Breaching the blood-brain barrier to treat tumors

UC researchers examine use of RNA treatments delivered in nanosized particles to target brain cancer

Personalized medicine is becoming the promise for better patient outcomes, and RNA-based drugs are leading the way, as they hold the potential to change the standard of care for many diseases.

RNA helps to turn genes on and off, aids in chemical reactions, slices and dices other RNA and even builds proteins, so harnessing this power for targeted therapy could open the door to new, powerful treatments. RNA vaccines are among those now being used to combat COVID-19.

But so far, these drugs haven’t been quite as useful in getting through to the brain to treat tumors and other illnesses. 

Researchers at the University of Cincinnati, in collaboration with the Georgia Institute of Technology and Emory University, have found that using ultrasound combined with RNA-loaded nanoparticles could help infiltrate the blood-brain barrier and deliver targeted, more effective treatment to brain tumors, while eliminating uncomfortable side effects.

researchers in their lab

Daniel Pomeranz Krummel, PhD, research associate professor at UC, and Soma Sengupta, MD, PhD, associate director of the UC Gardner Neuroscience Institute’s Brain Tumor Center, were integral contributors to this research, which could lead to better treatments for brain tumors. Photo credit/Joe Fuqua/UC Creative + Brand

The study was published in the journal Science Advances and could lead to new treatments for patients with a cancer that historically has poor outcomes: medulloblastoma, the most common brain tumor in children.

Soma Sengupta, MD, PhD, associate director of the UC Gardner Neuroscience Institute’s Brain Tumor Center, and Daniel Pomeranz Krummel, PhD, were integral contributors to the research.

Pomeranz Krummel, research associate professor of neurology at UC, designed the RNA therapeutic used in the study. This is the first time that RNA therapeutics have been shown to successfully treat brain tumors.

RNA has enormous potential to function as a therapeutic to treat brain tumors, but the challenge is getting the RNA to the tumor in adequate amounts and keeping it safe from degradation. We have potentially overcome both challenges [with this study].

Daniel Pomeranz Krummel, PhD

RNA drugs have two major weaknesses: limited circulation time in the body and minimal absorption by cells. To overcome these challenges, researchers package the RNA drugs in nanocarriers, typically 100 nanometers in size, to improve their ability to be taken in by cells and delivered effectively. Still, these nanocarriers have been too large to penetrate the blood-brain barrier, the tightly connected and selective cells surrounding blood vessels in the brain, until now.

“RNA has enormous potential to function as a therapeutic to treat brain tumors,” says Pomeranz Krummel. “But the challenge is getting the RNA to the tumor in adequate amounts and keeping it safe from degradation. We have potentially overcome both challenges.”

Using animal models, the team used a modified version of ultrasound, the diagnostic imaging technique that uses sound waves to create images of internal body structures, such as tendons, blood vessels, organs and babies in utero.

Haworth in his lab with a colleague

Image of microscopic nanoparticles loaded with RNA (left), illustration of RNA (middle), to target brain tumors (red-orange in the brain of illustration, right; credit: Ikumi Kayama). Provided by Pomeranz Krummel.

The researchers combined this technology with microbubbles — tiny gas pockets in the bloodstream designed as contrast agents for imaging — which vibrate in response to ultrasound waves, opening the blood vessels just enough to let the RNA-loaded nanoparticles into the brain. 

“The first clinical trials using ultrasound to selectively open the blood-brain barrier have occurred in just the past few years. This latest work could be a game changer based on all the potential ways for RNA to treat a whole range of diseases, from Alzheimer’s disease to cancer. There is a real chance for this work to have a major impact on clinical care in the near future,” says Kevin Haworth, PhD, associate professor in the Division of Cardiovascular Health and Disease at UC who specializes in the study of ultrasound for therapeutic delivery. He and his lab will be joining the next phase of the study as experts in the field. His colleagues Christy Holland, PhD, also a faculty member in the division, and Douglas Mast, PhD, in the College of Engineering and Applied Science, have been studying for decades the use of ultrasound and microbubbles as a way to noninvasively deliver treatments throughout the body. They have built one of the top internationally recognized groups in therapeutic ultrasound.

Researchers packaged siRNA, a drug that can block the expression of genes that drive tumor growth which was designed by UC researchers, in nanoparticles and combined that with the focused ultrasound technique in pediatric and adult brain cancer models.

They found improvement in delivery of the drug almost 10 times of what it was previously, stopping tumor cells from reproducing and causing the tumor to shrink. 

This technology has enormous potential in treating all kinds of brain cancers in adults and children. This can greatly change the way brain cancers are treated.

Soma Sengupta, MD, PhD

Sengupta, associate professor of neurology at UC and UC Health neuro-oncologist, says this treatment could be especially desirable because it can be modified to fit the patient’s needs – physicians can fine-tune the ultrasound pressure to control drug delivery. Also, it’s noninvasive and very targeted in nature, because it’s being delivered directly to the tumor.

“Being able to deliver this type of targeted treatment, without medicines running their course through a person’s body, will help in eliminating potentially devastating side effects,” says Sengupta, who is also the Harold C. Schott Endowed Chair of Molecular Therapeutics. “This technology has enormous potential in treating all kinds of brain cancers in adults and children. This can greatly change the way brain cancers are treated.”

Following this study, Sengupta and Pomeranz Krummel are designing experiments with Haworth and co-authors at Georgia Tech and Emory to examine how this method can be used for treatment of tumors that are not able to be removed via surgery.

Featured photo: Kevin Haworth, PhD, associate professor in the Division of Cardiovascular Health and Disease at UC who specializes in the study of ultrasound for therapeutic delivery, says these latest findings could be a "game changer" for RNA treatments. Photo credit/Colleen Kelley/UC Creative + Brand

Impact Lives Here

The University of Cincinnati is leading public urban universities into a new era of innovation and impact. Our faculty, staff and students are saving lives, changing outcomes and bending the future in our city's direction. Next Lives Here.

Stay up to date on all UC's COVID-19 stories, or take a UC virtual visit and begin picturing yourself at an institution that inspires incredible stories.

This work was supported by the National Institutes of Health (NIH), grant No. R00 EB016971 and grant No. R37 CA239039; and the CURE Foundation. Authors cite no conflicts of interest.