Since the announcement of their discovery in the early 1960s, carboranes — molecular clusters of carbon, boron and hydrogen that form three-dimensional polyhedrons — have been touted by scientists as potential drug-delivery game changers. Because carboranes are stable in air and water, are non-toxic, and can readily bind with organic material, they seemed perfectly suited to act as tiny but ridged scaffolds upon which medicinal molecules could be constructed and dispatched to rogue cells. Cancerous tumors were among the targets researchers were most keen on hitting.
For years technical hurdles slowed progress. More recent projects, however, have shown great promise. Count among these an investigation by Mark Lee Jr., an assistant professor of chemistry, and a team of researchers at MU.
In a study published in the August 12 issue of the Journal of Medicinal Chemistry, Lee and his team detailed how they had used carboranes to bolster the effectiveness of a drug that disrupts cancer cells’ energy production, thereby hastening their demise. “Carboranes don’t fight cancer directly,” Lee says, “but they aid in the ability of a drug to bind more tightly to its target, creating a more potent mechanism for destroying the cancer cells.”
When medicinal chemists talk about “binding,” explains Lee, they're referring to the process by which a pharmaceutical molecule attaches itself to targeted enzymes in sickly cells. The power of that binding represents a critically important indicator of a drug's potential effectiveness.
“Drugs could be described as a key that fits into a specific lock. In this case the lock is most typically an enzyme — a kind of protein that regulates a specific chemical reaction in the cell,” says Lee. “When a drug binds to an enzyme, it interferes with its activity, most often shutting it down.”
The tighter the binding, the more effective the interference, he adds. And when drugs bind more tightly, additional good things happen: dosage size can be reduced, side effects are minimized, and therapeutic effectiveness is enhanced.
In the Medicinal Chemistry study, Lee's carborane-aided drug was shown to bind 10 times more powerfully to nicotinamide phosphoribosyltranferase, the metabolism-boosting enzyme he sought to inhibit, than the carborane-free drug.
“The reason why these drugs bind stronger to their target is because carboranes exploit a unique and very strong form of hydrogen bonding, the strongest form of interactions for drugs,” Lee says.
“Too often, after radiation or chemotherapy, cancer cells repair themselves and re-invade the body,” Lee said. “This drug not only selectively shuts off the energy production for the cancer cells, but it also inhibits the processes that allow those cancer cells to repair themselves. When we tested our carborane-based drugs, we found that they were unimaginably potent. So far, we have tested this on breast, lung and colon cancer, all with exceptional results.”
This is the first study to show systematically how carboranes can improve the performance of a drug. Lee believes that within a few years the research will open additional possibilities of improving drugs that are used to treat other diseases, not just cancer.
“The end result,” he says, “is that these new drugs could be many thousands of times more potent than the drugs that are used in the clinics today.”