Drug-delivery triggered by ultrasound

A promising application of ultrasound is the ability to control the release of active ingredients encapsulated in sono-activatable carriers. I am investigating the various ways to trigger drug delivery using ultrasound.

Vaporization of an encapsulated perfluorocarbon liquid (doi:10.1021/acs.langmuir.3c02272)

The most extensively studied mechanism is the ultrasound-induced vaporization of perfluorocarbon droplets, known as Acoustic Droplet Vaporization (ADV). In this process, a carrier encapsulates one or more perfluorocarbon droplets along with the active ingredients. When the droplet vaporizes, it leads to the destruction of the carrier, resulting in the complete release of the encapsulated active ingredients.

Several mechanisms have been proposed to explain the transition from the liquid to the gas phase (vaporization) in perfluorocarbon fluids. All of these mechanisms suggest that vaporization occurs due to the formation of a gas nucleus that can propagate throughout the fluid's volume. However, they differ in how the nucleus originates. The nucleus can form through the following processes:

1. Superharmonic focusing. This mechanism occurs in droplets with diameters of several tens of micrometers and at ultrasonic frequencies above 3 MHz. Here, harmonic pressure waves (i.e., at frequencies that are multiples of the fundamental ultrasonic wave) are focused within the droplet by its wall, leading to the formation of a nucleus at the focal point inside the droplet.
2. Homogeneous nucleation. This random process involves the spontaneous formation of a nucleus somewhere within the droplet's volume when the applied pressure is sufficiently low. The likelihood of this event depends on the energy required to create a nucleus within the fluid.
3. Heterogeneous nucleation. Similar to homogeneous nucleation, but the nucleus forms on the internal surface of the droplet.

While the first two mechanisms are well understood, with models that accurately predict their behavior, these models fail to account for experimental results observed in perfluorocarbon nanodroplets.

To address this, we have developed a model of heterogeneous nucleation tailored to flexible surfaces. This model predicts the vaporization pressure based on the number of droplets (assuming they are sufficiently spaced apart) and the properties of the droplets (i.e., radius and interfacial tensions of the various possible interfaces). This model is applicable to both nanodroplets and microdroplets when superharmonic focusing or homogeneous nucleation mechanisms do not apply.

Shell permeation (patent n°WO2021239578, 2021)

Oil-based droplets can be used to encapsulate hydrophobic drugs, with surfactants stabilizing the droplets by forming a protective shell around them, preventing the drugs from escaping the oil. When exposed to ultrasound, the surfactants gradually move apart, making the droplet shell permeable and allowing the drugs to be released."

Expulsion of encapsulated water droplets (patent n°WO2424126605 A1, 2024)

Double emulsions are for instance oil droplets, each containing one or more water droplets. This system is stable as the water droplets remain encapsulated within the oil droplet. Both oil and water droplets are stabilized by surfactants while the water droplets can encapsulate hydrophilic drugs. When an encapsulated water droplet comes into contact with the surface of the encapsulating oil droplet, the wall composed of the two layers of surfactants will break only under insonation, allowing the contents of the water droplet (including the drugs) to spread into the surrounding medium.

Destabilization of electostatic bonds (patent n°WO2022268284, 2022)

Certain polymers, such as alginate (which has negative charges), form a gel in the presence of calcium ions Ca²⁺. This gel can be used, for example, to trap therapeutic proteins. Ultrasound destabilizes the electrostatic bonds between alginate and Ca²⁺, allowing for the release of therapeutic proteins. The release stops as soon as the insonification ceases.