DDEL-19. A Novel Platform of Paclitaxel-Loaded Microbubbles with Focused Ultrasound for Enhanced Glioblastoma Drug Delivery and Treatment

Abstract Effective chemotherapy for glioblastoma (GBM) is severely limited by the impermeability of the blood-brain barrier (BBB). Although paclitaxel (PTX) demonstrates potent anti-glioma activity in vitro, its poor BBB penetration precludes its clinical use for GBM. We developed a novel PTX-loaded microbubble (PTX@MB) platform designed for targeted drug delivery to gliomas via low-intensity focused ultrasound (LIFU). PTX@MBs were fabricated using a perfluorocarbon (PFC) liquid core stabilized by Pluronic F-127, and their physicochemical properties were characterized. In vitro anti-tumor effects were evaluated using U87MG cells in both 2D culture and 3D spheroid models. For in vivo assessment, an orthotopic U87MG glioma mouse model was utilized. Following intravenous administration of PTX@MBs, LIFU was applied to the tumor region to induce localized drug release and transient BBB disruption. Therapeutic outcomes were evaluated by MRI, survival analysis, and histopathology. The synthesized PTX@MBs were spherical, with a high drug encapsulation efficiency of 89.1 ± 0.5%, and exhibited ultrasound-responsive drug release. In vitro, the combination of PTX@MBs and ultrasound exposure demonstrated dose-dependent cytotoxicity and significant inhibition of U87MG spheroid growth. In the orthotopic mouse model, the PTX@MB + LIFU treatment significantly suppressed tumor progression and prolonged median survival compared to the control group. While this treatment also showed a positive trend in efficacy over PTX alone, the difference did not reach statistical significance. This therapeutic benefit was achieved without notable systemic toxicity, and histopathological analysis confirmed a substantial reduction in tumor burden in the PTX@MB + LIFU group. This study demonstrates a clinically promising, ultrasound-responsive delivery system capable of overcoming the BBB for targeted paclitaxel delivery. The PTX@MB + LIFU platform effectively inhibits GBM growth in a preclinical model and represents a viable strategy for non-invasive, site-specific chemotherapy delivery in neuro-oncology.