Summary: Researchers have developed drug-bearing nanoparticles that cross the blood-brain barrier, allowing more efficient delivery to the brain than conventional drugs. Nanoparticles can enter tumors and kill glioblastoma brain cancer cells.
There are currently few good treatment options for glioblastoma, an aggressive type of brain cancer with high mortality. One of the reasons the disease is so difficult is that most chemotherapeutic drugs cannot penetrate the blood vessels that surround the brain.
A team of researchers at MIT is now developing drug-delivering nanoparticles that reach the brain more efficiently than drugs administered alone. Using a human tissue model that they designed to accurately replicate the blood-brain barrier, researchers have shown that particles can enter tumors and kill glioblastoma cells.
Many potential treatments for glioblastoma have shown success in animal models, but have subsequently failed in clinical trials. This suggests that a better kind of modeling is needed, says Joelle Straehla, a clinical researcher at Charles W. and Jennifer C. Johnson of the Koch Institute for Integrated Cancer Research MIT, an instructor at Harvard Medical School and a pediatric oncologist from Dana-Farber. Cancer Institute.
“We hope that testing these nanoparticles in a much more realistic model can save a lot of time and energy that is wasted testing things in the clinic that don’t work,” he says. “Unfortunately, hundreds of studies have been done with negative types of brain tumors.”
Straehla and Cynthia Hajal SM ’18, PhD ’21, postdoc at Dana-Farber, are the lead authors of a study that will appear this week in Proceedings of the National Academy of Sciences. Paula Hammond, Professor at MIT, Head of the Department of Chemical Engineering and Member of the Koch Institute; and Roger Kamm, acclaimed professor of biological and mechanical engineering Cecil and Ida Green, are the main authors of the article.
Modeling of the blood-brain barrier
A few years ago, Kamm’s lab began working on a microfluidic model of the brain and blood vessels that form the blood-brain barrier.
Because the brain is such a vital organ, the blood vessels surrounding the brain are much more restrictive than other blood vessels in the body to prevent potentially harmful molecules from entering them.
To mimic this structure in a tissue model, the researchers grew glioblastoma cells obtained from a patient in a microfluidic device. They then used human endothelial cells to grow blood vessels in small tubes surrounding the tumor cell sphere. The model also includes pericytes and astrocytes, two types of cells that are involved in transporting molecules across the blood-brain barrier.
While working on this model as a graduate student in Kamm’s lab, Hajal teamed up with Straehla, then a postdoctoral fellow in Hammond’s lab, to find new ways to model the delivery of nanoparticulate drugs to the brain.
Getting drugs across the blood-brain barrier is essential to improve the treatment of glioblastoma, which is usually treated with a combination of surgery, radiation, and temozolomide oral chemotherapy. The five-year survival of the disease is less than 10 percent.
Hammond’s laboratory pioneered a technique called layer-by-layer assembly, which they can use to create surface-functionalized nanoparticles that carry drugs at their core. The particles that the researchers developed for this study are coated with a peptide called AP2, which has been shown in previous work to help nanoparticles cross the blood-brain barrier.
However, without accurate models, it has been difficult to study how peptides help with transport across blood vessels and into tumor cells.
When researchers delivered these nanoparticles to glioblastoma and healthy brain tissue models, they found that AP2-coated particles penetrated the vessels surrounding the tumors much better. They also showed that transport occurred due to binding to a receptor called LRP1, which is more abundant near tumors than in normal cerebral vessels.
The researchers then filled the particles with cisplatin, a commonly used chemotherapy drug. When these particles were coated with a targeting peptide, they were able to effectively kill glioblastoma tumor cells in a tissue model. However, particles that did not have the peptides eventually damaged healthy blood vessels instead of targeting tumors.
“We saw increased cell death in tumors that were treated with peptide-coated nanoparticles compared to bare nanoparticles or free drug. These coated particles showed greater specificity in killing the tumor than killing it in a non-specific way,” says Hajal.
More efficient particles
The researchers then tried to deliver nanoparticles to mice using a specialized surgical microscope to monitor nanoparticles moving in the brain. They found that the ability of the particles to cross the blood-brain barrier was very similar to what they saw in their human tissue model.
They also showed that coated cisplatin-bearing nanoparticles could slow tumor growth in mice, but the effect was not as strong as what they saw in the tissue model. This could be because the tumors were at a more advanced stage, the researchers say.
They now hope to test other drugs carried by a number of nanoparticles to see which could have the greatest effect. They also plan to use their approach to model other types of brain tumors.
“This is a model we could use to design more efficient nanoparticles,” says Straehla. “We’ve only tested one type of brain tumor, but we really want to expand and test it with a lot of other, especially rare, tumors that are difficult to study because there may not be so many samples available.”
Researchers have recently described a method they used to create a model of brain tissue Natural protocols paper so that other laboratories can use it.
Financing: The research was partly funded by a collaboration award from the National Cancer Institute, the Horizon Award by the Department of Defense Peer Reviewed Cancer Research Program, Cancer Research UK Brain Tumor Award, Ludwig Center for Molecular Oncology Graduate Fellowship, Rally Foundation for Childhood Cancer Research / The Truth 365, Presidential Helen Gurley Brown initiative and the Koch Institute (basic) grant from the National Cancer Institute.
About these news from nanotechnology research
Author: Anne Trafton
Contact: Anne Trafton-MIT
Picture: Cynthia Hajal and Roger D. Kamm (MIT), edited by Chris Straehl
Original research: The findings appear in PNAS
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