The combination of ultrasound and bubbles helps drugs reach the brain

Ultrasound and bubbles help drugs reach the brain

The principle of “Acoustic Cluster Therapy”, ACT. Credit: EXACT Therapeutics

Fortunately, the brain has a filter that protects it and the rest of the central nervous system from foreign elements like pathogens that can damage tissue.

We call this filter the blood-brain barrier. It consists of proteins that bind to cells in the blood vessel wall, forming an effective physical barrier that is normally absolutely vital.

The filter usually stops 100% of the large molecules and 98% of the small ones found in the bloodstream.

Medications that cannot pass through the protective barrier

However, this filter can also present problems when treating diseases: the medication fails to penetrate the barrier.

“The blood-brain barrier prevents the effective treatment of many brain diseases,” says Catharina de Lange Davies, a professor in the NTNU Department of Physics.

Of the 7,000 medicines that consist of small molecules, only 5% are designed for the central nervous system. Few of them are particularly effective. This is largely due to the blood-brain barrier.

For example, the filter can stop cytotoxic drugs needed by people with brain tumors, as well as drugs for diseases such as Alzheimer’s or Parkinson’s.

Ultrasound and bubbles trick the filter

A solution that several researchers are working on is injecting microbubbles into the blood and treating the brain with ultrasound.

Ultrasound and bubbles help drugs reach the brain

This illustration compares the size of ordinary microbubbles made for ultrasound imaging with a large “Acoustic Cluster Therapy” bubble that is in direct contact with large parts of the blood vessel wall. Credit: EXACT Therapeutics

The ultrasound causes bubbles in the blood vessels of the brain to vibrate. This creates mechanical forces that act on the blood vessel wall and open the blood-brain barrier.

Researchers at the NTNU Department of Physics, in collaboration with the company EXACT Therapeutics, have used a completely new type of gas bubble that is larger than the gas bubbles previously used. This technique is called “Acoustic Cluster Therapy” or ACT.

  • The small clusters consist of a negatively charged microbubble adhering to a positively charged oil droplet. These are injected into the bloodstream.
  • The ultrasound is then directed at the brain. This causes the microbubble to vibrate and transfer energy to the oil droplet, which then coalesces into a single enlarged microbubble with a volume 1000 times greater than other commercial ultrasonic microbubbles.
  • The large size of the microbubble brings it into contact with many of the cells that form the blood-brain barrier along the wall of the blood vessels in the capillaries. A new set of ultrasonic pulses causes the large gas bubble to vibrate and effectively open the blood-brain barrier.

At the same time, medicines, such as drugs encapsulated in nanoparticles, can be injected. NTNU researchers have shown that these nanoparticles can cross the blood-brain barrier and reach brain tissue in mice when using ACT.

The results are very promising and safe.

the medication passes

“The method increases the permeability of the blood-brain barrier. It also increases the uptake of large molecules and nanoparticles in the brain,” says de Lange Davies. “In our experiments with mice, we have shown that the blood-brain barrier closes after about a day and we have not found any significant damage to the blood-brain barrier. brain tissue.

Ultrasound in combination with microbubbles is currently the only method to penetrate the blood brain barrier in a way that only affects conditions locally and does not destroy tissue.

Ultrasound and bubbles help drugs reach the brain

This figure shows red nanoparticles that crossed the blood-brain barrier (stained green) and entered brain tissue after ACT treatment. On the left, we see that no red nanoparticles cross the blood-brain barrier in an untreated brain. On the right is the increase (3.7-fold) in the number of nanoparticles (called CCPM) after ACT treatment compared to the untreated control. Credit: NTNU

Use of the method in patients with brain cancer

“This is a big step towards better treatment for various brain diseases,” says de Lange Davies.

Trials are now underway in patients with brain cancer and Alzheimer’s in other countries. Ultrasound is used in combination with smaller gas bubbles that are created as a contrast agent for ultrasound imaging. These studies show no side effects of treatment.

“We think these results are exciting and encouraging. We would now like to study the ACT technology in patients with malignant brain cancer,” says de Lange Davies.

More evidence that ultrasound can help in the battle against Alzheimer’s disease

More information:
Marieke Olsman et al, Acoustic Cluster Therapy (ACT®) enhances accumulation of polymeric micelles in the murine brain, Controlled Release Diary (2021). DOI: 10.1016/j.jconrel.2021.07.019

Citation: Combining Ultrasound and Bubbles Help Medications Reach the Brain (Aug 2, 2022) Retrieved Aug 2, 2022 from brain.html

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