Houston Methodist researchers have developed magnetic nanoparticles that in tests delivered drugs to destroy blood clots up to 1000 times faster than a commonly used clot-busting technique.

If the drug delivery system performs similarly well in planned human clinical trials, it could mean a major step forward in the prevention of strokes, heart attacks, pulmonary embolisms, and other dire circumstances where clots — if not quickly busted — can cause severe tissue damage and death, the researchers say.

“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 Paolo Decuzzi, Ph.D., co-principal investigator of the study reported in Advanced Functional Materials (early online).

Decuzzi leads the Houston Methodist Research Institute Dept. of Translational Imaging.

In experiments with human blood and mouse clotting models, Decuzzi’s group coated iron oxide nanoparticles inalbumin, a protein found naturally in blood. The albumin provides a sort of camouflage, giving the loaded nanoparticles time to reach their blood clot target before the body’s immune system recognizes the nanoparticles as invaders and attacks them.

The researchers chose iron oxide for the core because they plan to use the nanoparticles for magnetic resonance imaging, remote guidance with external magnetic fields, and for further accelerating clot dissolution with localized magnetic heating.

Brain-hemorrhage risk with current clot-busting drug treatment

The clot-busting drug loaded into the nanoparticles is tPA (tissue plasminogen activator), an enzyme found naturally in blood at low concentrations. In typical current treatments, a small volume of concentrated tPA is injected into a stroke patient’s blood upstream of a confirmed or suspected clot.

From there, some of the tPA reaches the clot, but much of it may cruise past or around the clot, potentially ending up anywhere in the circulatory system. tPA is typically used in emergency scenarios by health care staff, but it can be dangerous to patients who are prone to hemorrhage.

“Treating clots is a serious problem for all hospitals, and we take them very seriously as surgeons,” said cardiovascular surgeon and coauthor Alan Lumsden, M.D. “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.”

Lumsden, who is medical director of the Houston Methodist DeBakey Heart & Vascular Center, said the nanoparticles being developed in Decuzzi’s lab could solve both problems.

“The nanoparticle protects the drug from the body’s defenses, giving the tPA time to work,” he said. “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.”

Clots dissolved 1000 times faster

Decuzzi, Lumsden, and colleagues tested the effectiveness of tPA-loaded nanoparticles by using human tissue cultures to see where tPA landed and how long it took for the tPA to destroy fibrin-rich clots. In a series of in vivo experiments, the researchers introduced blood clots to a mouse model, injecting tPA-loaded nanoparticles into the bloodstream and using optical microscopy to follow the dissolution of the clots. In comparison to a control, the clots were destroyed about 100 times faster.

Although free tPA is usually injected at room temperature, a number of studies suggest tPA is most effective at higher temperatures (40 C or about 104 F). The same seems to be true for tPA delivered via Decuzzi’s iron oxide nanoparticles. So by exposing the iron oxide 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 another 10 times (to 1000) the rate of clot dissolution.

“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,” Decuzzi said.

Next step in the research, Decuzzi said, will be testing the nanoparticles’ safety and effectiveness in other animal models, with the ultimate goal of human clinical trials.

“We are optimistic because the FDA has already approved the use of iron oxide as a contrast agent in MRIs,” he 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.”

The work was funded by the George and Angelina Kostas Research Center for Cardiovascular Nanomedicine at the Houston Methodist Research Institute, which founded last year.

Abstract of TPA immobilization on iron oxide nanocubes and localized magnetic hyperthermia accelerate blood clot lysis

The low specificity and high risk of intracranial hemorrhage associated with currently approved thrombolytic therapies limit their efficacy in recanalizing occluded vessels. Here, a nanoscale thrombolytic agent is demonstrated by immobilizing tissue plasminogen activator molecules (tPA) over 20 nm clustered iron oxide nanocubes (NCs). The resulting nanoconstructs (tPA–NCs) are capable of dissolving clots via both direct interaction of tPA with the fibrin network (chemical lysis) and localized hyperthermia upon stimulation of superparamagnetic NCs with alternating magnetic fields (AMFs) (mechanical lysis). In vitro, as compared to free tPA, the proposed nanoconstructs demonstrate a ≈100-fold increase in dissolution rate, possibly because of a more intimate interaction of tPA with the fibrin network. The clot dissolution rate is further enhanced (≈10-fold) by mild, localized heating resulting from the exposure of tPA–NCs to AMF. Intravital microscopy experiments demonstrate blood vessel reperfusion within a few minutes post tail vein injection of tPA–NCs. The proposed nanoconstructs also exhibit high transverse relaxivity (>400 × 10^–3 m⁻¹ s⁻¹) for magnetic resonance imaging. The multifunctional properties and the 3 orders of magnitude enhancement in clot dissolution make tPA–NCs a promising nano-theranosis agent in thrombotic disease.

In an open-access paper published today in the Royal Society of Chemistry journal Nanoscale, more than 60 academics and industrialists lay out a science and technology roadmap for graphene, related two-dimensional crystals, other 2d materials, and hybrid systems based on a combination of different 2d crystals and other nanomaterials.

The roadmap covers the next 10 years and beyond, intended to guide the research community and industry toward the development of products based on graphene and related materials.

The project started in October 2013, when academia and industry came together to form the Graphene Flagship, now with 142 partners in 23 countries, and a growing number of associate members.

Graphene and related materials are expected to revolutionize the fields in which they are applied, and they have the potential to become the materials of the 21st century. They will supplement and at times replace existing substances in a range of applications. For example, graphene could be integrated into silicon photonics, exploiting established technology for constructing integrated circuits.

“The roadmap forms a solid foundation for the graphene community in Europe to plan its activities for the coming years,” says Jari Kinaret, director of the Graphene Flagship. “It is not a static document, but will evolve to reflect progress in the field, and new applications identified and pursued by industry.”

The roadmap highlights three broad areas of activity: identify new layered materials, assess their potential, and develop reliable, reproducible and safe means of producing them on an industrial scale.

Eleven science and technology themes are identified and addressed in the roadmap: fundamental science, health and environment, production, sensors, flexible electronics, energy conversion and storage, composite materials, and biomedical devices, and electronic devices, including spintronics, photonics and optoelectronics.

The author note that a recent independent assessment has confirmed that the Graphene Flagship is firmly on course, with with hundreds of research papers, numerous patents and marketable products to its name.

Roadmap timelines predict that, before the end of the 10-year period of the flagship, products will be close to market in the areas of flexible electronics, composites, and energy. They also hope to see advanced prototypes of silicon-integrated photonic devices, sensors, high-speed electronics, and biomedical devices.

Abstract of Science and technology roadmap for graphene, related two-dimensional crystals, and hybrid systems

We present the science and technology roadmap (STR) for graphene, related two-dimensional (2d) crystals, and hybrid systems, targeting an evolution in technology, with impacts and benefits reaching into most areas of society. The roadmap was developed within the framework of the European Graphene Flagship and outlines the main targets and research areas as best understood at the start of this ambitious project. In this document we provide an overview of the key aspects of graphene and related materials (GRMs), ranging from fundamental research challenges to a variety of applications in a large number of sectors, highlithing the roadmap to take GRMs from a state of raw potential to a point where they might revolutionize multiple industries: from flexible, wearable and transparent electronics to high performance computing and spintronics.