Ultrasound-activated nanoparticles deliver drugs to targeted brain regions

While ultrasound has been widely used for medical imaging, it also has a variety of therapeutic applications. The technology could potentially facilitate the release of medication in precise locations for disorders and conditions that require drug treatment.

Ideally, a drug would be released only in specific regions of interest and at a high concentration, to maximize the benefits and minimize side effects. However, releasing a drug selectively in specific locations in the body, including the brain, has been challenging. Researchers have tackled the problem by designing ultrasound-sensitive nanoparticles that release a drug at the targeted site when activated by focused ultrasound.

In a proof-of-concept study, University of Utah researchers tested whether this method could release a drug in a specific area of the brain of non-human primates.

The results, published in the Journal of Controlled Release, showed that the ultrasound-sensitive nanoparticles released a substantial dose of the anesthetic propofol in specific deep brain regions. The treatment was found to be safe and effective, and the result was reversible.

“The main benefit of using ultrasound-sensitive nanoparticles is that they encapsulate the drug so that it has minimal interaction with the body, except where it’s released by focused ultrasound,” said Jan Kubanek, Ph.D., assistant professor in biomedical engineering at the University of Utah and study corresponding author.

“This could potentially allow us to treat under-regulated or malfunctioning circuits in the brain without exposing the entire brain and the body to drugs,” he added.

Designing nanocarriers to deliver a drug payload

The researchers engineered new nanoparticles with three layers: an inner core made up of a contrast agent that responds to ultrasound activation, a second layer that encapsulates the drug, and an outer shell.

The design builds upon previous research in rodents that showed that nanoparticles can contain contrast agents that change from a liquid to gas upon interaction with high-frequency ultrasound waves. This approach facilitates a controlled release of the drug at a precise location.

However, a limitation of previous research was that the nanoparticles were unstable when they entered the bloodstream, which raised safety concerns.

Kubanek’s team increased the stability of the nanoparticles by choosing a different contrast agent and adding an outer shell to the design. They also encapsulated the drug to prevent it from interacting with surrounding tissues and organs until it was activated by the ultrasound and released in the targeted brain region.

Evaluation in large animal models

The researchers loaded the nanocarriers with a low dose of propofol (an anesthetic that suppresses neural circuits) to evaluate the safety and effectiveness of their combined method.

They chose propofol because the drug is used in the clinic, causes well-defined neural inhibition, and its effects on the brain circuits occur quickly. This allowed the researchers to test if the nanocarriers released the drug as intended.

They used an established visual choice experiment to determine whether releasing propofol in specific visual brain regions would impact the monkeys’ behavior. Briefly, the animals are shown two targets—a flash of light on the left and right. They indicate which target appeared first by making an eye movement in that direction.

The researchers focused on the right and left lateral geniculate nuclei, or LGN, which are small structures in the brain that are important for vision.

Because each LGN derives input from the opposite side, the researchers expected that inhibiting the LGN on one side would affect vision on the other side. For example, administering propofol directly to the right LGN would impair the animal’s visual perception on the left side, and the animal would be biased to choose the targets on the right side.

After propofol-loaded nanoparticles were administered into the bloodstream by injection, the researchers delivered 1-minute ultrasound pulses to the right or left LGN and observed how the animals reacted to the stimuli.

As predicted, the animals chose the target on the right when the propofol was released in the right LGN. The opposite also occurred, and the animals chose the target on the left when propofol was released in the left LGN.

The researchers concluded that the selective release of propofol modulated the subjects’ visual choice behavior, which was specific to propofol and the targeted side of the brain when compared with ultrasound alone.

The researchers also found that a low dose of propofol achieved a targeted brain delivery when activated by ultrasound and minimized its interaction with tissues and organs. This could indicate that lower doses of drugs could potentially achieve the desired effect.

In addition, the study found that the average time the nanoparticles circulated in the blood was about 30 minutes, which provides a practical time window for applications in humans.

“This study is important because it demonstrated a safe and effective approach to releasing drugs on demand in awake, behaving primates, as opposed to previous studies that used rodents, thus providing a critical step toward future clinical translation,” said Guoying Liu, Ph.D., director of NIBIB’s Division of Applied Science and Technology.

There were two reported limitations of the study: the release was not validated using an imaging modality and the reported behavioral effects could be subject to behavioral adaptation and potentially other cognitive influences.

However, these limitations were mitigated by contrasting the drug release across the two brain sites and by contrasting propofol-filled nanoparticles with saline and empty nanoparticles.

Looking ahead

The researchers aim to eventually apply their formulation to a variety of medications that produce side effects, including chemotherapy.

“A major strength of this approach is that the nanoparticles are designed to carry any drug and release it upon ultrasound activation so this system could be used to treat cancer, pain, or addiction,” said Kubanek.

Besides additional testing in non-human primates, the research team is also testing the potential of this targeted release approach in delivering chemotherapy in a mouse model of glioblastoma, the most common, aggressive, and deadly brain cancer.

This science highlight describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease.

Science is an unpredictable and incremental process—each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research.