Researchers at Oregon State University have developed a promising experimental strategy to treat glioblastoma, the most aggressive type of brain tumor. Less than 30% of patients survive 2 years after diagnosis.
The study, led by Ole Talatulla, Olena Talatulla, and Yoon Tae-goo from the OSU College of Pharmacy, focuses on two major issues that have long limited treatment for glioblastoma. First, the therapy must cross the blood-brain barrier, a tightly regulated network of cells that protects the central nervous system from substances circulating in the bloodstream. Second, the treatment must reach tumor cells without affecting healthy tissue.
Sugar-coated nanoparticles target brain tumors
Researchers used mouse models to test lipid nanoparticles loaded with genetic material designed to restore the body’s ability to suppress tumor growth. The particles were then coated with a sugar coating, which helped them enter the brain and concentrate within the tumor.
This approach increased the median survival time of glioblastoma mice by 50%, according to research published in the Journal of Controlled Release.
The sugar used in the coating is mannose, which is closely related to glucose, the body’s main energy source. Cells lining blood vessels in the brain normally contain a transporter called GLUT1, which transports glucose to the central nervous system. GLUT1 can also recognize mannose, allowing coated nanoparticles to cross the blood-brain barrier using the same pathway.
“Blood contains relatively high concentrations of glucose, which is why the nanoparticles compete for GLUT1’s attention,” Ole-Taratula said. “For nanoparticles to get that, they need a densely coated sugar surface, and that’s our central innovation. By chemically bonding mannose to cholesterol, the main structural component of nanoparticles, we improved surface coverage by a factor of six.”
Delivery of tumor suppressor mRNA
The nanoparticles contained messenger RNA that instructs cells to produce PTEN, a protein that helps prevent uncontrolled tumor growth. PTEN is often missing or inactive in glioblastoma cells.
To prevent the mRNA from breaking down before it reaches its target, the researchers added a positively charged cholesterol derivative that helps trap the genetic material tightly within the nanoparticles.
Glioblastoma cells also produce abnormally high levels of GLUT1. This difference allowed the sugar-coated particles to accumulate in larger quantities within the tumor after entering the brain.
“Glioblastomas are metabolically reprogrammed and express GLUT1 at three times the level of normal brain tissue, so particles preferentially accumulate in tumor tissue after crossing the blood-brain barrier,” said Olena Taratura. “And restoring PTEN expression in tumor cells restored growth control. Repeated administration resulted in tumor shrinkage without measurable organ toxicity.”
Deadly and difficult to treat cancer
Glioblastoma affects approximately 3.19 people per 100,000 people in the United States. It occurs more frequently in men than women, and the median age at diagnosis is 64 years. More than 95% of patients die within 5 years of diagnosis.
Vincent Cataldi, Vladislav Grigoriev, Neera Yadav, Tetiana Korzun, Chao Wang, and Adam Alani from the School of Pharmacy also contributed to the study.
This research was supported by the National Cancer Institute of the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Research Foundation of Korea.
