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

Abstract

Feng-Yi Yang1,*, Hsin-Ell Wang1,*, Guan-Liang Lin1, Hui-Hsien Lin1, Tai-Tong Wong21Department of Biomedical Imaging and Radiological Sciences, School of Biomedical Science and Engineering, National Yang-Ming University, 2Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan *These authors contributed equally to this workPurpose: 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.Materials and methods: 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.Results: 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.Conclusion: This method could allow enhanced synergistic effects with respect to other brain tumor treatment regimens.Keywords: focused ultrasound, blood–brain barrier, permeability, brain tumor, glioma