By Virginia Baldwin Gilbert
Of the Post-Dispatch

June 10, 2002

Nanobots, nanochips, nanotubes -- they sound like so much science fiction. But researchers and venture capitalists alike believe nanotechnology holds real promise.

The name comes from the scale -- a nanometer is one-billionth of a meter. In other words, a nanometer is to an inch as an inch is to 400 miles.

Nanotechnology seeks to replace the functions of ordinary things -- such as a computer chip, a mechanical device or a pill -- with one complex molecule.

"Single molecules, when organized into multiples, give us new structures with new properties," said George W. Gokel, head of the division of bio-organic chemistry at Washington University. Nanotechnology researchers are discovering that "we can use individual molecules to do things that engineered devices used to do."

And near the top of the list are nanopills, molecule-sized packages of medicine or other medical treatment. Researchers at the University of Missouri at Columbia and at Washington University are among the scientists who are working on chemical structures that could deliver drugs or remove unwanted material from the body at that tiny scale.

Each lab is collaborating with pharmaceutical companies, whose identities must be kept confidential. And each hopes to enter animal trials soon on a substance and process that could revolutionize the drug industry -- if it pans out.

The technology could hold the key to medical treatment at the cellular and molecular level, targeting problems, such as cancer, cystic fibrosis or high cholesterol, without side effects.

"We have a particle that's about 2 to 4 nanometers in diameter, and it has a drug substance inside it," said Jerry Atwood, chairman of the chemistry department at MU. He's working on programming the particle to go to a specific site where the drug would be needed.

"Or take the opposite approach," said Karen Wooley, a professor of chemistry at Washington University. "We're looking at using nano structures as containers to pick up something," such as excess cholesterol.

Both research labs are developing nano-sized containers, using the body's chemistry to aid the process.

The technology is "clearly something quite valuable, which is being looked at very closely by both industry and the business development community," said Michael Douglas, director of Washington University's Center for Technology Management.

Simple chemistry

Atwood says his research on drug delivery is really a question of "how you could enclose space." And that involves principles that have engaged scholars for thousands of years.

He combines the latest discoveries about viruses with traditional chemistry of the last 100 years and principles of geometry that date back to Plato in 380 B.C.

Few people think of Plato as a biologist, but "when Plato was putting together triangles, he couldn't know that at that time, nature had already addressed that question," Atwood said.

Plato and Archimedes described three-dimensional objects that could be made from equal-sided squares, triangles or pentagons. "All the things we've learned from the structure of viruses turn out to be nature's way of using the principles of Plato and Archimedes," Atwood said.

His lab has concentrated on finding square- and triangular-shaped molecules that would bind together in a hollow structure. He chose the snub cube -- made up of six squares and 32 triangles.

To be useful for drug delivery, the structure or capsule must act the same way gelatin does when it encloses a pill: It must not affect the medicine inside, it must get through the body to the point where it is needed, and then it must break apart and release the medicine.

Atwood's molecule is held together with chemical bonds common in organic chemistry. It is basically six parts that come together when heated. Whatever substance is in solution with the six parts when they join gets enclosed.

Another task is to get the drug-containing molecule to the right site in the body. Atwood describes the outer surface of the molecule as having "appendages" that reach out, seeking certain matching substances to grab onto.

"We can modify this delivery system in 24 ways," Atwood said. "We have 24 sets of hands on the outside" groping their way through a solution or the bloodstream, looking for just the right spot.

"Weak interactions are key," Atwood said. As the appendages feel along, one or another may tentatively bind to something. But if all of them don't latch on, the parts stay together and the molecule moves on.

When all the appendages of a molecular capsule have found a point of attachment, they let go of each other and bind to the new site. The molecule breaks apart, and the drug inside is released, Atwood said. "It's really simple chemistry."

Atwood has been refining his idea since he first published the concept in 1997. He has three patents pending.

Still to be tested is whether the capsule would be safe and effective as an oral medication. It survives stomach acid in the lab but has not yet been tested on animals or people.

"We have enough of these pieces of the puzzle now that I can see this happening," Atwood said. "There are ways that individual capsules might fail, but I don't see where the concept can fail."

He said he is working with a pharmaceutical company that has "a drug that's a blockbuster."

"The least I'd like them to do is license our technology for their drug," Atwood said. "But I would really like them to understand the concept and be willing to team up and use (the technology) for a wide range of drugs."

Atwood believes his molecular capsule -- his nanopill -- could bypass the parts of the body where unwanted side effects occur and deliver the drug directly to the site needing treatment, whether it's killing a cancer cell, soothing an aching muscle or replacing a necessary enzyme or protein.

Dumpling-shaped viruses

Wooley's research team works on molecules about 50 times larger than Atwood's snub cube.

Where Atwood is developing ways to deliver small-molecule drugs, Wooley is working on relatively larger stuff -- if you can call 100 nanometers large.

"Our particles in many ways resemble biological macro molecules -- lipoproteins, proteins, viruses," Wooley said. "We're taking drug delivery beyond small molecule-drugs to delivery of genes and large molecules, such as proteins. For that, you have to have a container of similar size."

Like Atwood, Wooley is studying the example of viruses, which assemble themselves and roam through the body, invading cells and forcing them to make more viruses.

Scientists have begun using viruses for gene therapy, inserting a desirable piece of genetic material into the virus and releasing it into a person's body in hopes that the virus will transfer the material -- and the trait -- to the person's genetic code.

But the treatment is risky. Viruses don't behave predictably, and some people have died when treatment didn't go as planned.

One big goal of her research "is to make a synthetic version of a virus, so we could turn it on and off," Wooley said. "We wouldn't run into the same risks that reconstituted viruses have."

When she first published scientific papers about the molecules she works with, Wooley called them "knedels" (kuh-NED-els), because a member of her lab thought they looked like Polish stuffed dumplings.

"Maybe we call them that around the lab," said Matthew Becker, a graduate student in Wooley's lab. "But if we publish anything, it's 'shell cross-linked nanoparticles.'"

Gene therapy is exerting the big push for such particles right now, especially to treat cystic fibrosis and some forms of diabetes.

"We're not the only people working on this," Becker said.

And that means they don't want to talk about exactly what they're researching or how their processes work or what collaborations are being formed.

"We're an academic lab," Wooley said. "We're only just now beginning to explore viable applications. So far, most of what we've been studying has been working quite well. But a lot of it I can't talk about. We're in collaboration with companies and throwing around the idea of starting up a company."

The potential is immense, says Douglas, the Washington University official working with Wooley to transfer the technology to the marketplace.

"It's all very early stage," Douglas said. "But there's great interest among the big players in the (pharmaceutical) industry and various people in the St. Louis community, to maybe take that nascent technology and put a company together around it."