Massachusetts Institute of Technology (MIT) researchers have engineered a human blood–brain barrier microfluidic model that will expedite vascular permeability analyses. Using the model, they were able to demonstrate that specialized nanoparticles can deliver chemotherapy across the barrier and reach glioblastoma cells.
Because the brain is such a vital organ, the blood vessels that surround it are much more restrictive than others in the body to keep out potentially harmful molecules. But this barrier is one of the reasons why glioblastoma—an aggressive brain cancer with a five-year survival rate of less than 10%—is so difficult to treat. Most chemotherapy drugs can’t penetrate this blood-brain barrier.
Many potential glioblastoma treatments have shown success in animal models but then ended up failing in clinical trials. According to Joelle Straehla, the 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, this suggests better modeling is needed.
“We are hoping that by testing these nanoparticles in a much more realistic model, we can cut out a lot of the time and energy that’s wasted trying things in the clinic that don’t work,” Straehla says. “Unfortunately, for this type of brain tumor, there have been hundreds of trials that have had negative results.”
To mimic the blood-brain barrier in a tissue model, the researchers grew patient-derived glioblastoma cells in a microfluidic device. They then used human endothelial cells to grow blood vessels in tiny tubes surrounding the sphere of tumor cells. The model also includes pericytes and astrocytes, two cell types that are involved in transporting molecules across the blood-brain barrier.
The particles the researchers developed for this study were coated with a peptide called AP2, which has been shown in previous work to help nanoparticles get through the blood brain barrier. However, without accurate models, it was difficult to study how the peptides helped with transport across blood vessels and into tumor cells.
When the researchers delivered these nanoparticles to tissue models of both glioblastoma and healthy brain tissue, they found that the particles coated with the AP2 peptide were much better at penetrating the vessels surrounding the tumors. They also showed that the transport occurred due to binding a receptor called LRP1, which is more abundant near tumors than in normal brain vessels.
The researchers then filled the particles with cisplatin, a commonly used chemotherapy drug. When these particles were coated with the targeting peptide, they were able to effectively kill glioblastoma tumor cells in the tissue model. However, particles that didn’t have the peptides ended up damaging the healthy blood vessels instead of targeting the tumors.
“We saw increased cell death in tumors that were treated with the peptide-coated nanoparticle compared to the bare nanoparticles or free drug. Those coated particles showed more specificity of killing the tumor, versus killing everything in a nonspecific way,” says Cynthia Hajal, a postdoc at Dana-Farber and coauthor.
The researchers then tried delivering the nanoparticles to mice, 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 had seen in their human tissue model.
They also showed that coated nanoparticles carrying cisplatin could slow down tumor growth in mice, but the effect wasn’t as strong as what they saw in the tissue model. This might be because the tumors were in a more advanced stage, the researchers say. 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 that we could use to design more effective nanoparticles,” Straehla says. “We've only tested one type of brain tumor, but we really want to expand and test this with a lot of others, especially rare tumors that are difficult to study because there may not be as many samples available.”
The researchers described the method they used to create the brain tissue model in a recent Nature Protocols paper, so that other labs can also use it.