In the past, numerous potential glioblastoma treatments have revealed success in animal designs however then ended up stopping working in clinical trials. This suggests that a better kind of modeling is required, says Joelle Straehla, the Charles W. and Jennifer C. Johnson Clinical Investigator at MITs Koch Institute for Integrative Cancer Research, an instructor at Harvard Medical School, and a pediatric oncologist at Dana-Farber Cancer Institute.
” We are hoping that by checking these nanoparticles in a lot more realistic design, we can cut out a lot of the time and energy thats wasted trying things in the clinic that dont work,” she states. “Unfortunately, for this kind of brain tumor, there have been hundreds of trials that have actually had unfavorable outcomes.”
Straehla and Cynthia Hajal SM 18, PhD 21, a postdoc at Dana-Farber, are the lead authors of the research study, which was published on June 1, 2022, in the Proceedings of the National Academy of Sciences. Paula Hammond, an MIT Institute Professor, head of the Department of Chemical Engineering, and a member of the Koch Institute; and Roger Kamm, the Cecil and Ida Green Distinguished Professor of Biological and Mechanical Engineering, are the senior authors of the paper.
Designing the blood-brain barrier
A number of years back, Kamms lab began dealing with a microfluidic design of the brain and the blood vessels that comprise the blood-brain barrier.
Because the brain is such a crucial organ, the blood vessels surrounding the brain are a lot more limiting than other capillary in the body, to keep out possibly damaging particles.
To imitate that structure in a tissue design, the scientists grew patient-derived glioblastoma cells in a microfluidic device. They utilized human endothelial cells to grow blood vessels in small tubes surrounding the sphere of tumor cells. The design likewise consists of astrocytes and pericytes, two cell types that are included in transporting molecules across the blood-brain barrier.
While Hajal was working on this model as a college student in Kamms lab, she got linked with Straehla, then a postdoc in Hammonds laboratory, who was interested in discovering new methods to model nanoparticle drug shipment to the brain. Getting drugs throughout the blood-brain barrier is vital for enhancing treatment for glioblastoma, which is typically treated with a mix of surgical treatment, radiation, and the oral chemotherapy temozolomide. The five-year survival rate for the disease is less than 10 percent.
Hammonds laboratory originated a method called layer-by-layer assembly, which they can use to produce surface-functionalized nanoparticles that bring drugs in their core. The particles that the scientists established for this study are covered with a peptide called AP2, which has actually been displayed in previous work to assist nanoparticles survive the blood-brain barrier. However, without accurate models, it was tough to study how the peptides assisted with transport across blood vessels and into growth cells.
When the scientists delivered these nanoparticles to tissue models of both glioblastoma and healthy brain tissue, they discovered that the particles coated with the AP2 peptide were better at permeating the vessels surrounding the tumors. They likewise revealed that the transport happened due to binding a receptor called LRP1, which is more abundant near tumors than in regular brain vessels.
The scientists then filled the particles with cisplatin, a commonly utilized chemotherapy drug. When these particles were coated with the targeting peptide, they were able to efficiently kill glioblastoma growth cells in the tissue model. Nevertheless, particles that didnt have the peptides wound up damaging the healthy capillary rather of targeting the growths.
” We saw increased cell death in tumors that were treated with the peptide-coated nanoparticle compared to the bare nanoparticles or complimentary drug. Those covered particles showed more specificity of eliminating the tumor, versus killing whatever in a nonspecific way,” Hajal says.
More reliable particles
The scientists then tried delivering the nanoparticles to mice, utilizing 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 extremely similar to what they had actually seen in their human tissue model.
They also showed that coated nanoparticles carrying cisplatin could slow down tumor development in mice, but the effect wasnt as strong as what they saw in the tissue design. They also prepare to utilize their technique to design other types of brain growths.
” This is a model that we might use to design more efficient nanoparticles,” Straehla says. “Weve only evaluated one kind of brain growth, but we truly want to expand and check this with a lot of others, especially unusual tumors that are challenging to study due to the fact that there may not be as lots of samples offered.”
The researchers explained the method they utilized to produce the brain tissue model in a recent Nature Protocols paper, so that other laboratories can also use it.
Recommendation: “A predictive microfluidic design of human glioblastoma to evaluate 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.DOI: 10.1073/ pnas.2118697119.
The research study was funded, in part, by a Cooperative Agreement Award from the National Cancer Institute, a Horizon Award from the Department of Defense Peer Reviewed Cancer Research Program, a Cancer Research UK Brain Tumour Award, a Ludwig Center for Molecular Oncology Graduate Fellowship, the Rally Foundation for Childhood Cancer Research/The Truth 365, the Helen Gurley Brown Presidential Initiative, and the Koch Institute Support (core) Grant from the National Cancer Institute.
MIT researchers have actually created a tissue model that enables them model drug delivery to brain tumors. Tumor cells (green) are surrounded by endothelial cells (purple). Credit: Cynthia Hajal and Roger D. Kamm (MIT), edited by Chris Straehla
Checked utilizing a brand-new brain tissue design, the small particles may be able to provide chemotherapy drugs for glioblastoma, an aggressive and fast-growing type of cancer.
Presently, there are really couple of good treatment choices for glioblastoma, an aggressive kind of brain cancer with a high death rate. One factor that the disease is so difficult to treat is that many chemotherapy drugs cant penetrate the capillary that surround the brain.
A group of researchers at MIT is now developing drug-carrying nanoparticles that appear to get into the brain more effectively than drugs given on their own. Using a human tissue model they designed, which precisely replicates the blood-brain barrier, the scientists revealed that the particles might enter growths and eliminate glioblastoma cells.
MIT scientists have actually produced a tissue model that permits them model drug delivery to brain tumors. While Hajal was working on this design as a graduate trainee in Kamms lab, she got connected with Straehla, then a postdoc in Hammonds laboratory, who was interested in finding brand-new methods to design nanoparticle drug shipment to the brain. Without accurate models, it was hard to study how the peptides helped with transport throughout blood vessels and into growth cells.
When these particles were covered with the targeting peptide, they were able to successfully eliminate glioblastoma tumor cells in the tissue model. They also plan to utilize their technique to model other types of brain growths.
