New nanoparticle system uses ultrasound to precisely deliver drugs

The trouble with many drugs is that they go where they shouldn't, producing unwanted side effects. Psychiatric drugs might cause dissociation, painkillers can induce nausea and chemotherapy often damages healthy cells. Now a team of Stanford Medicine researchers are closing in on a novel solution: a non-invasive system that can deliver drugs anywhere in the body with precision down to a few millimeters.

The system uses nanoparticles to encapsulate drugs along with ultrasound to unleash the drugs at their intended destinations. 

In a new study, published Aug. 18 in Nature Nanotechnology, the researchers show in rats that the latest version of their system can deliver ketamine to specific regions of the brain and painkillers to specific nerves in limbs. Thanks to a new formulation, the nanoparticles are safer, more stable and easier to produce.

And the key ingredient can be found in any kitchen.

Turns out just a little bit of sugar is all you need to make this work."

Raag Airan, MD, PhD, assistant professor of radiology and senior author of the new study

The researchers found that a 5% sucrose solution inside the nanoparticles made them relatively stable in the body, yet responsive to ultrasound stimulation. That means that even when the nanoparticles are delivered into the bloodstream and travel throughout the body, most of the drug is released only where it's needed. A narrow beam of ultrasound, externally applied, pinpoints the target, releasing the drug.

Such a system has the potential to make a wide range of drugs safer and more effective.

"We can maximize the therapeutic effect and minimize the off-target effects," Airan said.

Four members of Airan's lab share lead authorship of the study: research scientists Mahaveer Purohit, PhD, and Yun Xiang, PhD; graduate student Brenda Yu; and postdoctoral scholar Kanchan Sinha Roy, PhD.

Back to the drawing board

Ultrasound drug delivery has been on Airan's mind for nearly a decade. In 2018, his team published an early iteration of the system, which was able to deliver propofol, an anesthetic, to specific parts of the rat brain. 

Though that early version proved the principle, the researchers soon realized its shortcomings.

The nanoparticles consisted of a polymer shell filled with a liquid core of uncommon chemical compounds. They required a complex production process, had to be stored at -80°C and were less stable after thawing. Only a small amount of drug could be incorporated into the polymer shell, and it would begin to seep out at body temperature.

"The clinical translatability of that system was pretty limited," Airan said. "We had a real need to come up with something else, so we went back to the drawing board."

They switched to nanoparticles with a phospholipid shell, known as liposomes - the same structures used to encapsulate the mRNA in COVID-19 vaccines.

"There's a whole infrastructure for making liposomes as a byproduct of the pandemic," Airan said. "We know how to make this stuff very well now."

The drug could be loaded into the liquid core of the new nanoparticles, which contains mostly water.

But the nanoparticles had to be distinguishable by ultrasound, meaning they had to have a different acoustic impedance from their immediate surroundings. Acoustic impedance describes how easily sound waves travel through a material and depends largely on density.

"As long as there's an acoustic impedance difference of a particle compared with the medium, then you'll get a physical interaction with the ultrasound," Airan said.

Sweet discovery

The team tried adding a variety of common substances to the liquid core, from polymers to salts - whatever they had on the shelf - to modulate its response to ultrasound.

The final solution came to Airan while he was cooking. "What can make things dense and viscous?" he thought. "Well, sugar could do that."

After testing different types and concentrations of sugars, the researchers found that 5% sucrose added to the liquid core achieved the best balance of ultrasound response and stability at body temperature. More sugar could make the nanoparticles even more responsive to ultrasound, but it also increased the drug leakage without ultrasound.

The mechanism of how ultrasound causes drug release is still unclear. The researchers think the ultrasound oscillates the surface of the nanoparticles against the denser core, creating pores that release the drug.

Hitting the target

The researchers then tested the drug delivery system in rats, comparing animals who were given an injection of free, unencapsulated ketamine with those given ketamine encapsulated in nanoparticles with 5% sucrose. Without any application of ultrasound, the rats that received the nanoparticles had less than half the amount of ketamine in every organ the researchers tested. 

"We looked at the brain, liver, kidney, spleen, lung, heart and spinal cord - and wherever we had sufficient ability to detect it, we saw less ketamine with the liposomal formulation," Airan said.

When the researchers applied ultrasound to a particular brain region, the nanoparticles delivered about three times as much drug to that region as to other parts of their brain - demonstrating targeted drug release.

Though the targeted brain area received only about 30% more ketamine from the nanoparticles than from free ketamine, the selectivity of the increase made a significant difference to brain function.

"It's not just that we're getting the on-target effect. We're getting more of it than what you might expect, based on how much we're delivering to that part of the brain," Airan said.

The researchers found they could decrease anxious behavior in rats by targeting ketamine release to their medial prefrontal cortex, the brain region that controls emotional states. Rats that received the targeted treatment spent more time roaming the center of a box - a sign of less stress - compared with counterparts that received free ketamine or a saline control.

If the system works in humans, clinicians may be able to isolate the emotional effects of ketamine - to treat depression, for example - while blocking the dissociative effects of the drug.

Pain point

The researchers also demonstrated they could block pain in a specific part of the body by targeting a local anesthetic, ropivacaine, to a specific nerve. When researchers gave rats ropivacaine encapsulated in nanoparticles and applied ultrasound to the sciatic nerve in one leg, that leg would become numb to a prick. A 2.5-minute ultrasound session induced local anesthesia for at least an hour.

Such a procedure would have another advantage for patients in pain. Typically, local anesthetics require an injection at the source of the pain, which can add to a patient's discomfort. With the new system, the drug can be injected elsewhere as an ultrasound is applied non-invasively at the site of the pain.

Pending a greenlight by the U.S. Food and Drug Administration, Airan's team is planning the first human trial of the ultrasound drug delivery system, which will use ketamine to target a patient's emotional experience of chronic pain.

A few years ago, when Airan approached pharmaceutical companies about producing the earlier version of the nanoparticles, the calls would end when they heard about the exotic ingredients. This time around, a tiny spoonful of sugar has made the pitch more palatable. "It's eminently translatable," he said.

The study received funding from the National Institutes of Health (grants RF1MH114252, UG3NS114438 and UG3NS115637), the Stanford Wu Tsai Neurosciences Institute, an anonymous donor to the Stanford Medicine Department of Radiology, the Ford Foundation and the National Science Foundation.