EXTH-47. DEVELOPMENT OF NANOFIBER-BASED CONTROLLED LOCAL DRUG DELIVERY AS A NOVEL ADJUVANT MODALITY FOR TREATMENT OF GLIOBLASTOMA

摘要

There are only two chemotherapeutic agents that are approved by US Food and Drug Administration (FDA) for treatment of newly diagnosed glioblastoma. Gliadel wafer implantation was approved in 2003 as it improved survival in newly diagnosed glioblastoma patients. However, Gliadel wafer use is currently topic of controversy given its toxicity profile and difficult drug loading and drug release maintenance properties. Temozolamide was approved in 2005 but it only marginally improves patients’ survival. Despite rigorous research efforts, the life span of patients with glioblastoma has not significantly changed over the past two decades and further research efforts are crucial. We have discovered that Mycophenolic Acid (MPA), an FDA approved immunosuppressant, inhibits glioblastoma cell growth by depleting cells from their major energy source, GTP, which is reversed by addition of guanosine. Local drug delivery of MPA to glioblastoma is preferable over systemic delivery because i) recurrence predominantly appears adjacent to the original lesion, ii) MPA is metabolized in the liver and high systemic concentrations will be needed for effective tumor penetration, iii) the effect of MPA’s systemic immunosuppressive properties is not well characterized in glioblastoma patients. We therefore aimed to develop MPA-integrated nanofibers for post-surgical local MPA therapy in glioblastoma patients. We have formed MPA-containing electrospun fiber membranes and shown that coaxial MPA nanofibers release and maintain an MPA concentration of 10uM. In addition, these MPA-containing fiber membranes effectively inhibit glioblastoma cell lines and patient-derived neurospheres growth. This is rescued by addition of guanosine indicating that release of MPA is the active element in glioblastoma growth inhibition by MPA nanofibers. Our results indicate that MPA-containing electrospun membranes have a promising prospect for local treatment of glioblastoma. In addition, nanofiber membranes have the potential to be used as a novel platform in delivery of other molecularly targeted therapies in treatment of glioblastoma patients.