Scientists at Massachusetts Institute of Technology (MIT; MA, USA) have created a nanoparticle capable of delivering two different drugs directly to tumor cells in the brain, offering a novel therapeutic option to treat glioblastoma multiforme. The study, published recently in Nature Communications, highlights the ability of the nanoparticle to shrink tumors and prevent regrowth in mouse models of the disease.
Glioblastoma is one of the hardest to treat cancers; only a small number of drugs are approved to treat the brain cancer, leading to a median survival time of less than 15 months.
The spherical nanoparticle, known as a liposome, can transport both a drug that damages the DNA of the tumor cell and one that interferes with the cell’s DNA damage repair system. These are carried in the core and outer shell of the liposome, respectively.
"A vehicle that would allow us to use some of the more common chemotherapy regimens in brain tumors would be a real game-changer."
"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," commented senior author Paula Hammond, a David H. Koch Professor in Engineering at MIT.
The particles had to be adapted to cross the blood–brain barrier – a notorious problem faced by researchers designing drugs against targets in the brain. The scientists found that they could overcome this issue by coating the liposomes with transferrin, a protein which allowed the nanoparticles to cross into the brain much easier.
Furthermore, transferrin was found to bind directly to proteins on the tumor cells, while avoiding the healthy cells in the brain. This targeted approach allowed the particles to build up specifically on the tumor cells, potentially allowing high doses of chemotherapeutic agent to be delivered directly to the tumor and avoiding the severe side effects associated with administration of the first-line drug, temozolomide.
By packaging temozolomide into the center of the liposomes and encapsulating an experimental bromodomain inhibitor in the outer shell, the team was able to directly target tumor cells with a two-step punch. After the nanoparticle reached the tumor, the liposome degraded to release the bromodomain inhibitor and then, approximately 24 hours later, temozolomide.
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This method allows the DNA repair mechanism to be disrupted prior to attacking the cells’ DNA – launching an attack while the cells’ defenses are already down.
Michael Yaffe, a David H. Koch Professor of Science who is also an author on the paper, remarked, "This is yet another example where the combination of nanoparticle delivery with drugs involving the DNA-damage response can be used successfully to treat cancer."
The study revealed the transferrin-coated liposomes were more effective than both uncoated nanoparticles and temozolomide and the bromodomain inhibitor injected separately. The mice treated with the novel nanoparticle are suggested to have lived twice as long as the other models.
Moreover, the researchers highlighted the ability of the nanoparticle treatment to elicit much less damage to blood cells and other tissues, which are normally harmed by telozomolide. This, in part, is due to a polyethylene glycol coat surrounding the nanoparticle to prevent unwanted immune responses to the therapeutic.
"Our goal was to have something that could be easily translatable, by using simple, already approved synthetic components in the liposome."
"Our goal was to have something that could be easily translatable, by using simple, already approved synthetic components in the liposome," commented lead author Fred Lam. "This was really a proof-of-concept study [showing] that we can deliver novel combination therapies using a targeted nanoparticle system across the blood-brain barrier."
The scientists hope this method could also be trialed with other chemotherapeutic agents, including those that have never before crossed the blood–brain barrier.
"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," concluded senior author Scott Floyd, former Koch Institute clinical investigator.
"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."
Lam FC, Morton SW, Wyckoff J et al. Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles. Nat. Comms. doi:10.1038/s41467-018-04315-4 (2018); http://news.mit.edu/2018/tiny-particles-could-help-fight-brain-cancer-0524