Evaluation of the increase in permeability of the blood-brain barrier during tumor progression after pulsed focused ultrasound.

The purpose of this study was to evaluate the permeability of the blood-brain barrier after sonication by pulsed high-intensity focused ultrasound and to determine if such an approach increases the tumor:ipsilateral brain permeability ratio. F98 glioma-bearing Fischer 344 rats were injected intravenously with Evans blue with or without blood-tumor barrier disruption induced by transcranial pulsed high-intensity focused ultrasound. Sonication was applied at a frequency of 1 MHz with a 5% duty cycle and a repetition frequency of 1 Hz. The permeability of the blood-brain barrier was assessed by the extravasation of Evans blue. Contrast-enhanced magnetic resonance images were used to monitor the gadolinium deposition path associated with transcranial pulsed high-intensity focused ultrasound, and the influencing size and location was also investigated. In addition, whole brain histological analysis was performed. The results were compared by two-tailed unpaired t-test. The accumulation of Evans blue in brains and the tumor:ipsilateral brain permeability ratio of Evans blue were significantly increased after pulsed high-intensity focused ultrasound exposure. Evans blue injection followed by sonication showed an increase in the tumor:ipsilateral brain ratio of the target tumors (9.14:1) of about 2.23-fold compared with the control tumors (x4.09) on day 6 after tumor implantation. Magnetic resonance images showed that pulsed high-intensity focused ultrasound locally enhances the permeability of the blood-tumor barrier in the glioma-bearing rats. This method could allow enhanced synergistic effects with respect to other brain tumor treatment regimens.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To evaluate whether pulsed high-intensity focused ultrasound (HIFU) increases blood–brain/blood–tumor barrier permeability and raises the tumor:ipsilateral brain permeability ratio in glioma-bearing rats.

Animal model / Human subject Rat (Fischer 344), F98 glioma-bearing; age 9-12 weeks old; sex male

Disease model glioma

MRI or image guidance method Contrast-enhanced magnetic resonance imaging (MRI) to monitor gadolinium deposition path

Targeted brain region(s) Hemisphere (Glioma Implantation Site)

Target coordinates AP: 5 mm posterior to bregma; ML: 3 mm lateral; DV: 5 mm depth

Cargo name and characteristics Evans blue — vascular permeability tracer dye that binds serum albumin (forms a high‑molecular‑weight albumin–dye complex used to assess BBB/BTB permeability); Gadolinium-based MRI contrast agent — small‑molecule paramagnetic contrast agent used to visualize permeability/deposition on contrast-enhanced MRI.

Route of administration intravenous

Outcomes and Safety

Summary of Outcomes Transcranial pulsed HIFU (1 MHz, 5% duty cycle, 1 Hz repetition frequency) combined with microbubbles and sonication after Evans blue injection significantly increased blood–tumor barrier permeability in F98 glioma rats — increasing Evans blue accumulation, gadolinium contrast enhancement, local RBC extravasation, and the tumor:ipsilateral brain ratio (up to 9.14:1; ~2.23-fold vs control on day 6); effects were strongest when the ultrasound focal zone covered the tumor (days 6–8) and decreased by day 12.

Safety-related matter Histology showed local displacement and increased red blood cell extravasation with widened intercellular gaps in sonicated tumor tissues, but there was no significant difference in apoptosis between sonicated and control tumors; no other significant adverse effects were reported.

Brain Region

Ultrasound Parameters

Ultrasound instrument Single-element focused transducer (A392S Panametrics)

FUS Frequency 1 MHz

FUS Mode pulsed

Pulse duration 50 ms

Duration of a single FUS session 1 minute

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: 38 mm

Treatment frequency single

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