Reviewed by Lexie CornerJun 20 2024
US scientists from the University of Utah have developed a safe and efficient method for targeted drug delivery, which could soon be tested in humans. The study has been published in Frontiers in Molecular Biosciences.
Traditional drug delivery methods are often like using a sledgehammer to crack nuts. Whether the medication is inhaled, injected, or swallowed, it eventually diffuses to the majority of the body, including the parts where it is not needed or potentially harmful.
Imagine if the delivery could be precisely targeted to the exact spot needed. This would significantly reduce the total dosage, thereby minimizing potential side effects.
Researchers developed a method to refine an emerging promising approach to achieve just that. With their new protocol, they have made the method both safe and efficient for the first time.
Here, we show a method to deliver drugs to specific areas of the body where they are needed. 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.
Matthew G Wilson, Study First Author and Graduate Research Assistant, University of Utah
Nanoengineered Droplets
The nanocarriers are tiny droplets with an outer shell made of hollow polymer molecules, ranging in size from 470 to 550 nm. These polymers have two ends: one is hydrophilic (faces outward and mixes well with watery solutions like blood), while the other is hydrophobic (faces inward and does not mix with water).
Within the shell is an inner core of hydrophobic perfluorocarbons. These molecules consist mostly of carbon and fluorine and are mixed with an equally hydrophobic drug of interest.
The shells act as a barrier against the immune system and keep the cores apart, preventing them from combining into a single droplet. The result is comparable to mayonnaise, in which egg proteins create droplets of encapsulated oils when the water and oil separate.
The researchers released the medication using an ultrasound—a sound wave that is louder than the range of human hearing—of 300 or 900 KHz. By steering the ultrasonic beam in three dimensions, they could target an area of the body that is only a few mm across.
It is believed that the perfluorocarbons expand as a result of the ultrasound, lengthening the droplet’s shell and increasing its permeability to the medication, which diffuses into the necessary organs, tissues, or cells.
The anesthetic and sedative propofol was used as a representative drug, and the researchers compared the effectiveness of drug delivery between three different perfluorocarbons: perfluoropentane (PFP), decafluoropentane (DFP), and perfluorooctylbromide (PFOB). In vitro, ultrasonography was applied to the nanodroplets in 60 100-millisecond bursts spaced one minute apart.
Reaching the Boiling Point
The results demonstrated that for PFOB cores, there was an ideal balance between the stability of the nanodroplets and the effectiveness of delivery.
Previous studies have focused on perfluorocarbons with low boiling points—usually lower than the human body temperature. 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 kilohertz is applied. The ultrasound frequency turned out to be a critical factor in our study.
Matthew G Wilson, Study First Author and Graduate Research Assistant, University of Utah
Six doses of PFOB-based nanodroplets were injected into a single long-tailed macaque at one-week intervals to test for safety. The researchers then tracked the development of several blood biomarkers for immune response and liver and kidney function.
The University of Utah Institutional Animal Care and Use Committee approved this experiment, which demonstrated that the nanodroplets were well tolerated and had no discernible negative effects. These studies need to be repeated in Phase I trials or with microdosing in human subjects.
The authors also made their protocol for creating the nanodroplets publicly available as open science to allow other research teams to benefit directly from their findings.
The method we developed can be applied to any of a variety of conditions depending on the drug used. For psychiatric applications, localized 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.
Dr. Jan Kubanek, Study Senior Author, Assistant Professor, University of Utah
Journal Reference:
Wilson, G. M., et al. (2024) Targeted drug release from stable and safe ultrasound-sensitive nanocarriers. Frontiers in Molecular Biosciences. doi.org/10.3389/fmolb.2024.1408767