Nanodroplet drug carriers triggered by ultrasound

Monday, 24 June, 2024

Nanodroplet drug carriers triggered by ultrasound

Whether a drug is swallowed, injected, inhaled or absorbed through the skin, it ultimately diffuses to most parts of the body, including those where it isn’t needed — or where it even might cause harm. But what if the delivery could be targeted at exactly the right spot? Scientists from The University of Utah have been perfecting a method that does just that, with their results published in the journal Frontiers in Molecular Biosciences.

“Here we show a method to deliver drugs to specific areas of the body where they are needed,” said Matthew G Wilson, the study’s first author. “We do so using ultrasound waves, which trigger drug release from circulating nanocarriers when focused on the target.

“We developed a method to produce stable nanocarriers repeatably, and identified ultrasound parameters that can activate them.”

The nanocarriers are minuscule droplets, between 470 and 550 nm across, with a hollow outer shell composed of polymer molecules. These polymers have two distinct ends: a hydrophilic one, which mixes well with watery solutions like blood and which faces outward, and a hydrophobic one that doesn’t mix with water and which faces inwards.

Within the shell is an inner core of hydrophobic perfluorocarbons — molecules that consist mostly of fluorine and carbon, and which are mixed with an equally hydrophobic drug of interest. The shells keep the cores apart, preventing them from coalescing into a single droplet, and form a barrier against the immune system. The effect is much like mayonnaise, where proteins from eggs form droplets of encapsulated oils, where otherwise the oil and water would separate completely.

To release the drug, the researchers played back an ultrasound — a sound wave with a frequency beyond the upper limit of human hearing — of 300 or 900 kHz. The beam of ultrasound can be steered across three dimensions, to focus on a desired area within the body that is only a few millimetres across. The ultrasound is thought to cause the perfluorocarbons to expand, stretching out the droplet’s shell and making it more permeable to the drug, which then diffuses out to the organs, tissues or cells where it is required.

The researchers compared the efficiency of delivery of a representative drug (the anaesthetic and sedative propofol) between three different perfluorocarbons: perfluoropentane (PFP), decafluoropentane (DFP) and perfluorooctylbromide (PFOB). The ultrasound was delivered to the nanodroplets in vitro, in 60 pulses of 100 ms over one minute. The results showed that the balance between stability of the nanodroplets and the efficiency of delivery was optimal for PFOB cores.

“Previous studies have focused on perfluorocarbons with low boiling points — usually lower than the human body temperature,” Wilson said. “We found that droplets with a PFOB core, which has a boiling point of 142°C, are much more stable over time.

“Despite its high boiling point, PFOB can achieve similar levels of drug release when low-frequency ultrasound of 300 kHz is applied. The ultrasound frequency turned out to be a critical factor in our study.”

To test for safety, the researchers injected a single long-tailed macaque with six doses of PFOB-based nanodroplets at one-week intervals, and monitored the evolution of a range of blood biomarkers for liver, kidney and immune response function. This experiment showed that the nanodroplets were well tolerated, with no detectable side effects. These experiments will need to be replicated in microdosing or phase 1 trials on human volunteers.

By releasing the drug at exactly the desired spot in the body, this allows the total dose to be dramatically lower, which should minimise side effects. Furthermore, said senior author Assistant Professor Jan Kubanek, the method can be applied to a variety of conditions depending on the drug used.

“For psychiatric applications, localised delivery of propofol could be used as a diagnostic tool to identify brain regions causally involved in disorders for individual patients. For more lasting treatment, ketamine delivery could be a potent method to rewire neural circuits,” he concluded.

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