There are currently few good treatment options for glioblastoma, an aggressive type of brain cancer with a high mortality rate. One reason the disease is so difficult to treat is that most chemotherapy drugs cannot penetrate the blood vessels that surround the brain.
A team of MIT researchers is now working to develop drug-carrying nanoparticles that appear to reach the brain more efficiently than drugs given alone. Using their human tissue model, which accurately replicates the blood-brain barrier, the researchers showed that the molecules can enter tumors and kill glioblastoma cells.
Several treatments for glioblastoma have shown success in animal models but then end up failing in clinical trials. This points to the need for a better kind of modeling, say Joel Strella, Charles W. and Jennifer C. Johnson, clinical investigator at MIT’s Koch Institute for Integrative Cancer Research, an instructor at Harvard Medical School, and a pediatric oncologist at Dana Farber. Cancer Institute.
“We hope that by testing these nanoparticles in a more realistic model, we can cut out a lot of time and energy wasted trying things that don’t work in the clinic,” she says. “Unfortunately, for this type of brain tumor, there have been hundreds of trials that have had negative results.”
Straehla and Cynthia Hajal SM ’18, PhD ’21, a postdoctoral student at Dana-Farber, are the lead authors of the study, which appears this week in Proceedings of the National Academy of Sciences. Paula Hammond, MIT professor, chair of the chemical engineering department and a member of the Koch Institute. And Roger Cam, Distinguished Professor of Biological and Mechanical Engineering by Cecil and Ida Green, are senior authors on the research.
Modeling of the blood-brain barrier
Several years ago, Cam’s lab began working on a microfluidic model of the brain and blood vessels that make up the blood-brain barrier.
Since the brain is a vital organ, the blood vessels surrounding the brain are more constricted than other blood vessels in the body, in order to block potentially harmful particles.
To mimic this structure in a tissue model, the researchers grew patient-derived glioblastoma cells in a microfluidic device. Then they used human endothelial cells to grow blood vessels into microtubules that surround the field of tumor cells. The model also includes astrocytes and astrocytes, two types of cells involved in transporting molecules across the blood-brain barrier.
While Hajal was working on this model as a graduate student in Cam’s lab, she was in contact with Strella, then a postdoc in Hammond’s lab, who was interested in finding new ways to model nanoparticle drug delivery into the brain. Getting drugs across the blood-brain barrier is critical to improving treatment of glioblastoma, which is usually treated with a combination of surgery, radiation, and oral chemotherapy, temozolomide. The five-year survival rate for the disease is less than 10 percent.
Hammond’s lab has pioneered a technique called layer-by-layer aggregation, which can be used to create functional surface nanoparticles that carry drugs in their core. The particles the researchers developed for this study are coated with a peptide called AP2, which has been shown in previous work to help nanoparticles penetrate the blood-brain barrier. However, without accurate models, it has been difficult to study how the peptides helped transport through blood vessels and into cancer cells.
When the researchers applied these nanoparticles to tissue models of both glioblastoma and healthy brain tissue, they found that the AP2 peptide-coated particles were much better at penetrating the vessels surrounding the tumors. They also showed that the transfer occurred due to binding of a receptor called LRP1, which is more abundant near tumors than in normal brain vessels.
The researchers then filled the particles with cisplatin, a drug commonly used in chemotherapy. When these particles were coated with the target peptide, they were able to effectively kill glioblastoma tumor cells in a tissue model. However, the particles without the peptides ended up damaging healthy blood vessels rather than targeting tumors.
“We saw increased cell death in tumors treated with peptide-coated nanoparticles compared to bare nanoparticles or free drugs. These coated nanoparticles showed more specificity in killing the tumor, as opposed to killing everything in a nonspecific manner,” says Hajal.
More effective particles
The researchers then attempted to deliver the nanoparticles to mice by using a specialized surgical microscope to track the nanoparticles moving through the brain. They found that the particles’ ability to cross the blood-brain barrier was very similar to what they saw in a human tissue model.
They also showed that encapsulated nanoparticles carrying cisplatin could slow tumor growth in mice, but the effect was not as strong as they saw in the tissue model. Researchers say this may be because the tumors were at a more advanced stage. They now hope to test other drugs, carried by a variety of nanoparticles, to see which might have the greatest effect. They also plan to use their approach to model other types of brain tumors.
“This is a model we can use to design more efficient nanoparticles,” Strella says. “We only tested one type of brain tumor, but we really want to expand that type and test with a lot of other tumors, especially rare tumors that are difficult to study because there may not be many samples available.”
The researchers described the method they used to create a brain tissue model recently Nature’s Protocols Paper, so other labs can use it as well.
Reference: Straehla JP, Hajal C, Safford HC et al. A predictive microfluidic model of human glioblastoma to assess the trafficking of nanoparticles penetrating the blood-brain barrier. PNAS. 2022; 119 (23): e2118697119. doi: 10.1073/pnas.2118697119
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