The small particles, which have been put to the test using a novel model of brain tissue, may be able to administer chemotherapeutic treatments for the aggressive and quickly proliferating glioblastoma tumour.
Glioblastoma, an aggressive form of brain cancer with a high mortality rate, currently has relatively few effective therapeutic options. Most chemotherapy medications are unable to enter the blood arteries that surround the brain, which is one reason why the condition is so challenging to treat.
MIT researchers are now working on creating drug-delivery nanoparticles that seem to enter the brain more quickly than pills administered orally. The researchers demonstrated that the particles could enter tumors and destroy glioblastoma cells using a human tissue model they created that precisely simulates the blood-brain barrier.
Many possible glioblastoma therapies in the past had promise in animal models but ultimately failed in human clinical trials. According to Joelle Straehla, a pediatric oncologist at Dana-Farber Cancer Institute, an instructor at Harvard Medical School, and the Charles W. and Jennifer C. Johnson Clinical Investigator at MIT's Koch Institute for Integrative Cancer Research, this indicates that improved modeling is required.
“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,” she adds. “Unfortunately, for this type of brain tumor, there have been hundreds of trials that have had negative results.”
The work, which was released on June 1, 2022, in the Proceedings of the National Academy of Sciences, was co-authored by Straehla and Cynthia Hajal, SM '18, PhD '21, a postdoc at Dana-Farber. The paper's senior authors are Roger Kamm, the Cecil and Ida Green Distinguished Professor of Biological and Mechanical Engineering, and Paula Hammond, an MIT Institute Professor, chair of the Department of Chemical Engineering, and member of the Koch Institute.
Modeling the blood-brain barrier
Kamm's group started developing a microfluidic model of the brain and the blood vessels that make up the blood-brain barrier some years ago.
The blood arteries around the brain are significantly more constrictive than other blood vessels in the body since the brain is such an important organ and needs to keep out potentially dangerous substances.
The researchers expanded patient-derived glioblastoma cells in a microfluidic device to simulate that shape in a tissue model. Then, scientists grew blood arteries in microscopic tubes encircling the sphere of tumor cells using human endothelial cells. Pericytes and astrocytes, two cell types important in chemical transport across the blood-brain barrier, are also included in the model.
Hajal met Straehla while both were working on this model as graduate students in Kamm's lab. Straehla was looking for novel approaches to mimic the transport of drugs by nanoparticles to the brain and was a postdoc in Hammond's lab at the time. For glioblastoma, which is often treated with a combination of surgery, radiation therapy, and the oral chemotherapy medication temozolomide, getting medicines through the blood-brain barrier is crucial to improve treatment. Less than 10% of patients with the condition survive five years.
Layer-by-layer assembly, a method invented by Hammond's group, may be used to make drug-carrying nanoparticles with functionalized surfaces. A peptide known as AP2, which has been demonstrated in other studies to assist nanoparticles in crossing the blood-brain barrier, is coated on the particles that the researchers created for this investigation. Studying how the peptides aided in trafficking across blood arteries and into tumor cells was challenging without precise models, though.
The particles coated with the AP2 peptide were considerably better at accessing the capillaries around the tumors, the researchers discovered when they administered these nanoparticles to tissue models of both healthy brain tissue and glioblastoma. Additionally, they demonstrated that the transport was triggered by binding to the LRP1 receptor, which is more prevalent in tumors than in healthy brain arteries.
Then the scientists added cisplatin, a popular chemotherapy medication, to the particles. In the tissue model, these particles were able to efficiently kill glioblastoma tumor cells when they were coated with the targeting peptide. However, the absence of the peptides resulted in the particles harming the healthy blood arteries rather than the malignancies.
“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,” according to Hajal.
More effective particles
Using a sophisticated surgical microscope to monitor the nanoparticles' passage through the brain, the researchers subsequently attempted administering the nanoparticles to mice. They discovered that the particles' capacity to pass the blood-brain barrier was remarkably comparable to what they had observed in their model of human tissue.
Additionally, they demonstrated that cisplatin-coated nanoparticles may inhibit the development of tumors in mice, however the impact was not as potent as that in the tissue model. The researchers speculate that this may have been caused by the cancers' advanced state. They now intend to test other nanoparticle-carried medications to see which one would have the most impact. They intend to apply their method to simulate several different kinds of brain cancers.
“This is a model that we could use to design more effective nanoparticles,” Straehla explains. “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.”
In a recent Nature Protocols study, the researchers provided instructions on how to make the brain tissue model so that other laboratories may also utilize it.
Reference: “A predictive microfluidic model of human glioblastoma to assess trafficking of blood–brain barrier-penetrant nanoparticles” by Joelle P. Straehla, Cynthia Hajal, Hannah C. Safford, Giovanni S. Offeddu, Natalie Boehnke, Tamara G. Dacoba, Jeffrey Wyckoff, Roger D. Kamm and Paula T. Hammond, 1 June 2022, Proceedings of the National Academy of Sciences.
