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Researchers fling nano-weapons at lung disease

By Evelyn Boswell

Lungs, like loyal soldiers defending their borders, have dual duties that have long fascinated Allen Harmsen, head of Veterinary Molecular Biology at Montana State University.

Not only do they stave off invaders like diesel fumes or the unrestrained germs of a winter cold, but they also have to avoid friendly fire while doing so. The lungs, in other words, sometimes try so hard to fight intruders that they overreact and hurt themselves more than the enemy would have. Think of the asthmatic attacks where the response to pollen is more dangerous than the pollen, or the inflammation that's scarier than the cigar smoke.

Approximately 70 percent of acute human ailments begin in the lung.

"What's always amazed me about the lung is having to deal with this problem of being such a frequent site of infection, but still needing to protect itself from damage as a result of its response to infection," said Allen Harmsen who worked at the Trudeau Institute for 15 years before coming to MSU. The institute, in upper New York state, is well known for its research into tuberculosis.

Approximately 70 percent of acute human ailments begin in the lung, according to Harmsen. That would be bad enough, but the lung contains highly delicate tissue. It's a vital organ that has to function at all times.

"It can't shut down temporarily for infection like some of the other organs," Harmsen said. "The delicate structure of the lung has to remain intact for the lung to function."

Doctors typically treat lung infections by sending antibiotics into the blood stream, Harmsen explained. That means the medication travels throughout the body and can affect other organs and areas. Physicians sometimes try to minimize side effects by administering lower than optimum doses.

So what would happen if a scientist could design a tiny specialist to dash onto the lung's battlefield without having to stop first at an out-of-the-way heart or off-road kidneys? What if the diminutive doctor could carry a full dose of medication directly to the infection or inflammation?

Allen Harmsen The majority of acute human ailments begin in the lung, giving veterinary molecular scientist Allen Harmsen purpose in the research lab. (photo Erin Raley)

That's what Harmsen and other MSU researchers are trying to do with the help of nanotechnology and their knowledge of immunology, inflammation and cell targeting. They want to take the ultraminiature containers that the Center for Bio-Inspired Nanomaterials produces by cloning a protein gene into bacteria or yeast. Then they want to fill those containers with antibodies or anti-inflammatory material and attach proteins that will guide the containers to specific tissues that are inflamed or infected.

"It holds tremendous promise, but it's definitely going to be a research adventure," said Mark Jutila, who sees the project as an extension of what he's doing now in veterinary molecular biology. Jutila was part of the team that applied to the National Heart, Lung and Blood Institute for a grant to support this work. The institute had asked researchers to submit proposals for a project called "Local Pulmonary Delivery of Drugs by Nanoparticles." If MSU receives the money, the research team will initially include Harmsen, Jutila, David Pascual and Mark Quinn in veterinary molecular biology; Mark Young in plant sciences; and Trevor Douglas and Brian Bothner in chemistry. Their specialties will be lung biology for Harmsen, tissue targeting for Jutila and Quinn; nanotechnology for Young, Douglas and Bothner; and immunology for Pascual.

Even if MSU doesn't win the grant, the researchers said they'll continue the work they're already doing in this area. It's funded now with developmental money from MSU and money from the Department of Defense. They'll turn to other sources, too, Jutila said.

Their idea for treating lung diseases with nanoparticles looks promising, the researchers added.

"I'm not doing the nanotechnology, but from what it sounds like, it sounds very doable," Jutila said. "The delivery of compounds is a real thing."

Jutila's job will center on the compounds that could ride in the containers. MSU already has a compound called EL-246 that's highly effective at inhibiting lung inflammation, Jutila said. MSU generated EL-246 in the 1990s, and LigoCyte Pharmaceuticals of Bozeman holds the license. Jutila will explore the potential of other anti-inflammatory compounds and antibodies, as well.

"The thing that we hope to be able to do is really control it so the delivery is done in a very precise controlled manner," Jutila said. "The whole goal is to increase efficiency."

Harmsen said one challenge will be to engineer the compounds so they won't trigger dangerous responses from the immune system.

Pascual's efforts will concentrate on the protein particles that could be attached to the outside of the containers. He is researching answers to such questions as: How can they guide the containers so they deliver vaccines to the right spot, for example? Which materials can do the job now and which can be modified to target the proper tissues? How can scientists trick the host's immune response into not attacking the courier?

Douglas said the Center for Bio-Inspired Nanomaterials has already made containers, nanomaterials, that could be used in the project, loaded them with drugs or fluorescent imaging agents and followed them through the lungs of mice. Can the researchers go from there and attach a protein that will guide the containers to a specific tissue where they will unload their cargo?

"We're pretty close actually," Douglas said. "Independently, we can do these things, but putting them all together is the next challenge."

"It holds tremendous promise, but it's definitely going to be a research adventure."

The tests will be conducted first in mice, then in larger animals. Eventually, "If everything goes swimmingly well," Douglas said, "we will go into humans."

The project, if successful, should lead to an easier life for people who suffer from any number of inflammatory diseases, the researchers said. Asthma, bronchitis, emphysema all involve unwanted inflammations. So does arthritis.

"It's something I think really has a lot of potential," Harmsen said.



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