Blood‒brain barrier opening with Golay-coded ultrasound to improve therapeutic consistency in glioblastoma models

Transcranial-focused ultrasound has demonstrated potential for blood-brain barrier (BBB) opening and localized drug delivery to intracranial brain lesions, making it a promising therapeutic strategy for glioblastoma (GBM) treatment. However, consistent drug delivery is hindered by cranial beam distortions, particularly standing-wave formation, when conventional sinusoidal-periodic ultrasound transmission sequences are used. We propose a novel Golay-coded random (Golay-random) ultrasound transmission sequence to mitigate standing wave effects and address this challenge. The efficacy of the Golay-random sequence was validated through computational simulations, which revealed significantly reduced pressure fluctuations compared to that in sinusoidal-periodic sequences. In vivo experiments quantified the BBB opening using gadolinium contrast-enhanced magnetic resonance imaging (MRI). The Golay-random sequence demonstrated effective BBB opening, with BBB permeability-increasing with burst length from 1.25 to 2.50 ms and plateauing at 5.00 ms. In contrast, no consistent correlation between burst length and BBB opening was observed with the sinusoidal-periodic sequence. In GBM mouse models, posttreatment MRI revealed significantly smaller tumor sizes in the group receiving doxorubicin with Golay-random transmission (G-Dox: 3.72 ± 4.34 mm³) compared to those with sinusoidal-periodic transmission (P-Dox: 18.05 ± 11.81 mm³). Optical in vivo imaging corroborated these findings, showing reduced tumor progression in the G-Dox group (4.54 ± 5.67) relative to the P-Dox group (25.17 ± 33.71). These results highlight the Golay-random sequence as a superior alternative to conventional sinusoidal-periodic sequences, offering improved precision and reliability in drug delivery and enhanced therapies for GBM.