Microbubbles are not what form when you run your hot tub jets at high speed. Rather, they’re an artificial construct that consist of gas surrounded by a thin, fatty shell that ranges from one to 10 thousandths of a millimeter in diameter. These bubbles are one of the more exciting tools, when married with ultrasound, that are helping revolutionize cancer research and therapy.
At the forefront of that research is UNC Lineberger’s Paul Dayton, PhD, professor in the UNC & N.C. State Joint Department of Biomedical Engineering. The joint department is a unique and important association that boosts collaborative research efforts across North Carolina by bringing medical and engineering expertise together to solve problems in health care.
“Our workplace is called the ‘Non-Invasive Functional Imaging and Targeted Therapeutics Lab’ because the two go hand-in-hand, especially since ultrasound and microbubbles are used in all of our projects,” Dayton said. “Ultrasound is a really unique modality because it is both highly effective for imaging and for therapy, as we can do either independently as well as using imaging to guide therapy, the latter being crucially important for many non-invasive, targeted, non-pharmaceutical therapies.”
Advancements in ultrasound technology
Ultrasound is an imaging technique that has been in use for the past half-century. While major medical imaging tools, such as MRI, are quite large and are getting more expensive, ultrasound is getting smaller and cheaper. Many former limitations of ultrasound technology were related to electronics, but with the advances in integrated circuits and microchips, ultrasound systems are now as small as a cell phone, and they don’t cost much more than a cell phone either.
Currently, ultrasound is mainly used to evaluate anatomy and tissue differences, such as observing suspicious lesions to see if they appear cancerous. It is also used to image blood flow patterns which might suggest disease or pathology, or lack thereof. With the latest advancements, Dayton’s lab is exploring new ways to use ultrasound to look in great detail at the tiny blood vessels, or microvasculature, that course throughout the body.
“If there was a technique available that could image microvascular properties, it could tell physicians a lot about disease status,” said Dayton. “So, we are working on techniques to enable ultrasound to visualize small blood vessels, and these techniques involve contrast agents, primarily microbubbles, that flow through, and thus highlight, the microvasculature.”
Microbubbles in cancer research
Engineered microbubbles, which have been around for more than 30 years, scatter sound so they are easy to detect with ultrasound. Dayton’s lab needs bubbles that can last up to five minutes for imaging projects, so they use fluorocarbon gas, which is inert. For treatment applications, however, they use a gas that tumors are short on – oxygen – which exits the bubble and can flow into a tumor and make it more susceptible to treatment by radiation.
Recently, microbubbles received expanded approval from the U.S. Food and Drug Administration for visualizing the liver to help characterize liver lesions. Most crucially in the treatment realm, microbubbles can cause a range of biological effects. At low ultrasound intensities, such as those used for contrast ultrasound imaging, biological changes are believed to be very minimal, with adverse effects being less than other imaging contrast agents. However, at high ultrasound energies, microbubbles can have a range of effects, such as changing the permeability of blood vessels, enhancing immune response, and even destroying tissue at high intensity ranges. While these effects are not desirable for diagnostic imaging, they can also be helpful therapeutically if used in a controlled fashion, noted Dayton.
Better treatments for cancer are the ultimate goal for Dayton’s lab. For example, immunotherapies haven’t been used extensively or effectively against pancreatic cancer, but it might be possible that stimulating the immune system with microbubbles could be effective. However, there is much work to be done to make this a reality. “We are still trying to understand exactly what might be going on when trying to treat cancer with microbubbles. One hypothesis is that ultrasound using microbubbles induces mechanical agitation of diseased cells, leading to an increase in the release of antigens that could stimulate immune responses to attack cancer,” he said.
Developing targeted therapies
Dayton’s lab also works on targeted therapies. They are developing delivery vehicles that can be activated by ultrasound to release a drug to the target site. The goal is that local delivery of a drug will have improved efficacy to the diseased tissue and reduced systemic effects. Additionally, they hope to use ultrasound to modify the tissue itself. One example would be locally modulating the blood/brain barrier to allow systemically circulating drugs to cross the barrier and treat a brain disease.
So, what’s next? Dayton’s lab is working with two local companies he co-founded to advance his research: SonoVol is developing and selling advanced ultrasound imaging systems; Triangle Biotechnology is developing reagents for ultrasound applications in genetic and genomic analysis.
Ultimately, though, low cost, portability, safety and the improved image quality of new ultrasound devices are all reasons why Dayton thinks ultrasound married to microbubble use is going to play an increasingly important role in the future of cancer research and public health.
Dayton said the success of translating laboratory discoveries into potential clinical advances speaks to the collaborative spirit of UNC Lineberger and UNC Health faculty. “We are actively developing lots of different technologies, and if we can get some of them into the clinic to save lives, that would be huge,” he said.