Researchers creating 'magic bullet' to target
heart attacks, stroke

By Darla Brown

The day when a nanoparticle is injected into your vein, travels to your heart, identifies a potential fatal problem, attaches itself to it, and releases drugs to zap it, is not far away, according to researchers in the Medical School’s Division of Cardiology.

“This has been the dream of doctors and scientists for 100 years,” says Melvin Klegerman, Ph.D., associate professor of cardiology. “This magic bullet technology will widen the therapeutic window by delivering drugs with maximum efficacy and minimum toxicity.”

The agent being tested for this seemingly “Incredible Voyage”-like science is called a liposome – a miniature spherical vesicle that can be chemically coupled with proteins to target any structure in the body. With studies limited to animals at this time, Medical School researchers are looking at myriad functions for this tiny tool, including diagnostics, delivering targeted drug therapies, and using ultrasound in therapeutic applications.

Hunting for heart plaque

“We’re using liposomes as a smart tracer to diagnose disease and highlight vulnerable plaques,” says Susan Laing, M.D., associate professor of cardiology.

Vulnerable plaque is the soft, fatty plaque in the arteries that ruptures and kills via acute stroke and heart attack – 40 percent of the U.S. population is at risk.

“People think that it is the narrowing of the arteries due to buildup that is causing the trouble, but it is the composition of plaque not the severity of the clogged arteries that is the real danger,” Dr. Laing explains.

Seventy percent of heart attacks started at less than 50 percent stenosis (narrowing of the artery), and vulnerable plaque causes 85 percent of the heart attacks and strokes.

“The majority of 18 year olds already have plaque forming in their arteries, and with the growing incidence rate of obesity and diabetes, the prevalence will increase,” says Dr. Klegerman, who as a protein chemist has collaborated more than 15 years with the research group of Dr. David McPherson, director of the Division of Cardiology since June 2006.

Furthermore, “the artery walls remodel, so finding no significant narrowing of the artery may not mean that there is no coronary artery disease. Using newer imaging technology to evaluate plaque burden and high risk or vulnerable plaques has been a major cardiovascular focus,” Dr. Klegerman explains.

Currently there is no good, readily available device to detect vulnerable plaque. Physicians must rely upon traditional risk factors, imaging tools such as CT or MRI, or an invasive technique, intravascular ultrasound, which although effective is not as widely available. Blood tests for C-reactive protein also can be done to determine inflammation levels in the body as an indicator for vulnerable plaques.

“Our ultimate goal would be that a patient would come into a cath lab, or an imaging lab, and that vulnerable plaques could be diagnosed and treated via liposome technology and ultrasound before the occurrence of symptoms,” Dr. Laing says.

Employing the power of ultrasound

Making its way to the vulnerable plaque through the arteries of the heart, specially formulated liposomes loaded with plaque-fighting drugs have been created with a very important property – they are echogenic – meaning that they reflect ultrasound.

“These liposomes are very efficient when exposed to ultrasound. We are using ultrasound as a therapeutic modality not just a diagnostic instrument as liposomes can release their compounds when exposed to ultrasound,” Dr. Klegerman explains.

“In fact, the first ultrasound was used for therapeutics as a heating modality, not for diagnostics,” Dr. Laing adds. “We are just harnessing the potential of ultrasound for therapeutics as our liposomes can be used as a cavitation agent – releasing energy when a bubble bursts. When applied properly, this has a lot of potential for treatment.”

For the patients

Such a tool to not only diagnose but deliver therapies could be a powerful weapon in the war against the number one killer of Americans – heart disease.

“Using liposome technology, there are three patient populations that would benefit – asymptomatic patients at risk for coronary artery disease or stroke; those who have developed the condition and are already under treatment to see if they are responding; and those undergoing a clinical trial for medical treatment to be used as a surrogate endpoint,” says Patrick Kee, M.D., assistant professor of cardiology.

Presently, patients with vulnerable plaque are prescribed statin drugs to help in lipid lowering.

“We find that patients who have coronary heart disease have plaque buildup everywhere and therefore would need systemic therapy. However, additionally targeting high-risk plaques may be important so that we can deliver specific drugs exactly where they need it to be most effective,” Dr. Kee says.

In addition to new therapies, new diagnostics would be welcomed by physicians.

“Diagnostics are great tools – if I can show a patient that they have a vulnerable plaque, then I can convince them to modify their diet and exercise,” Dr. Kee says.

“It’s a great motivator for a patient to see a before and after test,” Dr. Laing adds.

Dr. Kee says that preventive measures also are important to stress to patients.

“We should focus on preventive measures even though we have effective therapies – I would label such therapies as palliative, extending the survival, not modifying the natural history of condition,” he says.

The future of liposomes

Such a therapy to diagnose and treat vulnerable plaque could greatly reduce mortality and morbidity not only in heart attack patients but also in stroke patients, as the UT researchers have been collaborating with a group of biomedical engineers at the University of Cincinnati, whose major interest is stroke. Cancer also is a potential focus of liposome technology.

The Division of Cardiology is an active research group and has two major National Institutes of Health grants to further their liposome research – one in the diagnostic area and one for gene and drug delivery, as well as a collaborative NIH grant on stroke with Christy Holland, Ph.D., from Cincinnati. In addition, they are funded through the American Heart Association and have other grants to further this burgeoning field of translational research.

A clinical trial to move this technology from animals to people is the current goal.

“This technology is at least five years out,” Dr. Laing says. “We have a niche in this field of using liposomes as a delivery agent for drugs, and we’ve only just begun to explore their potential for therapeutics.”