Glioblastoma is one of the most deadly forms of cancer. Affecting the brain, those unlucky enough to receive a diagnosis don't have many treatment options – and usually a median life expectancy of just over a year. Now, researchers at MIT have developed nanoparticles that could provide hope, crossing the blood-brain barrier and delivering two types of drugs to fight tumors.
The MIT nanoparticles are liposomes, fatty droplets that can carry one drug on the inside and another in the outer layer. On the inside, the particles were loaded with a common chemotherapy drug called temozolomide, while the outer shell contained a more experimental substance known as JQ-1.
This partnership was very carefully chosen. Temozolomide is widely known to damage the DNA of cancer cells, while JQ-1 is a type of bromodomain inhibitor, meaning it reduces the tumor's ability to repair that DNA damage. To help the nanoparticles sneak through the blood-brain barrier, the researchers coated them with a protein called transferrin, which also has the bonus effect of helping the liposomes bind to the cancer cells. And finally, the whole package was coated in a polymer called polyethylene glycol (PEG), which protects the nanoparticles from being attacked by the immune system.
"What is unique here is we are not only able to use this mechanism to get across the blood-brain barrier and target tumors very effectively, we are using it to deliver this unique drug combination," says Paula Hammond, senior author of the paper.
To test the nanoparticles, the researchers administered them to mice with glioblastoma tumors and found that the treatment successfully shrunk tumors and kept them from growing back. First, the outer layers dissolved and released the JQ-1, shutting down the cancer cells' repair systems. Then about a day later, the temozolomide was released into the now-vulnerable tumor.
The team also found that nanoparticles covered with transferrin were the most effective. Mice treated with those survived twice as long as animals that were treated with either nanoparticles that didn't contain transferrin, or just injections of temozolomide and JQ-1 into the bloodstream.
Wrapping the drugs in the particles didn't just help get the treatment to the tumor, but it drastically reduced side effects too. As effective as temozolomide is at shrinking tumors, it also damages blood cells throughout the body, causing bruising, nausea, weakness and other unwanted issues. Mice treated with the nanoparticles saw much less of these side effect than animals given the drugs straight.
Most promising is the fact that all of the individual components of the nanoparticles have already been approved for human use by the FDA, which should speed up the transition to clinical trials. That said, the researchers point out that another bromodomain inhibitor should probably be used, because JQ-1 has too short a half-life to be practical.
The study represents a proof-of-concept of the nanoparticle design, regardless of the specific components used. Since this method can get into the brain, it could carry different drug payloads that might have been previously overlooked.
"Because there's such a short list of drugs that we can use in brain tumors, a vehicle that would allow us to use some of the more common chemotherapy regimens in brain tumors would be a real game-changer," says Scott Floyd, senior author of the study. "Maybe we could find efficacy for more standard chemotherapies if we can just get them to the right place by working around the blood-brain barrier with a tool like this."
The research was published in the journal Nature Communications.
Source: MIT
