Successfully Opening a Larger Volume of the Blood-Brain Barrier


Key Points

  • In a preclinical study, researchers sought to determine the optimal method to use focused ultrasound and microbubbles to open a larger volume of the blood-brain barrier.
  • The research team also attempted to deliver an immune checkpoint inhibitor to the brainstem.
  • Ultimately, the group is working to develop the technology for treating brainstem tumors.

Comparison of Sonication Patterns and Microbubble Administration Strategies for Focused Ultrasound–Mediated Large-Volume Drug Delivery

The research team at Washington University in St. Louis led by Hong Chen, PhD, sought to determine the optimal method to use focused ultrasound and microbubbles to open a larger volume of the blood-brain barrier (BBB) than what has typically been opened. The reason for increasing the volume of the BBB opening is to develop the technology for treating diffuse intrinsic pontine gliomas (DIPGs).

DIPGs are fatal brainstem tumors that occur in children. Increasing the volume of focused ultrasound—based BBB opening for the brainstem could allow new cancer therapies like immune checkpoint inhibitors (ICIs) reach DIPG and other difficult cancers. Opening the BBB near a DIPG tumor is challenging because DIPGs are tough to penetrate, they have a complicated microenvironment, and they spread and migrate quite rapidly.

In the preclinical study, which was conducted in wild-type mice (not a DIPG model), the research team tested and compared two sonication patterns and two methods of microbubble administration. After conducting the experiments, the team determined that an interleaved sonication pattern combined with a bolus injection of microbubbles (Definity, Lantheus Medical Imaging, N. Billerica, MA, USA) led to the most efficient and homogenous results.

To assess safety during the process, the researchers used passive cavitation imaging and physiological monitoring. They noted that the base of the skull reflected acoustic energy at higher pressures (0.45 MPa), which can cause microhemorrhages near the bottom of the brainstem (as little as 2 mm above the base of the skull).

The group then used interleaved sonication and bolus injection of microbubbles to deliver an ICI to 15 mice. They measured the amount that reached the brainstem at three different sonication pressures. A correlation was found between the cavitation dose and the amount of the ICI at each of the pressures (0.15, 0.30, and 0.45 MPa).

See IEEE Transactions on Biomedical Engineering >