Researchers at Oregon State University have potentially found a new way to treat the most aggressive form of brain cancer, glioblastoma, whose two-year survival rate is less than 30%.
The study led by Oleh Taratula, Olena Taratula and Yoon Tae Goo of the OSU College of Pharmacy addresses what they describe as the two most persistent obstacles to effective glioblastoma treatment: Delivering therapeutic agents through the blood-brain barrier, the cell network that acts as a security checkpoint between the bloodstream and the central nervous system, and then getting those agents to preferentially target tumors.
In research published in the Journal of Controlled Release, the scientists demonstrated the novel treatment technique in a mouse model. They loaded lipid nanoparticles with genetic material that promotes tumor suppression, then coated the nanoparticles with a type of sugar. The result was a 50% median increase in glioblastoma survival time.
The sugar they used was mannose, a close relative of glucose, the body's primary source of energy. The brain's endothelial cells are lined with a transporter, GLUT1, tasked with shuttling glucose into the central nervous system. However, the transporter recognizes mannose as well, and that's what gets the nanoparticles through the blood-brain barrier.
"Blood contains relatively high concentrations of glucose, and that's what the nanoparticles are competing against for GLUT1's attention," Oleh Taratula said. "For the nanoparticles to get it, they need a densely coated sugar surface, and that's our central innovation. By chemically connecting mannose to cholesterol, a major structural component of the nanoparticles, we improved surface coverage sixfold."
Inside the nanoparticles is messenger RNA that enables the production of PTEN, a tumor-thwarting protein that's frequently lost in glioblastoma. To prevent the cargo from being disrupted, the scientists added a cationic cholesterol derivative that safeguards the mRNA encapsulation.
"Glioblastoma is metabolically reprogrammed and expresses GLUT1 at three times the levels of normal brain tissue, so the particles preferentially accumulate in tumor tissue after crossing the blood-brain barrier," Olena Taratula said. "And restoring PTEN expression in tumor cells reinstates growth control. Across repeated dosing, tumor shrinkage occurred without any measurable organ toxicity."
In the United States, glioblastoma has an incidence rate of 3.19 per 100,000 people. It's more common in males than females, and the median age of onset is 64; more than 95% of patients live less than five years from the time of diagnosis.
The College of Pharmacy's Vincent Cataldi, Vladislav Grigoriev, Neera Yadav, Tetiana Korzun, Chao Wang and Adam Alani also contributed to the research, which was supported by 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.
