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

Hong-Jian Wei; Pavan S Upadhyayula; Antonios N Pouliopoulos; Zachary K Englander; Xu Zhang; Chia-Ing Jan; Jia Guo; Angeliki Mela; Zhiguo Zhang; Tony J C Wang; Jeffrey N Bruce; Peter D Canoll; Neil A Feldstein; Stergios Zacharoulis; Elisa E Konofagou; Cheng-Chia Wu

doi:10.1016/j.ijrobp.2020.12.019

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

Int J Radiat Oncol Biol Phys. 2021 Jun 1;110(2):539-550. doi: 10.1016/j.ijrobp.2020.12.019. Epub 2020 Dec 17.

Authors

Hong-Jian Wei¹, Pavan S Upadhyayula², Antonios N Pouliopoulos³, Zachary K Englander², Xu Zhang⁴, Chia-Ing Jan⁵, Jia Guo⁶, Angeliki Mela⁷, Zhiguo Zhang⁴, Tony J C Wang⁸, Jeffrey N Bruce⁹, Peter D Canoll¹⁰, Neil A Feldstein², Stergios Zacharoulis¹¹, Elisa E Konofagou³, Cheng-Chia Wu¹²

Affiliations

¹ Department of Radiation Oncology, Columbia University Irving Medical Center, New York, New York.
² Department of Neurological Surgery, Columbia University Irving Medical Center, New York, New York.
³ Department of Biomedical Engineering, Columbia University, New York, New York.
⁴ Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York; Department of Pediatrics, Columbia University Irving Medical Center, New York, New York.
⁵ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York; Division of Molecular Pathology, Department of Pathology, China Medical University and Hospital, Taichung, Taiwan; Department of Medicine, China Medical University, Taichung, Taiwan; Translational Cell Therapy Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
⁶ Department of Psychiatry, Columbia University, New York, New York.
⁷ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York.
⁸ Department of Radiation Oncology, Columbia University Irving Medical Center, New York, New York; Department of Neurological Surgery, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, New York, New York.
⁹ Department of Neurological Surgery, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, New York, New York.
¹⁰ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, New York, New York.
¹¹ Department of Pediatrics, Columbia University Irving Medical Center, New York, New York.
¹² Department of Radiation Oncology, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, New York, New York. Electronic address: cw2666@cumc.columbia.edu.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Phytogenic / administration & dosage*
Antineoplastic Agents, Phytogenic / analysis
Blood-Brain Barrier / diagnostic imaging
Blood-Brain Barrier / physiology*
Brain Neoplasms / chemistry
Brain Neoplasms / diagnostic imaging
Brain Neoplasms / drug therapy*
Brain Neoplasms / mortality
Cell Line, Tumor
Chromatography, Liquid
Contrast Media / administration & dosage
Disease Progression
Etoposide / administration & dosage*
Etoposide / analysis
Glioblastoma / chemistry
Glioblastoma / diagnostic imaging
Glioblastoma / drug therapy*
Glioblastoma / mortality
Magnetic Resonance Imaging
Male
Mice
Microbubbles
Sonication
Tandem Mass Spectrometry
Ultrasonography, Interventional / methods*

Substances

Antineoplastic Agents, Phytogenic
Contrast Media
Etoposide

Abstract

Publication types

MeSH terms

Substances

Grants and funding