Tissue plasminogen activator (tPA) is a drug commonly used by surgeons to bust open blood clots in a patient's bloodstream, but it does have its limitations. Once injected, there's no guarantee it will reach the site of the blood clot, and even then, having it arrive in the correct dosage can be tricky, with the risk of hemorrhage a very real possibility. Researchers have now found that using a new type of magnetic nanoparticle to deliver the drug offers a much more efficient journey to the site, promising to destroy blood clots 100 to 1,000 times faster and aid significantly in the prevention of heart attacks and strokes.
When using clot-busting tPA (an enzyme that also occurs naturally in the blood) in treatment, surgeons will generally inject a small quantity upstream of where the clot is thought to be. While there is the chance that the tPA will travel directly to the clot, there is also a chance that it will bypass the clot and never serve its intended purpose. Furthermore, the drug is broken down quickly in the blood, necessitating higher volumes in order to achieve an effective dose, something that heightens the risk of hemorrhage, which can prove fatal.
In looking to improve on these current methods, scientists from Houston Methodist Research Institute loaded magnetic nanoparticles with tPA, the idea being that the drug wouldn't be broken down so quickly once injected. To offer further shielding, the team then coated the nanoparticles in a protein found in the blood called albumin. This acts as a camouflage, tricking the body's immune system so the nanoparticles aren't identified as invaders and destroyed before they reach the site of the clot. This design has the potential to solve two problems inherent in current treatment techniques.
"The nanoparticle protects the drug from the body's defenses, giving the tPA time to work," says one of the study's co-authors, Alan 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."
Lumsden and his team tested the new nanoparticles in human tissue cultures, observing where the tPA arrived and exactly how long it took to destroy blood clots. They also administered the nanoparticles to mice with blood clots and used optical microscopy to track its effectiveness. They reported that the clots were destroyed around 100 times faster than normal.
There is chance that the method could yet prove even more efficient, however. The team used iron oxide for the core of the nanoparticles, which not only enables the team to use them for magnetic resonance imaging, but opens up possibilities in remote guidance and localized magnetic heating to hasten the breaking up of the clots.
"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," says Paolo Decuzzi, who led the study.
Decuzzi's line of thinking is rooted in previous research indicating that, while tPA is normally injected at room temperatures, it preforms better at higher temperatures (around 40° C (104° F)). His team exposed iron oxide particles to external magnetic fields with the aim of creating friction and heat, and indeed found that the warmed tPA acted faster, raising the speed of clot-busting by another factor of 10 (1,000 in total).
The team now plans to test out the nanoparticles in other animal models with a view to moving to human clinical trials.
"We are optimistic because the FDA has already approved the use of iron oxide as a contrast agent in MRIs," says 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."
The research was published in the journal Advanced Functional Materials.