Focused Ultrasound-Mediated Blood-Brain Barrier Opening Increases Delivery and Efficacy of Etoposide for Glioblastoma Treatment
| Autor: | Angeliki Mela, Tony J. C. Wang, Xu Zhang, Jeffrey N. Bruce, Pavan S. Upadhyayula, Elisa E. Konofagou, Peter Canoll, Zachary K. Englander, Antonios N. Pouliopoulos, Cheng-Chia Wu, Hong-Jian Wei, Chia-Ing Jan, Stergios Zacharoulis, Neil A. Feldstein, Jia Guo, Zhiguo Zhang |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Cancer Research Brain tumor Contrast Media Blood–brain barrier Article 030218 nuclear medicine & medical imaging 03 medical and health sciences Mice Sonication 0302 clinical medicine Tandem Mass Spectrometry Cell Line Tumor medicine Animals Radiology Nuclear Medicine and imaging Survival rate Etoposide Ultrasonography Interventional Radiation Microbubbles medicine.diagnostic_test business.industry Brain Neoplasms Magnetic resonance imaging medicine.disease Antineoplastic Agents Phytogenic Magnetic Resonance Imaging medicine.anatomical_structure Oncology Tumor progression Blood-Brain Barrier 030220 oncology & carcinogenesis Drug delivery Cancer research Disease Progression business Glioblastoma medicine.drug Chromatography Liquid |
| Zdroj: | Int J Radiat Oncol Biol Phys |
| ISSN: | 1879-355X |
| Popis: | Purpose Glioblastoma (GBM) is a devastating disease. With the current treatment of surgery followed by chemoradiation, outcomes remain poor, with median survival of only 15 months and a 5-year survival rate of 6.8%. A challenge in 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 an 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 used to evaluate the 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 demonstrate the safe and successful BBB opening with FUS. The combined treatment of an FUS-mediated BBB opening and etoposide decreased tumor growth by 45% and prolonged median overall survival by 6 days: an approximately 30% increase. The FUS-mediated BBB opening increased the brain tumor-to-serum ratio of etoposide by 3.5-fold and increased the etoposide concentration in brain tumor tissue by 8-fold compared with treatment without ultrasound. Conclusions 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. |
| Databáze: | OpenAIRE |
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