Concentrating and Releasing Drugs in the Brain with Pinpoint Accuracy

Focused, low-energy ultrasound helps researchers deliver drugs only to where their effect is desired, without compromising the blood-brain barrier.

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Scientists at ETH Zurich say they have developed a technique for concentrating and releasing drugs in the brain with great accuracy. This could make it possible in the future to deliver psychiatric and cancer drugs and other medications only to those regions of the brain where this is medically desirable, according to the team.

The researchers add that such targeted delivery is practically impossible—drugs traveling through the bloodstream reach the entire brain and body and sometimes cause side effects. The new method is noninvasive, with drug delivery in the brain controlled from outside the head using ultrasound.

Mehmet Fatih Yanik, PhD, professor of neurotechnology, and his group published their findings, “Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers,” in the journal Nature Communications.

“Non-invasive, molecularly-specific, focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatments of brain disorders. We systemically inject engineered ultrasound-controllable drug carriers and subsequently apply a novel two-component Aggregation and Uncaging Focused Ultrasound Sequence (AU-FUS) at the desired targets inside the brain,” wrote the investigators.

“The first sequence aggregates drug carriers with millimeter-precision by orders of magnitude. The second sequence uncages the carrier’s cargo locally to achieve high target specificity without compromising the blood-brain barrier (BBB). Upon release from the carriers, drugs locally cross the intact BBB. We show circuit-specific manipulation of sensory signaling in motor cortex in rats by locally concentrating and releasing a GABAA receptor agonist from ultrasound-controlled carriers.”

“Our approach uses orders of magnitude (1300×) less drug than is otherwise required by systemic injection and requires very low ultrasound pressures (20-fold below FDA safety limits for diagnostic imaging). We show that the BBB remains intact using passive cavitation detection (PCD), MRI-contrast agents and, importantly, also by sensitive fluorescent dye extravasation and immunohistochemistry.”

To prevent a drug from acting on the entire brain and body, the new method involves special drug carriers that wrap the drugs in spherical lipid vesicles attached to gas-containing ultrasound-sensitive microbubbles. These are injected into the bloodstream, which transports them to the brain.

Next, the scientists use focused ultrasound waves in a two-stage process. Focused ultrasound is already employed in oncology to destroy cancer tissue at precisely defined points in the body. In the new invention, however, the scientists work with much lower energy levels, which do not damage the tissue.

In the first step, the scientists use low-energy ultrasound waves to cause the drug carriers to aggregate at the desired site within the brain.

“What we’re doing is using pulses of ultrasound essentially to create a virtual cage from sound waves around the desired site. As the blood circulates, it flushes the drug carriers through the whole brain. But the ones that enter the cage can’t get back out,” Yanik explains.

In the second step, the researchers use a higher level of ultrasound energy to get the drug carriers to vibrate at this site. Shear forces destroy the lipid membranes around the drugs, releasing the drugs to be absorbed by the nerve tissue present at the site.

The researchers report that they have demonstrated the effectiveness of the new method in experiments on rats. First, they encapsulated a neuroinhibitory drug in the drug carriers. Then, using the new technique, they successfully blocked a specific neural network connecting two areas of the brain. The scientists were able to show in the experiments that only this one particular part of the neuronal network was blocked and that the drug did not act on the entire brain.

“Because our method aggregates drugs at the site in the brain where their effect is desired, we don’t need nearly as high a dose,” Yanik asserts. In their experiments on rats, for instance, the investigators found that they could use a quantity of drug 1,300 times smaller than the typical dose needed.

“In our approach, the physiological barrier between the bloodstream and nervous tissue remains intact,” Yanik continues.

The scientists are currently testing the effectiveness of their method in animal models, testing drugs for mental illness and neurological disorders, and targeting lethal brain tumors that are surgically inaccessible. Once its effectiveness and advantages have been confirmed in animals, will researchers be able to advance application of the method to alleviate suffering in humans.

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