A study led by a team of Massachusetts General Hospital (MGH) investigators has analyzed, for the first time, the mechanisms underlying the use of focused ultrasound to improve the delivery of anti-cancer drugs across the blood-brain barrier into brain tumors. 

Their report published in PNAS uses advanced microscopy techniques and mathematical modeling to track the potential of this promising, minimally invasive treatment approach in an animal model of breast cancer brain metastasis. The team also included investigators from Georgia Institute of Technology, the University of Edinburgh and Brigham and Women's Hospital.

"The blood-brain barrier is a challenge in the treatment of brain malignancies, as it can hinder drug delivery," said co-corresponding and co-lead author Costas Arvanitis, Ph.D.

"Even when a drug reaches the brain's circulation, abnormal blood vessels in and around tumors lead to non-uniform drug delivery, with low concentrations in some areas of the tumor," said Arvanitis.

"If a drug makes it to a region of the tumor and crosses the abnormal blood vessel wall, it encounters dense tissue within the tumor that can block access to malignant cells," said Arvanitis.

"We sought to use a new methodology that may improve these abnormal transport properties to enhance drug delivery and efficacy throughout a brain tumor," said Arvanitis.

Arvanitis, an assistant professor at Georgia Institute of Technology, worked on this study at both the Edwin L. Steele Laboratories for Tumor Biology in the MGH Department of Radiation Oncology and his new Biomedical Acoustics and Image-Guided Therapy laboratory at Georgia Tech.

The blood-brain barrier

Focused ultrasound concentrates multiple beams of ultrasound energy on a single spot within the body. Microbubbles tiny lipid bubbles that vibrate in response to ultrasound signals injected into the circulation can temporarily breach the blood-brain barrier at the target site.

Although this approach has been studied in animal models with promising results leading to phase 1 clinical trials in conditions including primary brain tumors such as glioblastoma the underlying mechanisms have not been well understood.

To learn more about the properties of focused ultrasound treatment of brain tumors, the team employed advanced microscopy techniques in live mice that had received implants of HER2-positive breast cancer cells in their brains.

In their experiments, the researchers explored the ability of focused ultrasound to enhance delivery of two types of anti-cancer agents – the common chemotherapy drug doxorubicin and the targeted drug T-DM1, which combines the HER2-antibody-based drug trastuzumab (Herceptin) with cytotoxic DM1.

Not only did the approach improve delivery of both drugs across blood vessel walls, with even greater improvement for the smaller doxorubicin molecule, it also improved the distribution of both drugs within tumor tissue.

For the first time, the MGH team's experiments showed that focused ultrasound enhanced the permeability of the endothelial cells that line tumor blood vessels, leading those cells to take up doxorubicin.