Thinking Small to Cure Brain Cancer
In the treatment of cancer, chemotherapy describes the use of drugs to kill cancer cells, stop their spread, or slow their growth. But when it comes to treating glioblastoma and other malignant brain tumors, drugs face unique obstacles.
“The brain is a privileged site within the body,” said Dr. Rachael Sirianni, an assistant professor of neurobiology at Barrow Neurological Institute. “Most systemically administered pharmaceutical agents do not reach the brain in therapeutic concentrations.”
Drugs delivered through the body’s bloodstream usually fail to cross the blood-brain barrier, which serves as a filter to protect the brain, and those delivered directly to the brain are subject to a variety of transport forces that restrict the amount of tissue that can be treated.
These barriers to effective drug delivery are the focus of Dr. Sirianni’s laboratory, which was established at Barrow in 2011. One strategy to improve drug delivery is to encapsulate drugs within nanoparticles, which are defined as having one dimension that measures 100 nanometers or smaller.
“We use polymer nanoparticles to control the release of drugs so that they have a more sustained presence in the body, and we also engineer the nanoparticles to have specific surface properties that facilitate their interaction with the central nervous system,” Dr. Sirianni said. “By improving nanoparticle interaction with the brain and spinal cord, we can improve delivery of the drugs to those tissue sites as well.”
One of the methods used to make nanoparticles is a process called emulsion, which Dr. Sirianni compared to mixing oil and vinegar together to make salad dressing. A polymer, which is a large molecule made up of many smaller molecules bonded together, is dissolved in an organic solvent, and the chemotherapy drug is added. This oil phase is then mixed with a water phase, which contains emulsifier to keep the two from separating. Finally, energy is introduced to break up the oil into very small droplets — smaller than 100 nanometers.
“We work a lot on nanoparticle design for different kinds of drugs, so we pair up with other biologists and brain tumor researchers to identify compounds that would be effective if they could be delivered to the brain,” Dr. Sirianni said. “For each of those compounds, we then determine how to make particles to encapsulate the high quantity of the drug to have prolonged release of the drug over time. Depending on the composition of the particle, the drug will come out at different rates.”
Dr. Sirianni said this controlled release of a drug is one of the advantages of nanoparticles. She and her team argue that although crossing the blood-brain barrier is not so easy, nanoparticle delivery strategies can still be beneficial for the treatment of diseases that affect the brain and spinal cord.
“Instead, we see a lot of more general reasons why polymer nanoparticles can be effective,” she said. “Those include improving tolerability to compounds, solubilizing them so that a higher dose can be delivered, prolonging their release which reduces peak concentration and can reduce toxicity, and reducing delivery to off-target organs. Even if that nanoparticle is not crossing into the brain, by improving its interaction with the blood vessels in the brain, we can have a higher concentration of drug available for delivery to the brain. Thus, we develop nanoparticle systems that can capitalize on these known benefits of controlled release while pursing targeting or blood-brain barrier passage as a longer-term research goal.”
However, identifying where a nanoparticle has landed within the body is difficult, which is why Dr. Sirianni and her team also study ways to track nanoparticle distribution within the body.
By improving nanoparticle interaction with the brain and spinal cord, we can improve delivery of the drugs to those tissue sites as well.
-Dr. Rachael Sirianni, Assistant Professor of Neurobiology
“We spend a lot of time working on better methods for understanding the fate of the particle in the body so that we can test whether our approaches are effective at bypassing these biological barriers,” she said.
Another aspect of Dr. Sirianni’s laboratory is tissue engineering. She and her team use polymeric biomaterials to understand how patient-derived cells interact with their microenvironment. These materials, or hydrogels, serve as a 3-D support for cells to grow and to mimic important aspects of the brain microenvironment.
“By manipulating those artificial environments, we can selectively study how cells respond to biological signals that are present in the brain,” she said. “That’s important for understanding how cells will respond to treatment.”
Dr. Sirianni and her team specifically study microenvironments in the context of glioblastoma, the deadliest of the tumors that originate in the brain.
While most of the research into nanoparticles is still being conducted in laboratories, Dr. Sirianni said some therapies are beginning to reach clinical trials.
“I think the outlook is promising,” she said.