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A Better Toxicity Test for Drugs

A device that can reveal if compounds are toxic to living cells could be a fast and accurate way to detect liver toxicity.

A new method of sensing slight changes in the structure of liver cells, based on the way they scatter light, could provide a faster, more efficient way to test the toxicity of drugs and the harmful effects of environmental pollutants.

Rat liver cells placed on a porous silicon chip light up (b) as they die from a toxic dose of acetaminophen (Tylenol). (Courtesy of Sara Alvarez, Austin Derfus and Michael Schwartz, UCSD.)

Liver toxicity is the most common reason for manufacturers to withdraw drugs and for the Food and Drug Administration to refuse approval of new drugs. Indeed, one-third of all drugs fail clinical trials because of such toxicity. What’s more, current in-vitro toxicity tests are tedious and complicated, because researchers have to periodically look at the cells under a microscope or insert a fluorescent dye into the cells genetically. Moreover, existing tests frequently use chemicals that kill the cells, so that researchers have to use a number of different cell cultures during a study, which affects the result.

The new device was developed by Michael Sailor, professor in the department of chemistry and biochemistry at the University of California, San Diego, and Sangeeta Bhatia, associate professor in the department of health sciences and technology and the department of electrical engineering and computer science at MIT. It consists of a porous silicon chip on which cells can live for days, and an inexpensive charged-coupled-device detector like those found in digital cameras. It can continuously monitor living cells and indicate earlier than current tests whether a compound is harming the cells, based on how much light they reflect (paper abstract).

The researchers create the porous substrate by placing silicon chips in hydrofluoric acid and passing an electric current through the solution. This forms cylindrical wells a few hundred nanometers in diameter on the surface. The tiny wells make the porous silicon reflect light at a sharp frequency, a well-known property not seen in regular silicon. The researchers can engineer the pores to control the frequency.

Next, the researchers cover the chip with polystyrene to make a surface similar to a Petri dish. When cells are placed on the surface, they scatter the reflected light, decreasing the intensity of light falling on the detector. As the cells wither or die, their structure changes, which increases the intensity of light at the detector. “The cells light up like little lighthouses when they die,” says Sailor.

In the lab, the researchers placed rat liver cells on the chip and treated them with toxic doses of cadmium and the pain-killer acetaminophen. They found that the sensor detected changes in the cells at least two hours before conventional tests. They plan to test the device with human liver cells soon.

Others are impressed by how early on the device appears to detect toxicity in the cells. “When some traditional ways would not give a reading yet, this method already shows the toxic effect,” says Erkki Ruoslahti, who studies cell biology and cancer at the Burnham Institute for Medical Research in La Jolla, CA. “This may give a quick, high-throughput answer in a shorter time and with much less effort.”

Sailor says that the simple technique could save pharmaceutical companies time and money because they could eliminate toxic compounds early in the drug-testing process. “It’s a tool to speed up the process of drug discovery,” he says, adding that it would augment current cellular tests.

Right now, scientists screen new drugs before human trials with in-vitro tests on rat liver cells. In these tests, they introduce the drug into liver cells grown in Petri dishes placed in incubators. At regular time intervals, they have to analyze the cells under microscopes, to find out how many cells are dead. To do that, they must add chemicals that either modify or kill the remaining cells. Furthermore, every experiment needs hundreds of Petri dishes and cell cultures, adding to the cost. “You’d rather make measurements in real time, and instead of pulling a dish out every half hour, have something monitoring cells in the incubator,” Sailor says.

Jonathan Dordick, professor in the department of chemical and biological engineering at the Rennselaer Polytechnic Institute, says the technique’s big advantage is that it can monitor a toxin’s gradual effect on cells. “This is useful because many compounds are not immediately toxic,” he says. It allows, he suggests, a simple way to follow the health of the same group of cells over time without altering or killing them.

Furthermore, Sailor says the new device could allow multiple experiments simultaneously. A quarter-sized porous silicon chip could contain up to 10,000 different test sites, each made to reflect light at a specific frequency. One could then put small bunches of cells on the sites and test the toxic effect of various toxin concentrations or drug combinations.

The team has a research agreement with the Hitachi Chemical Research Center in Irvine, CA, which will attempt to commercialize the technology.

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