University of Nottingham scientists in the U.K. report that a polymer originally designed to help mend broken bones could be successful in delivering chemotherapy drugs directly to the brains of patients suffering from brain tumors. Their preclinical study (“Adjuvant Chemotherapy for Brain Tumors Delivered via a Novel Intra-Cavity Moldable Polymer Matrix”), published in PLOS ONE, shows that the biomaterial can be easily applied to the cavity created following brain cancer surgery and used to release chemotherapy drugs over several weeks, according to the researchers.
“Our system is an innovative method of drug delivery for the treatment of brain tumors and is intended to be administered immediately after surgery by the operating neurosurgeon,” explained Ruman Rahman, Ph.D., of the University’s Children’s Brain Tumor Research Center (CBTRC). “Ultimately, this method of drug delivery, in combination with existing therapies, may result in more effective treatment of brain tumors, prolonged patient survival, and reduced morbidity.”
The Nottingham polymer formulation is made from two types of microparticles called PLGA and PEG and has been developed and patented by Kevin Shakesheff, Ph.D., based in the university’s School of Pharmacy. A powder at room temperature, it can be mixed to a toothpaste-like consistency with the addition of water.
“PLGA/PEG matrices can be molded around a pseudo-resection cavity wall with no polymer-related artifact on clinical scans,” wrote the researchers. “The polymer withstands fractionated radiotherapy, with no disruption of microparticle structure. No toxicity was evident when tumor or endothelial cells were grown on control matrices in vitro. Trichostatin A, etoposide, and methotrexate were released from the matrices over a 3–4 week period in vitro and etoposide released over 3 days in vivo, with released agents retaining cytotoxic capabilities.”
In the lab, the Nottingham scientists were able to successfully demonstrate the slow-release properties of the material by placing paste loaded with three commonly used chemotherapy drugs into a solution of saline and measuring the quantities of the drugs given out by the material over time.
To establish whether the material itself is safe to use on patients in this form of therapy, they used it to create a 3D model onto which they were able to grow brain tumor cells and healthy brain blood vessel cells without any toxicity. They then simulated surgery on a sheep's brain from an abattoir by moulding the paste around a brain cavity and warming the brain to human body temperature to harden the polymer.
The brain was then scanned using CT and MRI technology to demonstrate that it is still possible to distinguish the polymer from normal brain tissue on a routine brain scan, an aspect crucial for doctors when dealing with follow-up care for brain tumor patients who have undergone surgery.
Finally they showed that a chemotherapy drug called etoposide could be effective at killing brain cancer cells in a mouse when released from the polymer formulation. The next stage of the research will be to extend the study in mice with brain tumors to test whether animals with the drug-loaded polymers survive longer. The team is also investigating the release of other chemotherapeutic drugs that hold promise, supported by a recent grant award from Sparks.