Microchip speeds up drug development

STANFORD (US) — A microchip packed with highly-sensitive nanosensors could significantly accelerate the drug development process.

A single centimeter-sized array of the sensors are able to continuously monitor thousands of times more protein-bindings, a critical step for evaluating the effectiveness and possible side effects of a potential medication.

“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,” says Shan Wang, professor of materials science and engineering, and of electrical engineering, at Stanford University.

“In theory, in one test, you could look at a drug’s affinity for every protein in the human body,” says Richard Gaster, PhD candidate in bioengineering and medicine, and first author of a paper that is published online in the journal Nature Nanotechnology.

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 analytical model the researchers developed enables them to accurately predict 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.

“Their technology has the potential to revolutionize how we do bioassays,” says P.J. Utz, associate professor of immunology and rheumatology at Stanford, who was not involved in the research.

Researchers developed the magnetic nanosensor technology several years ago and demonstrated its sensitivity in experiments in which they showed 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 nanotags are tailored to attach to the particular protein being studied, so 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,” Gaster says. “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 determine that, the breast cancer proteins are placed on the nanosensor array, along with proteins from the liver, lungs, kidneys, and any other kind of tissue that they are concerned about.  The medication is then added with its magnetic nanotags attached to 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,” Gaster says. “So we can start to predict the adverse affects to this drug without ever putting it in a human patient.”

The increased sensitivity to detection that comes with the magnetic nanotags allows researchers 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,” Gaster says. That can be an important factor with numerous medications.

“I am surprised at the sensitivity they achieved,” Utz says.  “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 explains. “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.”

Although the chips used had a little more than 1,000 sensors per square centimeter, 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,” Wang says.

“The next step is to marry this technology to a specific drug that is under development. That will be the really killer application of this technology.”

Funding for the research came from the National Cancer Institute, the National Science Foundation, the Defense Advanced Research Projects Agency, the Gates Foundation, and National Semiconductor Corporation.

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