The UPS Man

David McPherson and his colleagues are working to dramatically improve the capacity and precision of drug delivery mechanisms.

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By Daniel Oppenheimer
Editor, Texas Health Journal

 
 

“Researchers have found ways to cure, or markedly improve the prognosis of, almost any disease,” says Dr. David McPherson. “Many cancers. Most types of heart disease. But in most instances it is impossible to deliver to patients the quantities of therapeutics needed to cure or alter the disease. These super-high doses cause terrible side effects or can even kill the patient. Therapeutic development is mature. Therapeutic delivery is not.”

In the gap between the two, says McPherson, Chair of the Department of Internal Medicine at the UTHealth McGovern Medical School, lies extraordinary potential for improving and saving lives.

“Think about chemotherapy drugs,” says McPherson, who is also Director of the Division of Cardiology and Principal Investigator of the Clinical Center for Translational Sciences at UTHealth. “When we inject chemotherapy drugs into the bloodstream, about one percent of the drugs ends up going to the part of the body where the cancer is. The other 99 percent goes to the rest of the body, where it can do a lot of damage.”

It can go to the liver, where it creates liver toxicity. It can go to the skin, making people lose their hair or skin. It can go to the stomach, and make people very  sick. It can go to the heart and cause major heart problems. Such imprecision, says McPherson, is the rule not just with injectable drugs, but with pills, inhalants, and every other method of drug delivery. To treat is often to harm as well.

What’s needed are new, better, more universal ways to get drugs where we need them and keep them away from where we don’t.

One of the solutions, on which his team has been working for more than 20 years, is a class of carriers called echogenic liposomes. They are essentially tiny submarines, with an outer lipid shell, that carry different types of substances and can travel through the bloodstream. The lipid superstructure keeps the drugs contained, protecting the body from their potentially toxic properties, until they reach the problem site. At that precise point, targeted ultrasound waves can pop open the shells, releasing the drugs. The liposomes that are elsewhere in the bloodstream will remain intact, protecting the body from the toxic effects of the drugs, until they either pass out of the patient’s system or are released gradually enough to limit negative side effects.

“We are developing carriers that entrap therapeutics that can be delivered to all different parts of the body for therapeutic delivery,” says McPherson. “The NIH and other agencies know us as the UPS people.”

The method is designed to be adaptable to different types of drug delivery, to address different conditions. Possibilities include more precise delivery of SSRIs for depression and anxiety, antibiotics for infections, stem cells for traumatic brain injury, and chemotherapy drugs for cancer. One example on which McPherson and his colleagues have made particularly strong progress, in recent years, is a liposome that is designed to deliver xenon gas to the brain in the hours immediately after a stroke.

For reasons that are somewhat, but not wholly, understood by researchers, xenon is a “bioprotective” agent. It stabilizes all kinds of cells, including brain cells. In the aftermath of a stroke, when brain cells are damaged and blood flow to the brain is dangerously reduced, exposure to xenon has the potential to repair and sustain brain cells until blood flow returns to normal and other reparative mechanisms are able to engage.

The bioprotective qualities of xenon have been known for a while, but to this point, its therapeutic potential has been mostly unrealized. It is an expensive gas to obtain, and a tricky one to deploy inside the human body. It exists only in trace quantities in the air, and is typically collected as a byproduct when companies pull nitrogen and other gases out of the air. Unless small quantities can do the trick, there won’t be enough to go around. When you inhale xenon, however, most of the xenon disperses throughout the body. It’s not efficient.

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Inhaling xenon in too great quantities is also dangerous. When it attaches to blood cells, as it does after inhalation, it can crowd out oxygen.

“There was great hope for xenon inhalation as a treatment for stroke,” said McPherson. “In the animal lab, researchers were able to administer xenon through a gas mask, and could stabilize stroke. It failed, however, when translated to clinical trials. You had to increase the amount of xenon to such a high level that people asphyxiated.”

Xe-ELIP can be infused intravenously and ultrasound applied over the common carotid artery for ultrasound-triggered priminary Xe release from circulating Xe-ELIP into the brain .

Xe-ELIP can be infused intravenously and ultrasound applied over the common carotid artery for ultrasound-triggered priminary Xe release from circulating Xe-ELIP into the brain.

The hope for xenon containing echogenic liposomes (Xe-ELIP), which McPherson and his colleagues have been testing, is that they’ll be cheaper, more effective, and safer. As soon as possible after a stroke, providers would inject the liposomes into the bloodstream of the patient. They’d also attach a collar to the patient’s neck that would emit low-intensity ultrasound waves. When blood containing the liposomes passes through the carotid artery at the neck, the ultrasound will pop open the liposomes, releasing the xenon into the bloodstream right at the point it is entering the brain.

The result in animal trials has been that a vastly greater amount of the xenon goes to the brain, which cuts down on the amount needed to provide effective treatment. It’s also much safer than inhalation, since the liposomes don’t compete with oxygen in the bloodstream. Most importantly, the xenon in the liposomes reduces death and brain damage in the animals. It cuts way down on brain bleeding after hemorrhagic stroke, and on brain cell death.

The hope is that paramedics would be equipped with the liposomes and the ultrasound collar. They’d pick up someone suffering from a stroke, administer the xenon, and the extra few hours of brain protection would enable doctors at the hospital to conduct scans and determine the optimal treatment. The xenon treatment could even be administered multiple times if necessary. And because it’s so targeted, the quantity needed would be tiny.

“There is enough xenon available to treat most patients if you can give it in small quantities,” says McPherson.  It’s the difference between having enough xenon to treat 100,000 people or having enough to treat 10.”

The xenon-containing echogenic liposome is just one example, says McPherson, of the flexibility of liposomes as therapeutic delivery vehicles. Because the carriers can be engineered to carry different substances, and to have different external properties, he and his colleagues can respond to a wide variety of clinical opportunities. In addition to their stroke projects, they’re currently working on treatments for deep vein thrombosis (DVT), atherosclerosis, and stabilizing blood vessels after stent placement, among other conditions.

They are also exploring whether liposomes can be developed to hook on to specific cancerous tumors, which often express unique structures on their exterior. By designing liposomes that snag on those structures, they could concentrate the therapeutic in one area, and therefore increase the amount that could be delivered without increasing the toxicity for the rest of the body.

“In an animal you can cure almost any disease in the world, but then they die,” he says. “It’s the toxicity of what we do that kills the patient. We have to be smarter about how we get product into the body. We are getting smarter, but we’re not there yet.”