The technique, developed by MIT professor and Howard Hughes Medical Institute investigator Sangeeta Bhatia, Ph.D., relies on nanoparticles that interact with tumor proteases, each of which can trigger release of hundreds of biomarkers that are then detectable in a patient's urine.
“When we invented this new class of synthetic biomarker, we used a highly specialized instrument to do the analysis,” said Dr. Bhatia. “For the developing world, we thought it would be exciting to adapt it instead to a paper test that could be performed on unprocessed samples in a rural setting, without the need for any specialized equipment. The simple readout could even be transmitted to a remote caregiver by a picture on a mobile phone.”
Dr. Bhatia, who is also a member of MIT's Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, is the senior author of a paper (“Point-of-care diagnostics for noncommunicable diseases using synthetic urinary biomarkers and paper microfluidics”) describing the particles in Proceedings of the National Academy of Sciences.
In 2012, Dr. Bhatia and colleagues introduced the concept of a synthetic biomarker technology to amplify signals from tumor proteins that would be hard to detect on their own. These proteins, known as matrix metalloproteinases (MMPs), help cancer cells escape their original locations by cutting through proteins of the extracellular matrix, which normally holds cells in place.
The MIT nanoparticles are coated with peptides targeted by different MMPs. These particles congregate at tumor sites, where MMPs cleave hundreds of peptides, which accumulate in the kidneys and are excreted in the urine.
In the original version of the technology, these peptides were detected using a mass spectrometer. However, these instruments are not readily available in the developing world, so the researchers adapted the particles so they could be analyzed on paper, using a lateral flow assay.
“We describe the design of exogenous agents that serve as synthetic biomarkers for NCDs [noncommunicable diseases] by producing urinary signals that can be quantified by a companion paper test. These synthetic biomarkers are composed of nanoparticles conjugated to ligand-encoded reporters via protease-sensitive peptide substrates,” wrote the investigators. “Upon delivery, the nanoparticles passively target diseased sites…where up-regulated proteases cleave the peptide substrates and release reporters that are cleared into urine. The reporters are engineered for detection by sandwich immunoassays, and we demonstrate their quantification directly from unmodified urine.”
In tests in mice, the researchers were able to accurately identify colon tumors as well as blood clots. Dr. Bhatia says these tests represent the first step toward a diagnostic device that could someday be useful in human patients.