FOCUSED ULTRASOUND–MEDIATED BLOOD–BRAIN BARRIER OPENING IN NEURO-ONCOLOGY: CLOSED-LOOP CAVITATION CONTROL, PRECISION DRUG DELIVERY, AND THE PROPOSED SONO-BRIDGE FRAMEWORK

Abstract

Background. The blood–brain and blood–tumor barriers restrict homogeneous drug delivery to infiltrating brain-tumor cells, particularly beyond contrast-enhancing regions. Microbubble-enhanced focused ultrasound can temporarily and spatially increase vascular permeability through controlled mechanical interactions with cerebral microvessels.

Materials and methods. Prospective clinical trials, phase I–II studies, pharmacokinetic investigations, translational experiments, and technical reports published through July 2026 were synthesized. Evidence was organized according to skull acoustics, targeting, microbubble exposure, acoustic-emission monitoring, permeability imaging, drug properties, tumor phenotype, treatment timing, and toxicity.

Results. Noninvasive magnetic-resonance-guided, neuronavigation-guided, and implantable ultrasound platforms have repeatedly produced reversible barrier opening in glioblastoma, high-grade glioma, and brain metastases. Implantable low-intensity pulsed ultrasound increased delivery of albumin-bound paclitaxel and carboplatin in recurrent glioblastoma. The multicenter BT008NA phase I–II study combined repeated transcranial microbubble-enhanced focused ultrasound with adjuvant temozolomide and reported feasible barrier opening, acceptable safety, exploratory survival signals, and enhanced plasma tumor-biomarker release. Clinical evidence also supports increased trastuzumab delivery to HER2-positive brain metastases. However, drug penetration remains influenced by molecular size, plasma pharmacokinetics, extracellular diffusion, efflux transport, interstitial pressure, and regional tumor heterogeneity.

Conclusion. Focused ultrasound is a drug-delivery platform rather than an independent antitumor treatment. Safe translation requires individualized acoustic planning, real-time cavitation control, temporal coordination with systemic therapy, quantitative confirmation of permeability, and prospective demonstration that increased drug exposure improves patient-centered outcomes.