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. 2021 Jun 1;110(2):539-550.
doi: 10.1016/j.ijrobp.2020.12.019. Epub 2020 Dec 17.

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

Hong-Jian Wei  1 , Pavan S Upadhyayula  2 , Antonios N Pouliopoulos  3 , Zachary K Englander  2 , Xu Zhang  4 , Chia-Ing Jan  5 , Jia Guo  6 , Angeliki Mela  7 , Zhiguo Zhang  4 , Tony J C Wang  8 , Jeffrey N Bruce  9 , Peter D Canoll  10 , Neil A Feldstein  2 , Stergios Zacharoulis  11 , Elisa E Konofagou  3 , Cheng-Chia Wu  12
Affiliations

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

Hong-Jian Wei et al. Int J Radiat Oncol Biol Phys. .

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.

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Figures

Figure 1.
Figure 1.
In vitro cytotoxicity of chemotherapy drugs in of mouse glioma cells. Cell viability (mean ± SD) of MGPP3 cells treated with etoposide, carboplatin, and TMZ for 72 hours assessed by MTT assay.
Figure 2.
Figure 2.
Validation of intracranial GBM model. (A) Representative T1-weighted contrast-enhanced images of mice intracranially injected with MGPP3 cells. Images were taken 6, 13, and 17 days after tumor implantation. Red dotted line: tumor cavity as defined by T1-post contrast enhancement. (B) Representative T1-weighted contrast-enhanced and non-contrast T2 images of mice 10 days after intracranial injection of MGPP3 cells. Left panel: injection tract (arrow), contrast enhancing tumor (arrowhead), and hyperintensity demonstrating peritumoral edema region (asterisk). Right panel: injection tract (arrow) and lightly hyperintense, poorly demarcated, and irregularly tumor lesion (asterisk). (C) Representative H&E staining of brain tumor showing the histological features of MGPP3-derived xenograft. Left panel: original magnification × 100; Right panel: original magnification × 400.
Figure 3.
Figure 3.
FUS-mediated BBB opening confirmed by MR imaging and acoustic emissions measurement. (A) Schematic diagram of the targeted strategy for BBB opening. (B) Representative T1-weighted contrast-enhanced images of GBM tumor-bearing mice before and after FUS sonication. Red dotted line: tumor; Yellow dotted line: BBB opening. In vivo passive cavitation detection measurements. (C) Acoustic energy, (D) spectral amplitude, (E) spectrogram of MBs cavitation during FUS exposure. (F) The dose of stable harmonic cavitation (SCDh), stable ultraharmonic cavitation (SCDu), and inertial cavitation (ICD) during FUS exposure. Red arrowhead: MBs administration; Blue arrowheads: movement of the transducer.
Figure 4.
Figure 4.
Comparison of BBB opening in vivo. (A) Time course of the experiment. The quantification of MR images for (B) BBB opening volume (mm3) and (C) contrast enhancement (%). (D) Average stable harmonic (SCDh), stable ultraharmonic (SCDu) and inertial (ICD) cavitation dose during FUS sonication. Values are means + SD; P values between FUS and FUS+Etop are indicated by using unpaired t-tests with Welch’s correction.
Figure 5.
Figure 5.
Therapeutic efficacy and delivery of etoposide enhanced by FUS in GBM tumor-bearing mice. (A) Representative T1-weighted contrast-enhanced images of mice intracranially injected with MGPP3 cells with indicated treatment. Images were taken 7 and 14 days after tumor implantation. (B) Quantitative analysis of the relative tumor progression. Fold changes are the tumor volume by MR image on day 14 normalized to the tumor volume on day 7. Values are means + SD; * indicates P<0.05 in unpaired t test with Welch’s correction, compared to the control group. (C) Kaplan-Meier plot of survival of mice intracranially injected with MGPP3 cells with indicated treatment. Ctrl: control group; Etop: etoposide alone group; FUS: FUS alone group; FUS+Etop: the combination of FUS and etoposide group. (D) The tumor-to-serum ratios of etoposide concentration (E) and the concentration of etoposide in brain tumors with or without FUS.
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