A project to develop an ultrasound-based drug delivery system began at Stanford University School of Medicine in 2018. At the time, the nanoparticles consisted of a polymer shell filled with a liquid core of rare chemical compounds. Their production required a complex process, they had to be stored at -80°C, and after thawing, they became less stable. The polymer shell could only accommodate a small amount of the drug, which began to leak at body temperature. In other words, the clinical applicability of this system was quite limited.
Therefore, researchers have switched to nanoparticles with a phospholipid shell, known as liposomes. Experience with their use was gained during the coronavirus pandemic, as the same liposomes were used in vaccines to encapsulate mRNA. The drug can be loaded into the liquid core of the new nanoparticles, which consists primarily of water.
However, the nanoparticles needed to be distinguishable, meaning they needed to have an acoustic impedance different from their immediate surroundings, so they could be stimulated by ultrasound. The scientists tested several options and settled on a 5% sucrose additive. It provided the best balance between ultrasonic response and stability at body temperature.
The mechanism by which ultrasound-induced drug release occurs remains unclear to scientists. Researchers believe that ultrasound causes the surface of the nanoparticles to vibrate against the denser core, creating pores through which the drug is released.
The researchers then tested the drug delivery system on rats. Without ultrasound, the rats injected with nanoparticles produced less than half the amount of ketamine in their organs. "We examined the brain, liver, kidneys, spleen, lungs, heart, and spinal cord—and wherever we could detect it, we found less ketamine when using the liposomal form," said Raag Airan, the project's lead author.
When the scientists applied ultrasound to a specific area of the brain, the nanoparticles delivered approximately three times more drug there than to other parts of the brain, indicating targeted drug release. Although the target brain area received only approximately 30% more ketamine from the nanoparticles than from free ketamine, the selectivity of this increase significantly impacted brain function.
If clinical trials show the system works in humans, doctors will be able to isolate ketamine's beneficial effects—for example, in treating depression—while blocking the drug's adverse side effects.
The results of a major 2023 study have proven the effectiveness of ketamine for treatment-resistant depression. Before the experiment, patients had unsuccessfully tried all available treatments. A month after ketamine, one in five participants had completely recovered from their depression, and half had significantly improved their condition.
