Focused Ultrasound-Mediated Blood-Brain Barrier Opening Increases Delivery and Efficacy of Etoposide for Glioblastoma Treatment

Abstract Purpose Glioblastoma (GBM) is a devastating disease. With the current treatment of surgery followed by chemoradiation, outcomes remain poor with only a median survival of 15 months and a 5-year survival of 6.8%. One challenge to treating GBM is the heterogeneous integrity of the blood-brain barrier (BBB) which limits the bioavailability of systemic therapies to the brain. There is a growing interest in enhancing drug delivery by opening the BBB with the use of focused ultrasound (FUS). We hypothesize that FUS-mediated BBB opening can enhance the delivery of etoposide for a therapeutic benefit in GBM. Methods and Materials A murine glioma cell line (Pdgf+, Pten-/-, P53-/-) was orthotopically injected into B6(Cg)-Tyrc-2J/J mice to establish the syngeneic GBM model for this study. Animals were treated with FUS and microbubbles to open the BBB to enhance the delivery of systemic etoposide. Magnetic resonance (MR) imaging was utilized to evaluate BBB opening and tumor progression. Liquid chromatography tandem mass spectrometry was used to measure etoposide concentrations in the intracranial tumors. Results The murine glioma cell line is sensitive to etoposide in vitro. MR imaging and passive cavitation detection demonstrates the safe and successful BBB opening with FUS. The combined treatment of FUS-mediated BBB opening and etoposide decreased tumor growth by 45% and prolonged median overall survival by 6 days, an approximately 30% increase. FUS-mediated BBB opening increased brain tumor-to-serum ratio of etoposide by 3.5-fold and increased etoposide concentration in brain tumor tissue by 8-fold as compared to without ultrasound. Conclusion The current study demonstrates that BBB opening with FUS increases intratumoral delivery of etoposide in the brain, resulting in local control and overall survival benefits.