“Our technique also allows us to concentrate drug activity to a much higher degree than is possible with systemic administration,” explains team leader Jordan Green. “For instance, in the experiments described in this work, we used only one tenth of the typical dose of the drug propofol – a small molecule anaesthetic.” This should help minimize a drug’s side effects, he adds, since it would be concentrated in just a small area of the brain."

The researchers designed nanoparticles composed of a nanodroplet of a high-vapour-pressure perfluorocarbon encapsulated (or caged) and emulsified by a hydrophobic polymer that is also expandable. When ultrasound waves – delivered noninvasively across the scalp and skull – hit the perfluorocarbon in the centre of the nanoparticles, the liquid turns into a gas, thinning the surrounding cage and letting the propofol escape.

Nanocage released into the intravascular medium

“We intravenously administered this nanocage containing propofol into mice that had been given another drug that cases epileptic seizures,” explains team member and lead author of the study Raag Airan, who is now at Stanford University in California. “After waiting a few minutes to allow the nanoparticles to distribute in the blood, we then applied ultrasound to particular parts of the brain thought to be central in generating these chemically-induced seizures – the hippocampus and thalamus. The drug was then released from the nanocages into the intravascular medium, from where it then crossed the blood–brain barrier to anesthetize those regions of the brain.”

The researchers used magnetic resonance imaging (MRI) to guide the application of the ultrasound to the rat’s brain and then release the propofol as it passed through the brain’s blood vessels. As soon as ultrasound had been applied, the rat’s seizures stopped.

"Brain mapping" applications

The blood–brain barrier is a structure that lines the surface of every capillary feeding the brain. It is there to protect the brain from infection and from swelling that can be caused by the body’s immune system. Only tiny drug molecules that dissolve in oil can pass through this barrier.

Airan says that one of the most immediate applications for the new technique is in “brain mapping”, which is needed before many neurosurgeries. “Currently, knowing where a surgeon is able to cut when removing a tumour, for example, requires keeping the patient awake while exposing their brain and probing it with electrodes and assessing responses. The ultrasound method would allow us to use a drug like propofol to briefly ‘turn off’ specific areas of the brain one at a time prior to the surgery with nothing more invasive than a needle stick.”

Decreasing costs

Ultrasound, MRI and each of the nanocomponents used in this study are already approved for other uses in humans so the technique might be transferred to the clinic relatively quickly – although it might be somewhat limited by the cost and accessibility of the MRI scans, admit the researchers. “Our current model requires real-time mapping of the brain while ultrasound is being applied,” says Airan. “This can cost more than $30,000 at a time but we are working on software that would allow us to synchronize a single MRI image with the ultrasound guidance system to decrease the cost significantly.”

The technique might also come in helpful in psychiatric settings, he adds. “When working with a patient who has post-traumatic stress disorder, for example, it would be nice to ‘quiet’ the overactive part of the brain (for instance, the amygdala) during talk therapy sessions. Current technologies can at best quieten down half the brain at a time, so they are too non-specific to be useful here.

Adapting the particles to cage a wide variety of drugs

“As a clinician, my goal is to translate this technology to my own practice,” he tells nanotechweb.org. “To this end, we are looking into how to produce the nanoparticles on a much larger scale, given that the human body is more than 300 times bigger than a rat’s. We also need to do this in an aseptic manner with pharmaceutical-grade purity and precision.”

The researchers, reporting their work in Nano Letters DOI: 10.1021/acs.nanolett.6b03517, say that they are trying to better refine the spatial and temporal precision of the uncaging mechanism. “The chemistry of these particles means that they can be encapsulated by almost any molecule that would itself cross the blood–brain barrier,” adds Green. “We are now adapting these particles to cage a wide variety of additional drugs, focusing on the antidepressant and anti-anxiety classes,” says Airan.