A new engineering solution may help deliver tumor killing drugs directly to the brain tumor without the toxic body effects of systemic chemotherapy. The new study published in the journal Nature Scientific Reports reports on the use of coaxial electrospinning, an industrial fabrication technology, in the production of membranes that incorporate drugs to treat glioblastoma multiforme (GBM), an aggressive cancer of the brain.
UC research associate Daewoo Han works in UC's Nanoelectronics Laboratory. He is lead author of a new study on glioblastoma. Photo/Joseph Fuqua II/UC Creative Services
Cancers are most effectively treated with long-term controlled administration of therapeutic drugs to a target site.
The brain tumor called GBM is a common and aggressive cancer that causes over 50% of brain tumors and claims the lives of almost 240,000 people worldwide every year. Only 5% of patients with this tumor are alive at 5 years. It does not respond well to chemotherapy or radiation therapy. In fact, the average GBM patient lives only 15 months after diagnosis.
Current treatment standards depend on cutting out as much of the tumor as is achievable with safety, followed by radiation therapy with chemotherapy.
Systemic vs local chemotherapy in brain cancer
A major issue with systemic chemotherapy in brain tumors is the requirement of high doses in order to make sure that adequate levels of the drug get through to the brain, through the blood-brain barrier. At such high dosage, the body may suffer more severe side effects.
The current work builds on earlier research by two of the co-researchers, who in 2003 developed Gliadel, a biodegradable wafer treatment that treats brain tumors locally. It delivers the drug carmustine in a polymeric wafer inserted into the resection cavity. It is administered along with radiation therapy and another systemic chemotherapy, and this triple therapy stretched average survival by another 6 months. It has a few issues such as the rapid breakdown of the drug and the polymer, and quick release of the drug.
To reduce the overall exposure to the drug, the researchers turned to coaxial electrospinning. This is a technique in which multiple materials are spun into a single nanofiber with one of the materials as the core while the other forms the sheath. Both can thus be exploited for its unique properties, while the combination helps the drug reach the right place either all at once or over time. The parameters such as the base materials, the shape of the fibers, their concentration, the additives used, the porous structure of the fiber and its surface area, and the sheath thickness can be controlled to precisely regulate the rate of drug release. As researcher Andrew Steckl says, “We can produce a very sophisticated drug-release profile.”
The electrospun drug-containing membrane is implanted straight into the post-surgical cavity from where the tumor was removed to mop up residual tumor cells. Three animal studies have looked at the safety, toxicity and efficacy of the drug as well as the rate of membrane breakdown. They concluded that the use of electrospun-fiber in chemotherapy increased the survival rates. The studies did not show any direct toxic effect of the polymer membranes on the rat brains even though the discs were able to remain intact within the brain tissue for long periods of time. “This represents a promising evolution for the current treatment of GBM,” the researchers say.
Benefits of this format
The advantages of electrospun-fibers is that two different sets of polymer attributes can be incorporated into one fiber, more than one functional molecule can be sheathed within the outer layer, and the rate of drug release is controllable by careful modulation of the parameters, as discussed above.
For the sake of convenience, which will determine its suitability for widespread use, many layers of the electrospun-fiber is used to create a disc, somewhat like a pill, which provides for the application of a greater amount of drug, reduces the amount released in the initial burst, and allows a more sustained release of the drug over time. This ensures that drugs such as antibiotics or pain relievers are rapidly and acutely released, while other drugs have a more sustained-release pattern.
Long-term drug release
There have been many earlier electrospun-fibers containing chemotherapeutic agents, but none have compared with the cutting-edge wafers so far, as far as their lifespan and drug release is concerned. The use of hydrophobic sheath layers should prevent rapid release in an aqueous medium, enabling long-term application, drug protection and higher stability. In contrast to bulk wafers of polymer, where the initial drug release near the surface is high, and then slowly reduces as the drug from the center of the wafer diffuses to the surface, a multi-layered porous fiber membrane disc will have relatively constant diffusion kinetics because the hydrophobic layer prevents rapid wetting of the outside of the disc. For the first 30 days the drug release is slow, but then accelerates, to finally reduce to a slower constant rate over the long term, once the whole disc is completely wetted.
The dosage will be uniform over a longer period of time, according to researcher Daewoo Han. He says, “For the current treatment, most drugs release within a week, but our discs presented the release for up to 150 days.”
Multiple drug use
Electrospinning can incorporate more than one drug, though only one was used in the current study. The use of multiple drugs loaded on different layers from outer to inner can help to apply one drug after the other in a predefined sequence, or simultaneously, for long-term treatment. this is extremely useful when it comes to newer cancer therapies which focus on the use of multiple drugs to avoid the emergence of resistance and to boost efficacy.
This study could thus help treat multiple types of cancer. Steckl says, “Looking ahead, we are planning to investigate ‘cocktail’ therapy where multiple drugs for the combined treatment of difficult cancers are incorporated and released either simultaneously or sequentially from our fiber membranes.”
Han, D., Serra, R., Gorelick, N. et al. Multi-layered core-sheath fiber membranes for controlled drug release in the local treatment of brain tumor. Sci Rep 9, 17936 (2019) doi:10.1038/s41598-019-54283-y, https://www.nature.com/articles/s41598-019-54283-y?draft=collection