Ultrasound enhanced delivery of macromolecular agents in brain tumor rat model.

The purpose of this study was to evaluate the permeability of the blood-brain barrier (BBB) after focused ultrasound (FUS) exposure and to investigate if such an approach increases the tumor-to-ipsilateral brain permeability ratio. Normal rats and F98 glioma-bearing rats were injected intravenously with Evans blue (EB); these treatments took place with or without BBB disruption induced by transcranial FUS of one hemisphere of the brain. Sonication was applied at an ultrasound frequency of 1 MHz with a 5% duty cycle, and a repetition frequency of 1 Hz. The permeability of the BBB was quantitatively assessed by means of the extravasation of EB. Contrast-enhanced MR images were used to monitor the gadolinium deposition path associated with transcranial FUS and the influence of size and location was also investigated. Furthermore, whole brain histological analysis was performed. The results were compared by two-tailed unpaired t test. The accumulation of EB in brains and the tumor-to-ipsilateral brain permeability ratio of EB were significantly increased after FUS exposure. EB injection followed by sonication showed an increase in the tumor-to-ipsilateral brain ratio of the target tumors of about two-fold compared with the control tumors on day 8 after tumor implantation. MR images showed that FUS locally enhances the permeability of the BBB in the glioma-bearing rats. The BBB can be locally disrupted with FUS in the presence of microbubbles. This technology may offer new opportunities that will allow enhanced synergistic effects with respect to other brain tumor treatment regimens.