha" moment,according to Bhatia, a member of MIT's David H. Koch Institute for IntegrativeCancer Research. Cancer cells have "limited production capacity," she noted,but "What if you could deliver something that could amplify that signal?"
One of the many products of cancer cells are large amountsof proteases known as matrix metalloproteinases (MMPs), which help cancer cellsspread beyond their original birth points by cutting through proteins of theextracellular matrix. According to EMD Millipore, MMPs are "secreted ortransmembrane proteolytic endopeptidases that process and degrade extracellularmatrix proteins. MMPs play critical roles in many normal growth anddevelopmental aspects of tissue remodeling, wound healing and angiogenesis. Ina pathological context, MMPs are associated with cell migration, invasion,arthritis and cancer tumor progression."
The team coated the nanoparticles—ones that interact withproteases and which the lab had been working on originally as imaging agentsfor tumors—with peptides that are targeted by several MMP proteases. Thenanoparticles gather at tumor sites, traveling via the leaky blood vessels thatgenerally surround and are put out by tumors, and once there, the proteasescleave hundreds of peptides from the nanoparticles. Once cleaved, thenanoparticles are released into the bloodstream, where they are then carried toand accumulate in the kidneys and excreted in urine, at which point they can bedetected with mass spectrometry.
For more precise biomarker readings, the nanoparticles weredesigned to express 10 different peptides, with each one cleaved by a differentMMP protease. In addition, the peptides are all differently sized, allowing foreasier differentiation with mass spectrometry.
The amplification system could be used to monitor diseaseprogression and track the response of tumors to treatment as well, Bhatianoted. She added that researchers' search for biomarkers has become morecomplicated of late due to the recent discovery that many cancer types, includingbreast cancer, actually consist of groups of several diseases with differentgenetic signatures.
For this study, the nanoparticles were tested in mousemodels to detect the early stages of colorectal cancer as well as formonitoring the progression of liver fibrosis (progressive scarring as a resultof liver injury or liver disease). The mouse models demonstrated that thenanoparticles provided feedback much faster than biopsies in the case of liverfibrosis. In addition, the nanoparticles were also able to accurately revealthe early formation of colorectal tumors. Moving forward, the nanoparticleswill be studied to determine their ability to gauge tumor response tochemotherapy as well as metastasis.
The MIT researchers, working alongside a team from BethIsrael Deaconess Medical Center, reported the nanoparticle technology in a Nature Biotechnology paper on Dec. 16,2012. Gabriel Kwong, a postdoctoral in the MIT Institute for MedicalEngineering and Science and the Koch Institute, was lead author of the paper,titled "Mass-encoded synthetic biomarkers for multiplexed urinary monitoring ofdisease."

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