OTHER MECHANISMS OF ACTION
Focused ultrasound is a platform technology that can produce multiple biological effects either through thermal or mechanical means that act therapeutically on the target.
These effects are dependent on the nature of the tissue (e.g. muscle vs. bone) and the ultrasound parameters (power, duration, and mode—continuous versus pulsed). The availability of a variety of biomechanisms creates the possibility of treating a variety of disorders.
TARGETED DRUG DELIVERY
Increased Vascular Permeability.
The endothelium creates a barrier to movement of molecules—drugs in particular—from the inside of the blood vessel to the surrounding tissue. Ultrasound increases the permeability of the blood vessels, which allows drugs to enter tissue where they would otherwise be excluded. In particular, the barrier between blood and the brain is especially dense and impenetrable, impairing the delivery of important drugs to the central nervous system. Focused ultrasound can temporarily disrupt the blood brain barrier, enhancing the possibilities for pharmacological therapy.
Focused ultrasound has been shown to cause blood vessels to widen in a targeted location. This effect, known as vasodilation, is most likely caused by the release of nitric oxide induced by the change in acoustic pressure generated by ultrasound. Vasodilation increases the volume of blood flowing through a targeted region, peak systolic velocity, and permeability of blood vessels, all allowing for the more effective delivery of drugs to a specific region.
A mild temperature elevation to 42°C (107°F) performed continuously over a few hours induces hyperperfusion, a physiological response that increases delivery of blood and drugs in the bloodstream to the targeted region.
Drug Delivery Vehicles
Drugs can be loaded into carriers such as microbubbles or liposomes. Focused ultrasound can cause the release of drugs from their carriers through either mechanical or thermal effects, only at the point where the ultrasound is focused. This increases their effect in a targeted area while minimizing their impact on the rest of the body.
Most drugs act from the inside of cells; however, cell membranes frequently prevent drugs from entering their interior. The non-thermal effects of focused ultrasound can temporarily create pores in the cell membrane, allowing drugs to pass through the membrane and access the interior.
Sensitization to Chemotherapy
Heating tumors makes them more susceptible to chemotherapy, an effect known as sensitization. Sensitization can increase the transportation of chemotherapeutic agents to the tumor and enhance their local effects while diminishing systemic damage by decreasing the dose needed to achieve clinical benefit.
Sensitization to Radiotherapy
Local hyperthermia induced by focused ultrasound can increase the delivery of oxygen to tumors and enhance their metabolic rate. These effects make tumors more susceptible to radiotherapy.
Ultrasound can stimulate or block neural activity without damaging the neural structures. Using pulsed, low energy focused ultrasound, it is possible to stimulate or reversibly block neural impulses. This effect has potential to block epileptic seizures and induce muscular contractions.
Certain chemical agents induce natural cell death when exposed to specific wavelengths of light or ultrasound. This mechanism is thought to be caused by the production of reactive oxygen species in cells exposed to such photosensitive and sonosensitive agents.
Blood Vessel Occlusion and Coagulation
Using focused ultrasound with high power and energy makes it possible to thermally coagulate and thereby occlude blood vessels.
Amplification of Cancer Biomarkers
Tumors release biomarkers into the bloodstream that indicate their presence in the body. These markers are usually released in very small quantities. Radiation forces from low-intensity focused ultrasound can cause the amplified release of biomarkers and aid in diagnosing cancer.
When focused ultrasound interacts with blood vessels with pulses of a very short duration, it can temporarily cause blood vessels to reduce in diameter. Similarly, the thermal effects of focused ultrasound can produce long term vasoconstriction, allowing for the potential to correct venous abnormalities.
After a focused ultrasound tissue ablation procedure, the exposed proteins and cellular debris that remain in the body can trigger an increased immune response to the treated tumor.
Mechanical energy from focused ultrasound can cause vibrations around targeted blood clots. These vibrations make it possible to either break clots apart directly or make them susceptible to the effect of drug treatments.