Research Project
9347787
Abstract Glioblastoma multiforme (GBM) is the deadliest form of brain tumor. The current treatment includes a combination of surgical resection, chemotherapy, radiation, and electrical disruption of mitosis has only extended survival to approximately 1 to 2 years. Preliminary pre-clinical findings suggest the potential effectiveness of the candidate drug cyclopamine. However, the drug is toxic to systemic stem cells when given intravenously, and at high concentrations in the nervous system may cause toxicity to astrocytes. Furthermore, poor solubility has precluded effective transport of drug to tumor in the central nervous system. The Molecular Neurosurgery Laboratory (led by the STTR PI (neurosurgeon Dr. Steven Toms at the Geisinger Medical Center) has expertise in nanoparticulate delivery to brain tumors, and has developed a human glioblastoma stem cell derived xenograft model for in vitro and in vivo testing of therapies for GBM. STTR applicant Weinberg Medical Physics LLC has developed a new method of transporting drug across the blood brain barrier directly to target sites within the brain. This approach accesses the brain via administration of magnetically-propelled nanoparticles into the cranium with magnetic focusing of the drug-laden nanoparticles in a novel combined MR imaging/magnetic focusing apparatus. In this proposal, we will demonstrate the safety and efficacy of drug delivery of the magnetic nanoparticle:cyclopamine construct using the MR imaging/magnetic focusing apparatus by measuring cyclopamine drug concentrations in animal tissues. In addition, we will confirm that there are no neuropathological changes to the animals as a result of the magnetic propulsion process and demonstrate that this method of drug delivery improves survival in rodent GBM xenograft models. The results of this collaborative work will lay the foundation for Phase II studies that will collect information needed for clinical trials.
