Nasal drops could be the key to treating aggressive brain tumors, according to researchers at Washington University School of Medicine in St. Louis and their collaborators at Northwestern University. Their groundbreaking technology uses precisely engineered structures made from nanoscale materials to deliver potent tumor-fighting medicine directly to the brain via nasal drops. This novel approach is less invasive than similar treatments in development and has shown promising results in mice, effectively treating glioblastoma by boosting the brain's immune response.
Glioblastoma, a rapidly progressing and almost always fatal brain cancer, has no curative treatments due to the difficulty of delivering medicines to the brain. However, researchers have developed a noninvasive strategy to activate the immune response against glioblastoma by stimulating a cellular pathway called STING, which is triggered when a cell detects foreign DNA. Past studies have shown that drugs activating STING in glioblastoma tumors can prime the immune system to better fight the cancer, but these agents break down quickly in the body and require direct intratumoral administration, which is highly invasive.
To overcome this challenge, the research team, led by Alexander H. Stegh, PhD, collaborated with Chad A. Mirkin, PhD, and his team at Northwestern University. Mirkin invented spherical nucleic acids, a class of nanostructures that arrange DNA or RNA densely around a nanoparticle core, and has demonstrated their greater therapeutic potency compared to standard delivery methods. The researchers prepared a new class of spherical nucleic acids with gold cores studded with short snippets of DNA to trigger the STING pathway in specific immune cells. They then turned to the nose for delivery, as intranasal therapy has been explored as a potential method for medications targeting the brain.
The team's study revealed that this approach could be used to deliver the medicine selectively to the brain, and that it would act on the appropriate cells once it got there. The nanomedicine, when delivered as droplets into the nasal passages of mice with glioblastoma, traveled along the main nerve connecting facial muscles to the brain. The immune response evoked in the brain by the medicine was concentrated in specific immune cells, especially those in the tumor itself, and triggered helpful responses in the lymph nodes. Importantly, the medicine did not spread to other parts of the body, potentially causing unwanted side effects.
Examinations of immune cells in and near the tumor showed that the therapy successfully activated the STING pathway and armed the immune system to fight the tumor. When applied in combination with drugs designed to help activate T lymphocytes, the new therapy eradicated the tumors with just one or two doses and induced long-term immunity against their recurrence. The results were significantly better than those of current STING-activating immune therapies.
Stegh emphasized that while activating the STING pathway is a crucial step, it is not sufficient to cure glioblastomas without reinforcement from other therapeutic approaches. The tumor has various mechanisms to block or shut down the immune response that STING is meant to activate. The team is now looking to add capabilities to their nanostructure that activate other immune responses, potentially doubling or tripling the therapeutic targets in a single therapy.
Stegh expressed optimism about the potential for safer, more effective treatments for glioblastoma and other immune treatment-resistant cancers, marking a significant step toward clinical application. The research was supported by various grants and institutions, including the National Cancer Institute of the NIH, the Melanoma Research Foundation, and the Chicago Cancer Baseball Charities at the Lurie Cancer Center of Northwestern University.
