Blood clots, which lead to heart attacks and strokes, are a leading cause of death worldwide. The main goal of emergency medicine in such cases is to dissolve the blood clot and restore blood flow in the affected vessel as quickly and safely as possible. An important need is for drugs that target the clot and dissolve it without causing problems in unaffected blood vessels. Now, a new study describes how magnetic nanoparticles that deliver clot-dissolving enzymes in a targeted fashion may offer an effective solution.

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This schematic of the composite material shows a framework of porous magnetite surrounding the clot-dissolving enzyme.
Image credit: ITMO University

In the journal Scientific Reports, researchers from ITMO University and Mariinsky Hospital in Saint Petersburg, Russia, report how they developed and tested the new type of drug.

They note how the magnetically controlled, enzyme-based drug is safe for intravenous injection and dissolves clots up to 4,000 times more effectively than current drugs.

The researchers suggest their findings will not only point the way to more effective clot-dissolving drugs, but also reduce drug dosage and thus avoid numerous side effects.

When a blood clot or thrombosis occurs, it blocks blood flow in the affected blood vessel and stops essential oxygen and nutrients reaching surrounding tissue. If the clot is not removed within a few hours, the tissue begins to die.

However, even if the clot is dissolved quickly, there is a risk of side effects, because current enzyme-based drugs affect the whole circulation system, not just the clot.

The researchers note that, on average, in developed countries, clot-dissolving treatment is effectively carried out in 15 percent of cases. In Russia the figure is much lower, nearer to 2 percent. People not fortunate enough to benefit from the procedure face the likelihood of disability or death.

Because the currently available clot-dissolving drugs contain enzymes that attack the clot, once they are injected into the body, the immune system begins to attack it, quickly reducing its effectiveness. To overcome this, the drugs are given in knock-out doses, in the hope that some at least will reach the clot area before they lose their effect.

It is like “using a sledge-hammer to crack a nut,” says co-author Ivan Dudanov, who heads Mariinsky hospital’s regional cardiovascular center.

Even to dissolve a small clot blocking a vessel that is only 1-2 millimeters wide, the drug affects the whole network of blood vessels, Dudanov explains, and adds:

“In order to change the situation, we decided to develop a method of targeted drug delivery that would allow us to considerably reduce the dosage and ensure that the whole therapeutic effect is focused on the clot.”

In their study, the researchers describe how they made a composite material that combines a porous magnetite framework with molecules of urokinase – an enzyme frequently used in medicine as a clot-dissolving or thrombolytic agent.

The material can be used in two ways: either as a clot-dissolving coating for artificial blood vessels, or as an injectable solution of nanosized particles that can be guided to clots using an external magnet.

An important feature of the new material’s magnetite framework is that it protects the clot-dissolving enzyme from attack by the blood.

The researchers note they are not the first to propose using a composite material to carry clot-dissolving enzymes. However, most other solutions are based on slow-release, which eventually loses its potency.

In their study, the researchers show how their material acts in a different way – the clot-dissolving enzyme does not leach out and preserves its potency for a much longer period.

The authors conclude that the new composite “shows good thrombolytic activity.” They add:

“Here we report, for the first time, the production of thrombolytic magnetic composite material with non-releasing behavior and prolonged action.”

First author Andrey Drozdov, a researcher in advanced materials and technologies at ITMO University, says:

“The rate at which the new drug can dissolve the clot outperforms unprotected enzymes by about 4,000 times.”

He and his team say their material should be safe for human use because it comprises components that have already been approved for intravenous injection.

They suggest the material may also have a role in preventing clots – it could circulate in the blood and gently clean the blood vessels. It could stay active there for a long time and when spent would naturally pass through the liver and be excreted like any other metabolite.

The team is now planning to carry out preclinical studies of their new thrombolytic system in mammals.

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