New Biosensor Microchip Could Speed Up Drug Development

The microchips, stuffed with highly sensitive "nanosensors” analyze how proteins bind to one another, a vital step for assessing the effectiveness and possible side effects of a potential medication.

A 1-cm-sized array of the nanosensors can monitor simultaneously and continuously thousands of times more protein-binding events than any existing sensor. The new sensor is also able to detect interactions with greater sensitivity and deliver the results significantly faster than the present gold standard method.

"You can fit thousands, even tens of thousands, of different proteins of interest on the same chip and run the protein-binding experiments in one shot,” said Dr. Shan Wang, a professor of materials science and engineering, and of electrical engineering, Stanford University (Stanford, CA, USA), who led the research effort.

"In theory, in one test, you could look at a drug's affinity for every protein in the human body,” said Richard Gaster, MD/PhD candidate in bioengineering and medicine, who is the first author of a paper describing the research that is in the April 2011 issue of Nature Nanotechnology, also available online.

The power of the nanosensor array lies in two advances. First, the use of magnetic nanotags attached to the protein being studied--such as a medication--greatly increases the sensitivity of the monitoring. Second, an analytic model the researchers developed enables them to predict accurately the final outcome of an interaction based on only a few minutes of monitoring data. Current techniques typically monitor no more than four simultaneous interactions and the process can take hours.

"I think their technology has the potential to revolutionize how we do bioassays,” said Dr. P.J. Utz, associate professor of medicine (immunology and rheumatology) at Stanford University Medical Center, who was not involved in the research.

Members of Dr. Wang's research group developed the magnetic nanosensor technology several years ago and demonstrated its sensitivity in research in which they demonstrated that it could detect a cancer-associated protein biomarker in mouse blood at a thousandth of the concentration that commercially available techniques could detect. That research was described in a 2009 paper in Nature Medicine.

The researchers customized the nanotags to attach to the particular protein being studied. When a nanotag-equipped protein binds with another protein that is attached to a nanosensor, the magnetic nanotag alters the ambient magnetic field around the nanosensor in a small but distinct way that is sensed by the detector.

"Let's say we are looking at a breast cancer drug,” Mr. Gaster said. "The goal of the drug is to bind to the target protein on the breast cancer cells as strongly as possible. But we also want to know: How strongly does that drug aberrantly bind to other proteins in the body?”

To establish that, the researchers would put breast cancer proteins on the nanosensor array, along with proteins from the liver, lungs, kidneys, and any other kind of tissue about which they are concerned. Then they would add the medication with its magnetic nanotags attached and see which proteins the drug binds with--and how strongly. "We can see how strongly the drug binds to breast cancer cells and then also how strongly it binds to any other cells in the human body such as your liver, kidneys, and brain,” Mr. Gaster said. "So we can start to predict the adverse affects to this drug without ever putting it in a human patient.”

It is the increased sensitivity to detection that comes with the magnetic nanotags that enables Mr. Gaster and Dr. Wang to determine not only when a bond forms, but also its strength. "The rate at which a protein binds and releases, tells how strong the bond is,” Mr. Gaster said. That can be an important factor with numerous medications. "I am surprised at the sensitivity they achieved,” Dr. Utz said. "They are detecting on the order of between 10 and 1,000 molecules and that to me is quite surprising.”

The nanosensor is based on the same type of sensor used in computer hard drives, Wang said. "Because our chip is completely based on existing microelectronics technology and procedures, the number of sensors per area is highly scalable with very little cost,” he said.

Although the chips used in the research described in the Nature Nanotechnology paper had a little more than 1,000 sensors per square centimeter, Dr. Wang stated it should be no problem to put tens of thousands of sensors on the same footprint. "It can be scaled to over 100,000 sensors per centimeter, without even pushing the technology limits in microelectronics industry,” he said.

Dr. Wang reported that he sees a promising future for increasingly powerful nanosensor arrays, because the technology infrastructure for making such nanosensor arrays is in place. "The next step is to marry this technology to a specific drug that is under development,” he concluded. "That will be the really killer application of this technology.”

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