Plasmin Delivered with Ultrasound Bubble-Busting Technology More Effective Busting Clots Than TPA

A new study has revealed that when delivered with the use of ultrasound, the natural enzyme plasmin is more effective at dissolving stroke-causing blood thromboses than the current standard of care, recombinant tissue plasminogen-activator (rt-PA).

The innovative delivery technique involved snaring plasmin into bubble-like liposomes, delivering them to the clot intravenously and bursting it via ultrasound. That technique is necessary, according to University of Cincinnati (UC) College of Medicine (OH, USA) associate professor of emergency medicine George Shaw III, MD, PhD, because plasmin cannot be delivered through conventional techniques. Intravenous (IV) delivery of rt-PA is designed to resolve that hurdle by catalyzing the conversion of existing plasminogen inside the body to plasmin, which then degrades blood clots.

“Plasmin is the enzyme that actually chews up the fibrin in clots,” said Dr. Shaw. “The problem is you can only give plasmin interarterially, which has safety risks and takes longer to deliver. IV therapy is always easier and quicker, but if you give plasmin intravenously, the body inhibits it immediately. If you can encapsulate it, it doesn’t get inhibited and you can target it to the clot.”

Dr. Shaw and researchers Madhuvathi Kandadai, PhD, and Jason Meunier, PhD, in their in vitro study, enclosed plasmin and a gas bubble inside a liposome. They then delivered the liposome to a clot in an in-vitro lab clot model and dissolved it using ultrasound waves, thereby delivering the plasmin enzyme to the clot. Thromboses treated with plasmin, after 30 minutes, demonstrated considerably greater degradation than clots treated with rt-PA. They worked with colleague Christy Holland, PhD, professor in UC’s cardiovascular diseases division, to develop the technique. As director of the Image-guided Ultrasound Therapeutics Laboratories at UC, Holland has evaluated the use of liposomes and ultrasound to deliver drugs in a less invasive, more targeted manner.

The standard of care for acute ischemic stroke is intravenous (IV) delivery of US Food and Drug Administration (FDA)-approved rt-PA within three hours of stroke onset. Ischemic stroke is the most typical type of stroke, accounting for approximately 87% of all strokes.

However, Dr. Shaw noted that there is a critical need for a safer and more effective thrombolytic, as rt-PA carries a risk of hemorrhaging. Intracranial hemorrhage currently occurs in 6% of patients receiving rt-PA therapy. “Previous in vivo studies have demonstrated better safety of plasmin as compared with rt-PA,” he said. “Currently, intra-arterial plasmin is undergoing clinical trials. Our next step is to work on targeting the liposome by putting antibodies on its surface that will stick it to the clot. We also want to improve the efficiency of encapsulating the plasmin in the liposome. Right now, about 15% of the plasmin gets into the liposome—we’re aiming for 50%.”

Dr. Kandadai, a postdoctoral fellow in the UC department of emergency medicine, presented their findings at the Society for Academic Emergency Medicine annual meeting, held May 14-18, 2013, in Atlanta (GA, USA). Dr. Meunier, a research assistant professor of emergency medicine, is also a coauthor.

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