Researchers have developed a noninvasive way to deliver drugs to the brainstem in patients with tumors in that part of the brain. The technique may bring medicine one step closer to curing brain-based diseases such as diffuse intrinsic pontine gliomas (DIPG), a childhood brain cancer with a five-year survival rate of a scant two percent, a dismal prognosis that has remained unchanged over the past 40 years. To add perspective, the most common childhood cancer, acute lymphoblastic leukemia, has a five-year survival rate of nearly 90 percent.
A person’s brainstem controls some of the body’s most important functions, including heartbeat, respiration, blood pressure, and swallowing. Tumor growth in this part of the brain is therefore twice as devastating.
Not only can such a growth disrupt vital functions, but operating in this area is so risky, many medical professionals refuse to consider it as an option. Now, using the new method, researchers can pair ultrasound and its contrast agent — consisting of tiny bubbles — with intranasal administration to direct a drug to the brainstem and, potentially, any other part of the brain.
Diffuse Intrinsic Pontine Gliomas
The work was spurred by a conversation between Hong Chen, assistant professor of biomedical engineering in the School of Engineering & Applied Science and assistant professor of radiation oncology at Washington University School of Medicine in St. Louis, and Joshua Rubin, professor of pediatrics at the School of Medicine.
“My work in this field started with a conversation with him. He says, ‘Wow, this would be a perfect technique for treating this deadly disease.’ Without him to point me in this direction, I probably wouldn’t have known this application existed. Each year in the United States, there are no more than 300 cases. All pediatric diseases are rare; luckily, this is even more rare. But we cannot count numbers in this way, because for kids that have this disease and their families, it is devastating,”
Chen’s technique combines Focused UltraSound with IntraNasal delivery. The intranasal delivery takes advantage of a unique property of the olfactory and trigeminal nerves: they can carry nanoparticles directly to the brain, bypassing the blood brain barrier, an obstacle to drug delivery in the brain. Researchers demonstrated this unique capability of intranasal delivery in a 2017 paper in Scientific Reports.
“At the beginning, I couldn’t even believe this could work. I thought our brains are fully protected. But these nerves actually directly connect with the brain and provide direct access to the brain,”
Hong says of delivering drugs to the brain intranasally.
While nasal brain drug delivery is a huge step forward, it isn’t yet possible to target a drug to a specific area. Chen’s targeted ultrasound technique is addressing that problem.
When doing an ultrasound scan, microbubbles make up the contrast agent that highlights images. Once injected into the bloodstream, the microbubbles behave like red blood cells, traversing the body as the heart pumps.
Once they reach the site where the ultrasound wave is focused, they do something unusual.
“They start to expand and contract,”
Chen says. As they do so, they act as a pump to the surrounding blood vessels as well as the perivascular space—the space surrounding the blood vessels.
“Consider the blood vessels like a river. The conventional way to deliver drugs is to dump them in the river.” In other parts of the body, the banks of the river are a bit “leaky,” Chen says, allowing the drugs to seep into the surrounding tissue. But the blood brain barrier, which forms a protective layer around blood vessels in the brain, prevents this leakage, particularly in the brains of young patients, such as those with DIPG. We will deliver the drug from the nose to directly outside the river,” Chen says, “in the perivascular space.”
Then, once ultrasound is applied at the brain stem, the microbubbles will begin to expand and contract. The oscillating microbubbles push and pull, pumping the drug toward the brainstem. This technique also addresses the problem of drug toxicity — the drugs will go directly to the brain instead of circulating through the whole body.
In collaboration with Yongjian Liu and Yuan-Chuan Tai, both associate professors of radiology, Chen used positron emission tomography (PET scan) to verify that there was minimal accumulation of intranasal-administered nanoparticles in major organs, including lungs, liver, spleen, kidney, and heart.
So far, Chen’s lab has had success using their technique in mice for the delivery of gold nanoclusters made by the team led by Liu.
“The next step is to demonstrate the therapeutic efficacy of the new technique in the delivery of chemotherapy drugs for the treatment of DIPG,”
says lead paper author Dezhuang Ye, Chen’s graduate student from the mechanical engineering & materials science department.
The lab hopes to develop a new aerosol nasal delivery device to scale up the technique from a mouse to a large animal model. Chen says the team also hopes to translate the findings of this study into clinical trials for children with DIPG.
There are difficulties ahead, but Chen believes researchers will need to continue to innovate when it comes to solving such a difficult problem as treating DIPG.
The American Cancer Society, the Children’s Discovery Institute of Washington University, and St. Louis Children’s Hospital supported the work.
Dezhuang Yea, Xiaohui Zhangb, Yimei Yuec, Ramesh Raliya, Pratim Biswas, Sara Taylor, Yuan-chuan Tai, Joshua B. Rubin, Yongjian Liu, Hong Chen
Focused ultrasound combined with microbubble-mediated intranasal delivery of gold nanoclusters to the brain
Journal of Controlled Release Volume 286, 28 September 2018, Pages 145-153
Image: Washington University