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Boron neutron capture therapy for glioblastoma multiforme: enhanced drug delivery and antitumor effect following blood-brain barrier disruption induced by focused ultrasound.

Authors: Yang FY, Chen YW, Chou FI, Yen SH, Lin YL, Wong TT

This study investigated whether the efficacy of boron neutron capture therapy was enhanced by means of intravenous administration of boronophenylalanine (BPA) with blood-brain barrier disruption induced by focused ultrasound (FUS). BPA was administered, followed by pulsed FUS, and the boron concentration in the treated brains was quantified by inductively coupled plasma mass spectroscopy. Growth of the firefly luciferase-labeled glioma cells was monitored through noninvasive biophotonic imaging. Finally, the brain tissue was histologically examined after sacrifice. Compared with the nonsonicated tumor group, animals treated with an injection of 500 mg/kg of BPA followed by FUS exhibited not only significantly increased accumulation of the drug at the sonicated tumor site, but also a significantly elevated tumor-to-normal brain drug ratio (p < 0.05). The data demonstrated that FUS significantly enhances the tumor-to-normal brain drug ratio in the sonicated tumor and subsequently the efficacy of boron neutron capture therapy.

Introduction

Purpose Drug delivery with BBB opening
Study Objective To determine whether focused ultrasound (FUS)-induced blood–brain barrier opening enhances boronophenylalanine (BPA) delivery and improves the efficacy of boron neutron capture therapy (BNCT) in glioblastoma.
Animal model / Human subject Mice
Disease model Glioblastoma
MRI or image guidance method MRI-guided
Targeted brain region(s) Cerebral Hemisphere Glioblastoma (Gbm8401) Tumor Implantation Site.
Cargo name and characteristics Boron-containing small molecule(s) for boron neutron capture therapy (BNCT), e.g., boronophenylalanine (BPA) or sodium borocaptate (BSH)
Route of administration intravenous

Outcomes and Safety

Summary of Outcomes FUS significantly increased intratumoral BPA accumulation and the tumor-to-normal brain boron ratio, resulting in enhanced BNCT antitumor efficacy, reduced tumor growth, and increased tumor cell apoptosis compared with BNCT alone.
Duration of biological effect Enhanced boron accumulation was detected 1 hour after BPA administration, while the therapeutic effects—including reduced tumor growth, MRI changes, and increased apoptosis—persisted for at least 12 days after treatment and were evident through day 20 after tumor implantation.
Safety-related matter FUS enabled localized BBB opening and selective boron delivery with minimal toxicity to normal brain tissue, although focal red blood cell extravasation and tissue displacement were observed within the sonicated tumor region.

Brain Region

Ultrasound Parameters

Ultrasound instrument single-element focused transducer (A392S, Panametrics, MA, USA)
FUS Frequency 1 MHz
FUS Intensity 2.86 W
FUS Pressure 0.7 Mpa
FUS Mode pulsed
Pulse duration 50 ms
Duration of a single FUS session 60 s
Focal Characteristics In the shape of an elongated ellipsoid with a radial diameter (-6dB) of 3 mm
Treatment frequency Two FUS sessions, performed on days 12 and 16 after tumor implantation.

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