MIT, Harvard Team Builds Nanosensor for Monitoring Cumulative Biomarker Exposure

By Adam Bonislawski

Scientists from the Massachusetts Institute of Technology and Harvard University have devised a nanoparticle-based detection system for continuously monitoring protein biomarker levels over extended lengths of time.

According to Michael Cima, professor of engineering at MIT and one of the device's developers, it could enable researchers to measure the cumulative production of a target biomarker over periods of weeks, months, or possibly years, potentially providing biological data and diagnostic information unavailable via conventional single-time-point sampling techniques like blood draws.

The system consists of sensors housing iron oxide nanoparticles bound to antibodies for the protein of interest. When target proteins diffuse across the sensor membrane, these nanoparticles aggregate to them, which alters the transverse relaxivity of surrounding water protons. This change in relaxivity can be read via magnetic resonance imaging, and the biomarker can be quantitated based on this reading.

The coagulation of the antibody-bound iron oxide particles to the protein biomarker generates a "physical amplification," Cima told ProteoMonitor, "where the presence of a single analyte molecule actually affects billions and trillions of water molecules."

Because the biomarkers remain attached to the antibody-bound particles even as their concentration in a subject returns to normal, the signal produced by this reaction represents a cumulative measurement of protein biomarker levels for the time period in which the sensor is present, which might provide information not available from biomarker samples taken at discrete timepoints.

In a study published this month in the online edition of Nature Biotechnology, the MIT and Harvard scientists used a prototype of the device to measure the cardiovascular biomarkers cardiac troponin 1, creatinine kinase, and myoglobin in mice after acute myocardial infarctions.

In the case of MIs, the instantaneous biomarker concentration data provided by blood draws is "actually a problem for diagnoses because [cTn1, CK-MB, and myoglobin] change with time after a heart attack," Cima said. Often, he noted, physicians are faced with a mix of positive and negative biomarkers, making a definitive diagnosis difficult.

A cumulative biomarker reading could also be useful in detecting cases of unrecognized MIs, which are accompanied by few or no symptoms and which, according to data from the Framingham Heart Study, constitute 28 percent and 35 percent of heart attacks in men and women, respectively.

"A lot of heart attacks are pretty silent," Cima said. "People don't know that they're having one. And those are the kind of folks that end up – if they don't die of a heart attack – dying of congestive heart failure because their heart has so many lesions that it really stops functioning as a pump."

Depending on when they're measured, he noted, protein biomarkers linked to such MIs may not provide evidence of the event.

"For instance, after a heart attack myoglobin rises very quickly, but its half-life is very short and then it drops again. Our sensor still measures the presence of myoglobin even after it disappears," Cima said.

In the Nature Biotechnology study the researchers also found that the amount of the three biomarkers their sensors collected correlated to the magnitude of the infarction, providing a quantitative assessment of each heart attack as opposed to the simple positive or negative read-out provided by the biomarkers from a blood draw.

According to Allan Jaffe, a professor of medicine and laboratory medicine division chair at the Mayo Clinic who was not involved in the project, the system is potentially "a major advance" in that it could improve investigations into the progression of cardiovascular diseases.

"We have a tendency, because we can only sample intermittently, to perhaps not appreciate what the real tempos of some of these disease states are," he told ProteoMonitor, citing research by his team that looked at troponin values in heart failure patients and showed that troponin elevations were typically associated with short-term detrimental effects.

This raises the question, Jaffe said, of "whether things like heart failure, which we've presumed progress in slow, non-stepwise chronic fashion, actually progress in stepwise fashion in discrete events."

"If that were the case, and we could characterize those discrete events, then one potentially could develop interventions either at the time of those events or to prevent those events with the idea of improving patient care long-term and preventing the progression of heart failure," he said.

The researchers' sensor for cumulative biomarker exposure "conceptually is extremely attractive," Jaffe said, adding that it could potentially be used for a range of purposes, including monitoring heart attack patients immediately after the occurrence and long-term monitoring of high-risk patients.

He also suggested that so far as cardiovascular indications are concerned, the researchers should focus on optimizing the device for troponin detection and drop myoglobin and CK-MB, which, he said, tend to be less reliable biomarkers.

Troponin is a well known marker of cardiac tissue damage often used in acute settings to diagnose heart attacks. It has been less useful for long-term monitoring, however, because of the difficulty in measuring it at low enough concentrations to establish a baseline for healthy subjects.

In December, however, biotech firm Singulex announced it had been granted a US patent related to measuring the protein on its Erenna single-molecule immunoassay platform (PM 12/17/2010). The company, CEO Philippe Goix told ProteoMonitor, hopes that the platform's high sensitivity will make using troponin for long-term monitoring practicable.

The nanoparticle sensor could likewise be useful for measuring low abundance proteins, Cima suggested, noting that because many biomarkers exist in blood "at very low concentrations, instantaneous measurements are difficult with any degree of certainty. If you had an integrating sensor measuring the exposure accumulated over a period of time, that might allow you to turn those low levels into something clinically useful."

"From a clinical perspective, cumulative measurements are sought after," he said. Diabetics, for instance, "are constantly watching their blood glucose, but from a physician's point of view when they walk into the office blood glucose is irrelevant. What they look at is their glycosylated hemoglobin because that's a better measure of what their blood glucose has been over, say, two months."

The sensors are roughly the size of a grain of rice and could in theory be placed under a patient's skin and then read using an MRI wand waved over the device, Cima said. In terms of using them for long-term monitoring, the main obstacle is developing capture agents stable enough to remain active for months or years.

"The typical half-life for an antibody is six weeks. So it really has to do now with the chemical stability of the high-affinity moiety that we're using," he said. In addition to antibodies, the researchers are also looking into capture agents like aptamers, which might offer improved stability.

The scientists have applied for patents on the technology involved in the device, Cima said, but haven't yet started any work to commercialize it.

Several corporate research efforts into devices for measuring cumulative biomarker levels are also underway, Jaffe said, however he declined to name any of the companies involved.


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