Traditionally, many pharmaceutical treatments face a significant challenge: their widespread distribution throughout the body often leads to unwanted side effects. For instance, psychiatric medications can induce dissociation, pain relievers might cause nausea, and chemotherapy frequently harms healthy cells in addition to cancerous ones. Addressing this critical issue, a team led by Dr. Raag Airan, an assistant professor of radiology at Stanford, has engineered a sophisticated solution. Their system utilizes advanced nanoparticles combined with focused ultrasound energy to achieve precision drug delivery down to a few millimeters.

The latest iteration of this system, recently unveiled in a publication within Nature Nanotechnology, demonstrates its efficacy in rat models. Researchers successfully delivered ketamine to specific brain regions to influence behavior and administered painkillers directly to nerves in limbs for localized pain management. A key advancement in this new formulation is the inclusion of a simple, readily available ingredient: sugar. The team discovered that a 5% sucrose solution within the nanoparticles significantly enhances their stability in the bloodstream while maintaining their responsiveness to ultrasound stimulation. This means that although the nanoparticles circulate throughout the body, the drug is primarily discharged only where it is specifically needed, activated by a narrow, externally applied ultrasound beam.

The journey to this innovation began nearly a decade ago, with Dr. Airan's team publishing an early version of their system in 2018, which showcased the targeted delivery of propofol, an anesthetic, to rat brains. While this initial work validated the concept, it also highlighted several limitations. The earlier nanoparticles featured a polymer shell and a liquid core composed of uncommon chemical compounds, demanding complex manufacturing processes and stringent storage conditions at -80°C. They also suffered from instability post-thawing, and only limited amounts of drug could be incorporated into the polymer shell, leading to drug leakage at body temperature.

Recognizing these shortcomings, the team embarked on a complete redesign. They transitioned to liposomes, which are phospholipid-shelled nanoparticles widely used to encapsulate mRNA in COVID-19 vaccines. This shift offered a substantial advantage, as the infrastructure for liposome production is well-established, making the new system more clinically translatable. Crucially, liposomes allowed drugs to be loaded into their mostly water-based liquid core. The next hurdle was ensuring these nanoparticles were distinguishable by ultrasound, requiring them to possess a different acoustic impedance—a measure of how easily sound waves pass through a material, largely determined by density—compared to their surrounding environment. Dr. Airan's "sweet discovery" of sucrose, identified during a cooking session, proved to be the missing link. Testing various common substances, the team found that a 5% sucrose concentration offered the optimal balance between ultrasound responsiveness and stability at body temperature. While higher sugar concentrations could increase ultrasound responsiveness, they also resulted in greater untargeted drug leakage.

The precise mechanism by which ultrasound triggers drug release remains under investigation, but researchers hypothesize that the ultrasound waves cause the nanoparticle surface to oscillate against its denser core, creating transient pores that facilitate drug expulsion. In animal experiments, rats receiving encapsulated ketamine showed significantly lower drug levels in organs compared to those given unencapsulated ketamine, demonstrating the system's ability to minimize systemic exposure. When ultrasound was applied to a specific brain region, that area received approximately three times more drug compared to other brain regions, confirming targeted delivery. This localized increase, although seemingly modest, had a profound impact on brain function, allowing researchers to reduce anxious behavior in rats by targeting the medial prefrontal cortex. This suggests a potential for clinicians to isolate the emotional benefits of drugs like ketamine for treating depression while avoiding their dissociative effects in human patients.

Beyond neurological applications, the researchers also successfully demonstrated pain alleviation by targeting the local anesthetic ropivacaine to the sciatic nerve in one leg of rats. A mere 2.5-minute ultrasound session induced local anesthesia for at least an hour. This method offers a distinct advantage for pain management: unlike traditional local anesthetic injections that can be painful, this system allows the drug to be injected elsewhere, with non-invasive ultrasound applied at the pain site. This innovation promises to enhance patient comfort and expand treatment possibilities. With positive preclinical results, Dr. Airan's team is now preparing for the first human trials, focusing on using ketamine to modulate the emotional experience of chronic pain. This promising technology, utilizing a ubiquitous ingredient, appears poised to transform how medications are delivered, making future treatments safer and more effective for countless patients.