June 24, 2002 GAINESVILLE, Fla. --- Using what might be described as a biological machine, University of Florida and Finnish researchers have demonstrated an experimental process for drug purification that one day could speed the production and decrease the cost of prescription drugs.
The researchers created antibodies that recognized and attached to a cancer-fighting drug molecule. They installed the antibodies in almost unimaginably small silica tubes, known as nanotubes, arranged in a membrane. In an experiment reported Friday in an article in the journal Science, the "smart membrane" transmitted the drug molecule far faster than other molecules in a mixture.
"What's new here is that we chemists have borrowed a couple of pages from the natural world to demonstrate the potential for a new approach for purifying drugs," said Charles Martin, a UF professor of chemistry and the lead author of the article.
Drug makers use several techniques to make antibiotics, chemotherapy drugs and other widely used pharmaceuticals. A common method is to nurture and grow bacteria that produce the desired drug molecule in a mixture. The hitch is this mixture also may contain tens or hundreds of unwanted and potentially harmful molecules or materials, sometimes including the bacteria themselves. As a result, the drug has to be separated from the mixture, or purified, a slow and expensive process.
The workhorse technology now used for purifying drugs, called chromatography, involves letting the mixture flow slowly down a column. Different compounds descend at different speeds, so as a mixture drips down the column, its molecules separate into pure bands. The desired drug can then be captured as a purified band. The process requires considerable use of expensive solvents and also is difficult to use for large-scale production. As a result, researchers have for some time discussed replacing chromatography with a membrane that would automatically capture the desired drug.
"The idea is you don't need to put this stuff in big columns, you don't need to pour a bunch of solvents over it, you just have this smart membrane in contact with the mixture that knows what molecule it wants and goes and grabs it," Martin said.
Complicating the picture is that most drug molecules are produced in what is known as chiral pairs, with one molecule the mirror image of the other. Typically, only one of the two molecules is beneficial, while the other is benign or even harmful. Before a drug can go on the market, drug makers must either prove the mirror image or "enantiomer" molecule is harmless or find a way to remove it.
In the Science paper, Martin and colleagues, including two UF graduate students in chemistry and two researchers at VTT Biotechnology in Espoo, Finland, prove the concept for a membrane that would separate a drug molecule from its enantiomer.
As part of the increasing trend toward biomimetics, or mimicking biological solutions in industrial processes, the researchers' ideas came from biological chemistry. Martin said the Finnish researchers recognized that antibodies, which identify and attack pathogens in the body, are good at identifying and attaching to highly specific molecules. So they engineered an antibody that would attach to the drug in question, an experimental anti-tumor designed for the treatment of breast cancer and currently in clinical trials.
The scientists next needed a way to deploy the antibody so that it could be used to separate the drug molecule from its enantiomeric twin. For that, they turned to Martin, who is known for his pioneering research in the science of nanotubes. Made from a variety of materials, the inside diameter of these tubes is infinitesimal, with diameters as small as 15 to 20 nanometers possible (1 nanometer equals one-billionth of a meter, or three to five atoms across) Nanotubes have been the subject of widespread excitement for their potential in super fast computers and other developing technologies.
Martin has developed techniques to vary nanotubes' diameter and manufacture large arrays containing millions of tubes arranged in parallel lines. Cells use similar small tubes, he noted.
"The nanotube is important because Mother Nature does a whole bunch of her business with nanoscopic channel proteins," he said. "She uses them to control what molecules go in and out of cells and also in neural processes."
Martin and the Finnish researchers found a way to attach the antibodies, which measure approximately 5 nanometers, to the inside of the tubes. In tests, they showed that the antibodies latch onto the desired drug molecule and pass them along through the tube "like a bucket brigade," Martin said. The resulting flow of the sought after drug molecule through the membrane is five times faster than its twin enantiomer molecule, he said. In other words, the desired drug flows through the membrane faster, making it feasible to separate from it the undesired one.
The experiment proves the concept of "biologically active membranes," Martin said. For such membranes to become a useful tool in the drug-making industry, both the rate and volume of flow of the desired molecule through the membrane would have to be far higher, he said. The process could reach the industry within five to 10 years.
Chad Mirkin, a professor of chemistry and director of the Institute for Nanotechnology at Northwestern University, agreed the process shows long-term promise.
"It's a fascinating nanotechnology approach to a very difficult separation problem," Mirkin said. "If it could be scaled up, it could have enormous potential. It is too early to talk about potential commercial impact."
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