Sonodynamic Therapy for Malignant Glioma Using 220-kHz Transcranial Magnetic Resonance Imaging-Guided Focused Ultrasound and 5-Aminolevulinic acid.
Authors: Yoshida M, Kobayashi H, Terasaka S, Endo S, Yamaguchi S, Motegi H, Itay R, Suzuki S, Brokman O, Shapira Y, Moriyama K, Kawase Y, Akahane T, Kato Y, Kamada H, Houkin K
Sonodynamic therapy (SDT) is used to treat various malignancies and can be applied to brain tumors using a transcranial magnetic resonance imaging-guided focused ultrasound (TcMRgFUS) device. This study investigated the efficacy of 220-kHz TcMRgFUS combined with 5-aminolevulinic acid (5-ALA) on malignant glioma in vitro and in vivo. F98 cells were irradiated with focused ultrasound (FUS) (4000 J, 20 W, 240 s, 100% duty cycle, target medium temperature <40°C) after treatment with 200 µg/mL 5-ALA, and cell viability and apoptosis were evaluated with the water-soluble tetrazolium-1 assay, triple fluorescent staining and Western blot analysis 20 h later. The anti-tumor effects of 5-ALA combined with FUS (500 J, 18 W, 30 s, 100% duty cycle, 10 repeats, target tissue temperature ≤42°C) were assessed on the basis of changes in tumor volume determined by MRI and histopathological analysis before and after treatment. The FUS/5-ALA combination reduced cell viability by inducing apoptosis and suppressed tumor proliferation and invasion as well as angiogenesis in vivo, while causing minimal damage to normal brain tissue. SDT with 220-kHz TcMRgFUS and 5-ALA can be safely used for the treatment of malignant glioma.
Introduction
Purpose
other
Study Objective
To evaluate the efficacy and mechanism of sonodynamic therapy using 220-kHz TcMRgFUS combined with 5-aminolevulinic acid against malignant glioma.
Animal model / Human subject
Rat, Fisher 344, female, 6-7 weeks old (~80-100 g)
Disease model
Malignant glioma (F98 cell line)
MRI or image guidance method
Yes (MRI and stereotactic)
Targeted brain region(s)
Hemisphere
Target coordinates
1 mm anterior, 3 mm lateral to bregma, depth 5 mm from brain surface
Cargo name and characteristics
5-aminolevulinic acid (5-ALA)
Route of administration
intraperitoneal
Outcomes and Safety
Summary of Outcomes
The combined treatment of FUS and 5-ALA (SDT) induced glioma cell apoptosis and significantly suppressed tumor proliferation, invasion, and angiogenesis in both in vitro and in vivo experiments. Although this antitumor effect was observed on day 16, it was temporary, as no difference compared to the control group remained by day 23. These results demonstrate that this non-thermal ablation method caused minimal damage to normal brain tissue, indicating it is a promising non-invasive therapeutic strategy.
Duration of biological effect
Tumor growth suppression was observed at 6 days post-treatment (day 16), but not sustained at 13 days post-treatment (day 23). By day 23, treatment group and control group show no differences on tumor growth
Safety-related matter
No structural damage (hemorrhage, necrosis) observed in normal brain tissue in treatment groups. The discussion notes a potential risk of intracranial hemorrhage related to cavitation signals in the rat model, but this was not a reported outcome in the treated animals.
Brain Region
Ultrasound Parameters
Ultrasound instrument
transcranial MRI-guided FUS system (ExAblate 4000, 220 kHz; InSightec, Haifa, Israel) consisting of 1024 hemispherical 30-cm-diameter US individually controllable transducer elements
FUS Frequency
220kHz
FUS Mode
continuous
Duration of a single FUS session
In vitro: 240 s
In vivo: 30 s per sonication, repeated 10 times (with 2 min recesses)
Focal Characteristics
Focal half-width: 4.2 mm, Focal length: 9.0 mm
Treatment frequency
single session
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