At Houston Methodist, Paolo Decuzzi, PhD, is using magnetic nanoparticles full of tissue plasminogen activator (tPA) to destroy clots 1,000 times faster than the traditional method of injecting concentrated tPA into a patient’s bloodstream. This research may lead to more effective prevention of strokes, heart attacks, pulmonary embolisms, and other clot-related trauma.
“Treating clots is a serious problem for all hospitals, and we take them very seriously as surgeons,” said Alan Lumsden, MD, co-author along with Dr. Decuzzi, in a news release. “Although tPA and similar drugs can be very effective in rescuing our patients, the drug is broken down quickly in the blood, meaning we have to use more of it to achieve an effective clinical dose. Yet using more of the drug creates its own problems, increasing the risk of hemorrhage. If hemorrhage happens in the brain, it could be fatal.”
To avoid these serious risks, the team at Houston Methodist coated iron oxide nanoparticles with albumin, the most abundant protein in the blood, to camouflage the particles from attack by the immune system before the particles can act therapeutically. Afterward, the team loaded tPA into the particles.
As described in the study, “TPA Immobilization on Iron Oxide Nanocubes and Localized Magnetic Hyperthermia Accelerate Blood Clot Lysis,” published in Advanced Functional Materials, the nanoparticles are 20 nanometers and composed of magnetic iron-oxide, a material selected because it can be guided with external magnetic fields, imaged using magnetic resonance imaging, and heated via magnets to further accelerate clot dissolution. “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,” said Dr. Decuzzi.
Localization of tPA makes the nanoparticles more effective than injection. Injecting tPA allows some tPA to reach the clot, but most ends up elsewhere in the circulatory system, posing a hazard to patients prone to hemorrhage. “The nanoparticle protects the drug from the body’s defenses, giving the tPA time to work, said Dr. Lumsden. “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.”
Experiments showed that clots were destroyed 100 times faster by nanoparticles than control treatment during in vivo clot experiments using mice. This was increased another 10 fold (to 1000 times faster) upon heating to 42 degrees Celsius. “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,” said Dr. Decuzzi.
The next step for the team at Houston Methodist is to use a larger animal model before going on to human clinical trials. “We are optimistic because the FDA has already approved the use of iron oxide as a contrast agent in MRIs,” said Dr. Decuzzi. “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.” If effective, the nanoparticles may be useful as nano-theranosis agents for use in thrombotic diseases.