iron oxide (red), albumin
(gray), and tPA (green)
Image courtesy of
Paolo Decuzzi lab
Results of preclinical experiments suggest that nanoparticles made of iron oxide and coated with tissue plasminogen activator (tPA) and albumin can directly target blood clots and destroy them faster than free tPA injected into the bloodstream.
Researchers found these nanoparticles could destroy blood clots 100 times faster than free tPA. And when the nanoparticles were heated using alternating magnetic fields, they destroyed clots 1000 times faster than free tPA.
Paolo Decuzzi, PhD, of Fondazione Istituto Italiano di Tecnologia in Genoa, Italy, and his colleagues described these experiments in Advanced Functional Materials.
The researchers created iron oxide nanoparticles and coated them with tPA. Typically, a small volume of concentrated tPA is injected into a patient’s blood upstream of a confirmed or suspected clot. From there, some of the tPA reaches the clot, but much of it may travel past or around the clot, potentially ending up anywhere in the circulatory system.
“We have designed the nanoparticles so that they trap themselves at the site of the clot, which means they can quickly deliver a burst of the commonly used, clot-busting drug tPA where it is most needed,” Dr Decuzzi said.
He and his colleagues used iron oxide as the nanoparticles’ core so the particles can be used for magnetic resonance imaging, remote guidance with external magnetic fields, and for further accelerating clot dissolution with localized magnetic heating.
“We think it is possible to use a static magnetic field first to help guide the nanoparticles to the clot, then alternate the orientation of the field to increase the nanoparticles’ efficiency in dissolving clots,” Dr Decuzzi said.
The team also coated the nanoparticles in albumin, which provides a sort of camouflage. It gives the nanoparticles time to reach a clot before the immune system recognizes the particles as invaders and attacks them.
“The nanoparticle protects the drug from the body’s defenses, giving the tPA time to work,” said Alan Lumsden, MD, of Houston Methodist Hospital in Texas.
“But it also allows us to use less tPA, which could make hemorrhage less likely. We are excited to see if the technique works as phenomenally well for our patients as what we saw in these experiments.”
The researchers tested the nanoparticles using human tissue cultures to see where the tPA landed and how long it took to destroy fibrin-rich clots. They also introduced blood clots in mice, injected the nanoparticles into the bloodstream, and used optical microscopy to follow the dissolution of the clots.
The nanoparticles destroyed clots about 100 times faster than free tPA.
Although free tPA is usually injected at room temperature, a number of studies have suggested the drug is most effective at higher temperatures (40° C or about 104° F). The same seems to be true for tPA delivered via the iron oxide nanoparticles.
By exposing the nanoparticles to external, alternating magnetic fields, the researchers created friction and heat. Warmer tPA (42° C or about 108° F) was released faster and increased the rate of clot dissolution 10-fold (to 1000 times greater than free tPA).
Dr Decuzzi said the next steps with this research will be testing the nanoparticles’ safety and effectiveness in other animal models, with the ultimate goal of clinical trials. He said his group will continue to examine the feasibility of using magnetic fields to guide and heat the nanoparticles.
“We are optimistic because the [US Food and Drug Administration] has already approved the use of iron oxide as a contrast agent in MRIs,” Dr Decuzzi said. “And we do not anticipate needing to use as much of the iron oxide at concentrations higher than what’s already been approved. The other chemical aspects of the nanoparticles are natural substances you already find in the bloodstream.”
