Dataset Information

Acoustic feedback enables safe and reliable carboplatin delivery across the blood-brain barrier with a clinical focused ultrasound system and improves survival in a rat glioma model.

ABSTRACT: The blood-brain barrier (BBB) restricts delivery of most chemotherapy agents to brain tumors. Here, we investigated a clinical focused ultrasound (FUS) device to disrupt the BBB in rats and enhance carboplatin delivery to the brain using the F98 glioma model. Methods: In each rat, 2-3 volumetric sonications (5 ms bursts at 1.1 Hz for 75s) targeted 18-27 locations in one hemisphere. Sonication was combined with Definity microbubbles (10 µl/kg) and followed by intravenous carboplatin (50 mg/kg). Closed-loop feedback control was performed based on acoustic emissions analysis. Results: Safety and reliability were established in healthy rats after three sessions with carboplatin; BBB disruption was induced in every target without significant damage evident in MRI or histology. In tumor-bearing rats, concentrations of MRI contrast agent (Gadavist) were 1.7 and 3.3 times higher in the tumor center and margin, respectively, than non-sonicated tumors (P<0.001). Tissue-to-plasma ratios of intact carboplatin concentrations were increased by 7.3 and 2.9 times in brain and tumor respectively, at one hour after FUS and 4.2 and 2.4 times at four hours. Tumor volume doubling time in rats receiving FUS and carboplatin increased by 96% and 126% compared to rats that received carboplatin alone and non-sonicated controls, respectively (P<0.05); corresponding increases in median survival were 48% and 66% (P<0.01). Conclusion: Overall, this work demonstrates that actively-controlled BBB disruption with a clinical device can enhance carboplatin delivery without neurotoxicity at level that reduces tumor growth and improves survival in an aggressive and infiltrative rat glioma model.

SUBMITTER: McDannold N

PROVIDER: S-EPMC6735504 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Acoustic feedback enables safe and reliable carboplatin delivery across the blood-brain barrier with a clinical focused ultrasound system and improves survival in a rat glioma model.

McDannold Nathan N Zhang Yongzhi Y Supko Jeffrey G JG Power Chanikarn C Sun Tao T Peng Chengueng C Vykhodtseva Natalia N Golby Alexandra J AJ Reardon David A DA

Theranostics 20190814 21

The blood-brain barrier (BBB) restricts delivery of most chemotherapy agents to brain tumors. Here, we investigated a clinical focused ultrasound (FUS) device to disrupt the BBB in rats and enhance carboplatin delivery to the brain using the F98 glioma model. <b>Methods</b>: In each rat, 2-3 volumetric sonications (5 ms bursts at 1.1 Hz for 75s) targeted 18-27 locations in one hemisphere. Sonication was combined with Definity microbubbles (10 µl/kg) and followed by intravenous carboplatin (50 mg ...[more]

PMID: 31534551

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Project description:To determine if focused ultrasound disruption of the blood-brain barrier (BBB) can be safely controlled by using real-time modulation of treatment pressures on the basis of acoustic emissions from the exposed microbubbles.All experiments were performed with the approval of the institutional animal care committee. Transcranial focused ultrasound (551.5 kHz, 10-msec bursts, 2-Hz pulse repetition frequency, 2 minute sonication) in conjunction with circulating microbubbles was applied in 86 locations in 27 rats to disrupt the BBB. Acoustic emissions captured during each burst by using a wideband polyvinylidene fluoride hydrophone were analyzed for spectral content and used to adjust treatment pressures. Pressures were increased incrementally after each burst until ultraharmonic emissions were detected, at which point the pressure was reduced to a percentage of the pressure required to induce the ultraharmonics and was maintained for the remainder of the sonication. Disruption was evaluated at contrast material-enhanced T1-weighted magnetic resonance (MR) imaging. Mean enhancement was calculated by averaging the signal intensity at the focus over a 3 × 3-pixel region of interest and comparing it with that in nonsonicated tissue. Histologic analysis was performed to determine the extent of damage to the tissue. Statistical analysis was performed by using Student t tests.For sonications resulting in BBB disruption, the mean peak pressure was 0.28 MPa ± 0.05 (standard deviation) (range, 0.18-0.40 MPa). By using the control algorithm, a linear relationship was found between the scaling level and the mean enhancement on T1-weighted MR images after contrast agent injection. At a 50% scaling level, mean enhancement of 19.6% ± 1.7 (standard error of the mean) was achieved without inducing damage. At higher scaling levels, histologic analysis revealed gross tissue damage, while at a 50% scaling level, no damage was observed at high-field-strength MR imaging or histologic examination 8 days after treatment.This study demonstrates that acoustic emissions can be used to actively control focused ultrasound exposures for the safe induction of BBB disruption.

Dataset Information

Acoustic feedback enables safe and reliable carboplatin delivery across the blood-brain barrier with a clinical focused ultrasound system and improves survival in a rat glioma model.

Publications

Acoustic feedback enables safe and reliable carboplatin delivery across the blood-brain barrier with a clinical focused ultrasound system and improves survival in a rat glioma model.

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