Glioblastoma is one of the most difficult cancers to treat. With a median life expectancy of less than 15 months after diagnosis and only a handful of approved drugs available, patients with glioblastoma face an urgent and largely unmet therapeutic need. A major obstacle has been the blood brain barrier, a protective membrane that separates the brain from circulating blood and blocks most large molecules, including many chemotherapy agents, from reaching tumor tissue. MIT researchers have now developed a drug delivering nanoparticle that crosses the blood brain barrier efficiently, targets glioblastoma cells directly, and delivers two complementary drugs in sequence to shrink tumors and prevent regrowth.
How the Nanoparticle Targets Glioblastoma Cells
The particles used in this research are liposomes, spherical droplets with a fatty outer shell and a liquid core that can carry different drugs in each compartment. To enable crossing of the blood brain barrier, the researchers coated the liposomes with a protein called transferrin. This coating allowed the particles to pass through the barrier with minimal resistance. Transferrin also binds to proteins found on the surface of glioblastoma tumor cells, causing the particles to accumulate directly at the tumor site while avoiding healthy brain tissue.
This targeted delivery mechanism is what distinguishes the approach from conventional chemotherapy. Standard administration of temozolomide, the first line chemotherapy drug for glioblastoma, distributes the drug throughout the body, causing systemic side effects including bruising, nausea, and weakness. By concentrating drug delivery at the tumor site, the nanoparticle system allows for substantially higher local doses with significantly reduced damage to blood cells and surrounding healthy tissue.
The Two Drug Strategy Against Glioblastoma
The nanoparticles carry two drugs designed to work together against glioblastoma in a sequential one two combination. Temozolomide, the standard glioblastoma chemotherapy agent, is loaded into the inner core of the liposome. The outer shell carries an experimental compound called a bromodomain inhibitor, specifically JQ 1, which interferes with the cellular machinery that cancer cells use to repair DNA damage.
The sequencing is deliberate and critical. Once the nanoparticles reach the tumor site, the outer layer degrades first, releasing the bromodomain inhibitor. Approximately 24 hours later, temozolomide is released from the core. By first disabling the glioblastoma cells’ DNA repair systems and then delivering a DNA damaging agent, the combination attacks the cancer while its defenses are down, a mechanism grounded in prior work by researchers Floyd and Yaffe on the DNA damage response of tumors.
Glioblastoma Mouse Study Results
In mouse models of glioblastoma, the transferrin coated nanoparticles outperformed every comparison condition. Mice treated with the targeted particles survived twice as long as those that received either uncoated nanoparticles or the two drugs injected into the bloodstream individually. The particles successfully shrank tumors and prevented them from regrowing, and animals in the targeted nanoparticle group experienced significantly less damage to blood cells and other tissues than those treated with standard temozolomide delivery.
All components of the liposome system, including the PEG polymer coating that protects the particles from immune detection, are already FDA approved for use in humans, a deliberate design choice intended to accelerate the path toward clinical translation. The research was published in Nature Communications.
What This Means for the Future of Glioblastoma Treatment
The bromodomain inhibitor JQ 1 used in this proof of concept study is unlikely to be suitable for human use due to its short half life, but other bromodomain inhibitors are currently in clinical trials, making the combination approach clinically viable with an appropriate substitute compound. More broadly, the transferrin coated liposome platform has potential applications well beyond this specific drug combination.
Because the blood brain barrier has historically excluded so many otherwise effective chemotherapy agents from use against glioblastoma and other brain tumors, a reliable delivery vehicle could open the door to testing a wide range of existing drugs in this context for the first time. As study co author Scott Floyd noted, a vehicle that allows more standard chemotherapy regimens to reach brain tumors by working around the blood brain barrier would represent a genuine game changer for this disease.
To read more about oncology research and clinical advances, visit the FOMAT blog. FOMAT conducts oncology clinical trials at sites across the United States. To learn more about active studies, visit FOMAT’s patient studies page.
For the full source, see the original article at MIT News.