Medical Device Daily National Editor

Drugs are wonderful things — at the right place, at the right time ... and with no toxicities or other side- or after-effects. And these qualifying requirements create maze-like barriers which are poorly solved in many cases with a pill or tablet, or even an injection.

This therefore provides opportunities for new device technologies to produce real efficacy, with one of the more novel strategies being pursued by researchers at Emory University (Atlanta) and the Georgia Institute of Technology (Georgia Tech; also Atlanta).

They noted previous research demonstrating the use of experimental anti-inflammatory medications injected into the heart to reduce damage following myocardial infarction, but always accompanied by significant toxicities.

Michael Davis, assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, told Medical Device Daily that the primary goal of his team's research was to reduce the toxicities associated with SB239063, an experimental anti-inflammatory.

Their method for doing this: a single injection of micron-sized particles, those particles embedded with anti-inflammatory drugs, the beads then absorbed and carried away by natural bodily processes.

In this proof-of-concept study, they used rats, injecting the microparticles following simulated heart attacks. The results showed that the procedure resulted in significant reduction of inflammation and scarring of the heart and boosting its ability to pump blood several weeks later.

Davis is senior author of a study using the microparticle approach, appearing in the online edition of Nature Materials and set for publication in its October/November issue.

"We noticed, and read in the literature and previous studies, other groups had used injections into the heart to see if they could get enough of these drugs there. They did things like direct injections twice a day, for weeks at a time."

But he said that the method came with significant systemic toxicities, making the method of delivery impractical. "There are clear issues if the whole body is exposed to the drug."

As an alternative, Davis and graduate student Jay Sy turned to microscopic particles made of a material called polyketals, developed by co-author Niren Murthy, PhD, assistant professor of biomedical engineering.

The microparticles break down over a few weeks in the body, releasing SB239063. The drug has been shown to inhibit MAP kinase, an enzyme which is important during the damaging inflammation that occurs after a heart attack.

When the particles were injected into rats' hearts, the researchers could see an inhibition of the MAP kinase enzyme lasting for a week. However, the effect on heart function was greater after 21 days. Davis says this result suggests that the main way the particles helped the heart was to prevent the scarring that sets in after the initial tissue damage of a heart attack.

He said the drug gradually leaches out of the polyketal particles, half gone after a week of just sitting around in warm water. In addition, the microparticles are broken down by white blood cells called macrophages.

In their work with rat hearts, he said the goal was to get directly to the specific cells of the heart musculature "because they're involved in the inflammatory response in the heart. The macrophages can surround and eat the particles, or fuse together if the particles are too big."
According to Davis, the polyketals have an advantage over other biodegradable polymers: they break down into neutral, excretable compounds that aren't themselves inflammatory.

Polyesters such as PLaGA (polylactic-co-glycolic acid) are approved for use in sutures and grafts. But he says that when they are made into particles small enough to be broken down in the body, polyesters cause inflammation — exactly what the drugs are supposed to stop.
Davis said that the polyketal particles offer a degree of flexibility that provides a platform opportunity for a variety of uses.

"You can control the size" — basically from 10 to 20 microns — "and the hydrolysis rate, to alter the release rate [and change] how quickly they degrade. They can be made to have a lot of different properties."

Davis said that the next step in their heart therapy work will be to use the microparticle approach in larger animals, primarily pigs. That could take, he estimated, another two years of work.

In humans, he said that the microparticles could be injected using current catheter technologies.

Though he said he couldn't predict when the approach might be used in human trials, Davis put the current development of the concept — from first idea (a 1) to clinical use in humans (at 10) — at a 5.

Davis said he and Murthy also are exploring the method for delivering drugs or proteins in other organs, such as the liver, lungs and spinal cord.

The research was funded by EmTech Bio (Atlanta), a support program for affiliate companies of Emory University and Georgia Tech; the National Science Foundation; the National Institutes of Health; the Department of Homeland Security; and Johnson & Johnson (New Brunswick, New Jersey).