Short-pulse ultrasound successfully delivers drugs across blood-brain barrier

A study published in Radiology on March 26 suggests rapid short-pulse ultrasound is as effective—and maybe more so—than standard and long-pulse therapy for delivering drugs across the blood-brain barrier.

In the past decade, ultrasound has been used to shrink brain tumors and improve cognitive function in animal models of Alzheimer disease, senior author James J. Choi, PhD, and colleagues at Imperial College London said, but researchers still have questions about the safety of the approach.

“Noninvasively applied pulses of ultrasound and microbubbles can locally deliver molecules to the brain,” Choi et al. wrote. “However, despite promising results, there remain concerns about potentially harmful effects from permeability changes to the blood-brain barrier.”

The authors explained that focused ultrasound transports molecules from the bloodstream to the brain by mechanically stimulating blood vessels with acoustically active microbubbles, which are composed of a lipid shell and gas core and can be administered with an IV. Pressure oscillations from the ultrasound trigger the microbubbles to expand and contract, transporting molecules like therapeutic drugs across the blood-brain barrier.

Choi and his colleagues studied whether low-energy, rapid, short-pulse ultrasound could efficiently and safely deliver drugs across the blood-brain barrier in a test group of 38 female mice, all of whom underwent focused ultrasound after they were injected with microbubbles and a model drug. Half the mice were exposed to low-energy short pulses to their left hippocampus using ultrasound emitted at a rapid rate of 1.25 kHz, while the other half were exposed to standard long pulses containing 150 times more acoustic energy.

The team found the rapid short-pulse sequence delivered drugs uniformly throughout the parenchyma, proving its efficacy next to the gold-standard method of longer pulses. Disruption in the blood-brain barrier lasted less than 10 minutes on average, and 3.4-fold less albumin was released into the brain than with long pulses. Hematoxylin-eosin staining didn’t reveal any safety barriers like vascular or tissue damage.

In addition to being safe and effective, Choi et al. reported that with rapid short-pulse sequences, delivered drug doses could be predicted from the acoustic energy emitted from stimulated microbubbles.

“The improved performance and safety profile of rapid short-pulse ultrasound may have positive implications for the treatment of neurologic diseases, such as Alzheimer disease, Parkinson disease and brain tumors,” the authors wrote. “These diseases are difficult to treat because they are collocated with healthy tissue and have large regions protected by the blood-brain barrier.”

The researchers said their next steps involve understanding how exactly rapid short-pulse ultrasound delivers drugs across the blood-brain barrier and how that differs from delivery using traditional long pulses.

“We will also characterize the long-term effects of rapid short-pulse-mediated drug delivery, such as whether microglial cells are activated or inflammation is triggered—responses which have been observed with long pulses,” they wrote. “We plan to optimize rapid short-pulse sequences for drug delivery, modifying not only the pulse shape and sequences but also the microbubbles and the protocol of microbubble administration.”