Ultrasound-Triggered Chemotherapy Extends Survival in a Genetically Engineered Glioblastoma Model

Abstract Glioblastoma (GBM) remains one of the most lethal primary brain tumors, in part because the blood–brain barrier (BBB), restricts delivery of most systemically administered chemotherapeutics. Although focused ultrasound (fUS) can transiently increase BBB permeability, therapeutic efficacy remains limited by reliance on systemic drug exposure and heterogeneous intratumoral distribution. Here, we report a pressure-gated ultrasound-triggered drug delivery strategy that enables localized intravascular release of chemotherapy at the site of sonication. Freebase doxorubicin and afatinib were encapsulated within ultrasound-sensitive mPEG–PDLLA/PFOB microdroplets and administered systemically to N-TVA::Ink4a/Arf lox/lox ;Pten lox/lox mice bearing genetically engineered glioblastomas. Animals received repeated transcranial focused ultrasound over a 30-day treatment period. Ultrasound-triggered release of the dual-drug formulation significantly extended survival compared with untreated controls, with median survival increased by over two weeks – approximately a 30% improvement. Furthermore, this survival improvement was reflected in histological analysis, showing decreased tumor burden and severity. These improvements were not found in any control groups, demonstrating that spatially and temporally controlled intravascular drug release can substantially improve therapeutic efficacy in an aggressive immunocompetent glioblastoma model. These findings support pressure-gated ultrasound-triggered chemotherapy as a promising activation-based strategy for overcoming BBB-associated delivery limitations and improving outcomes in malignant brain tumors. Graphical Abstract Highlights Pressure-gated focused ultrasound enables localized release of doxorubicin and afatinib in glioblastoma. Ultrasound-triggered chemotherapy significantly extends survival in a genetically engineered immunocompetent GBM model. Local activation outperforms systemic administration of identical drug combinations. This strategy shifts focused ultrasound therapy from general BBB opening to spatially controlled drug activation.