The project to create an ultrasound drug delivery system began at Stanford University School of Medicine in 2018. At that time, the nanoparticles consisted of a polymer shell filled with a liquid core of rare chemical compounds. They required a complex process to produce, had to be stored at -80 °C, and became less stable after defrosting. Only a small amount of the drug could be included in the polymer shell, which began to leak out at body temperature. In other words, the clinical applicability of this system was quite low.
So the researchers turned to nanoparticles with a phospholipid shell, known as liposomes. Experience with them 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 is made up mostly of water.
However, the nanoparticles had to be distinguishable, i.e. have an acoustic impedance different from their immediate surroundings, so that they could be affected by ultrasound. The scientists tested several options and settled on an additive of 5% sucrose. It provides the best balance between ultrasound response and stability at body temperature.
The mechanism by which the drug is released under the influence of ultrasound is still unclear to scientists. Researchers believe that ultrasound causes vibrations of the surface of the nanoparticles relative to the denser core, creating pores through which the drug is released.
The researchers then tested the drug delivery system in rats. Without the ultrasound, the rats injected with the nanoparticles had less than half the amount of ketamine in their organs. “We looked at the brain, liver, kidneys, spleen, lungs, heart, and spinal cord — and everywhere we had the ability to detect it, we found less ketamine when we used the liposomal form,” said Raag Airan, the project’s leader.
When the scientists applied ultrasound to a specific area of the brain, the nanoparticles delivered about three times more of the drug there than to other parts of the brain, indicating a targeted release of the drug. Although the target brain area received only about 30% more ketamine from the nanoparticles than from free ketamine, the selectivity of this increase had a significant impact on brain function.
If clinical trials show the system works in people, doctors could isolate ketamine's beneficial effects—for example, in treating depression—while blocking the drug's adverse side effects.
The results of the largest study in 2023 have proven the effectiveness of ketamine in resistant depression. Before the experiment, patients had unsuccessfully tried all currently available treatments. A month after ketamine, every fifth participant completely got rid of depression, and half significantly improved their condition.
