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Combining nanotechnology with traditional chemotherapy drug and resistance-inhibitors

A �Ӱ���Ƶ researcher has received a five-year, $2.82 million National Institutes of Health grant to make, in essence, stealth bombs that slip past the brain’s defenses to attack an incurable form of cancer. Efstathios Karathanasis, a biomedical engineer at Case School of Engineering, has developed chain-like nanoparticles that can carry drugs across the blood-brain barrier that keeps standard medicines from reaching their target—a highly aggressive brain cancer called glioblastoma multiforme. The nanochains will tote bombs of chemotherapy medicine and glioblastoma stem cell inhibitors identified by Jeremy Rich, chairman of the Department of Stem Cell Biology and Regenerative Medicine at Cleveland Clinic Lerner Research Institute. The researchers expect the chemotherapy will destroy the majority of tumor cells and the inhibitor will eliminate cancer cells that are resistant and can cause brain tumors to reoccur. Their goal is to develop a treatment that eradicates the cancer with one safe dose. “The grant enables our labs to integrate our technologies,” Karathanasis said. “We need integration to solve this problem.” Glioblastoma multiforme is the most common and most malignant tumors of glial cells, which provide structure to the brain. The median survival rate among adults is just under 15 months, according to the American Brain Cancer Association. The blood-brain barrier that normally protects the brain from harm becomes a deadly impediment when tumors are present, preventing drugs from crossing from the blood stream into the diseased tissue. And “surgeons can’t go in and cut liberally,” Karathanasis said. “Brain tumor cells are often invasive and spread throughout the normal brain, and drugs—if they get in—do nothing because of resistance that develops.” To reach inside tumors, Karathanasis’ lab developed a short chain of magnetic nanoparticles made of iron oxide and modified the surfaces so one links to the next, much like Lego building blocks. They link three and then chemically link a liposome sphere filled with a chemotherapy drug. The surface of the nanochain is also modified to penetrate and attach to the tumors’ vascular walls. When nanochains congregate inside a tumor, the researchers place a wire coil, called a solenoid, outside near the tumor. Electricity passed through the solenoid creates a weak radiofrequency field. The field causes the magnetic tails of the chain to vibrate, bursting the liposome spheres, releasing their drug cargo into the brain tumors. In testing with mouse models of aggressive brain tumors, the technology took out far more cancer cells, inhibited tumor growth better and extended life longer than traditional chemotherapy delivery. The targeted delivery system also used far less drug than used in traditional chemotherapy, saving healthy tissue from toxic exposure. To treat glioblastoma multiforme, which typically produces cells resistant to chemotherapy, the team will add inhibitors to traditional chemotherapy drugs. For instance, Rich’s lab has shown that inducible nitric acid synthase is a unique signal regulator in glioblastoma stem cells. The cancerous stem cells depend on the enzyme for growth and to form tumors. Normal neural cells do not. In testing with mouse models of the cancer, models injected with an inducible nitric acid synthase inhibitor had fewer and smaller tumors compared to control models. In addition to the grant money, the researchers will have access to the National Cancer Institute’s Alliance for Nanotechnology in Cancer, and will exchange ideas and resources, Karathanasis said. As a corollary to the NIH funding, Karathanasis, along with �Ӱ���Ƶ School of Medicine Professors James Basilion and John Letterio, is also funded by Prayers from Maria Children's Glioma Cancer Foundation to explore the use of nanotechnology to more effectively treat pediatric glioma brain tumors. Prayers from Maria’s 2014 grant was the first major funding award for application of this technology. The combined synergy of funding from Prayers from Maria and NIH offers great hope for both children and adults affected by brain cancers. The Karathanasis and Rich labs will work with Mark Griswold, professor of radiology at �Ӱ���Ƶ School of Medicine, who will build radiofrequency systems. Ketan Ghaghada, assistant professor of radiology at Baylor College of Medicine, will guide and oversee the steps taken to translate the research toward clinical trials. Over the next five years, they’ll optimize the drug-delivery system and mix of chemotherapy drug and inhibitor, study their effects and effectiveness in mouse models and evaluate the efficacy on human glioblastoma grafts in the models.