Transient Blood-Brain Barrier Opening by Focused Ultrasound Enhances Ferumoxytol Accumulation in Glioblastoma

Nanoparticle delivery to glioblastoma is limited by the blood-brain barrier (BBB), which restricts the transport of diagnostic and therapeutic agents into tumor tissue. Microbubble-mediated focused ultrasound (FUS) can transiently increase BBB permeability and enhance localized delivery of molecular probes and drugs. We tested whether MRI-guided microbubble-assisted FUS at 650 kHz enables spatially controlled and quantitatively measurable delivery of the FDA-approved ferumoxytol (FMX), an iron oxide nanoparticle formulation. Acoustic simulations were employed to quantify transcranial pressure fields and assess pressure-dependent BBB opening at a clinically relevant frequency and were experimentally validated in healthy mice. In mice bearing orthotopic U87 glioblastoma, MRI-guided microbubble-assisted FUS was focally applied to the tumor region, with intravenously administered Definity microbubbles mediating transient BBB opening, followed by intravenous injection of fluorescein-labeled FMX. Nanoparticle accumulation was quantified using in vivo MRI and postmortem fluorescence imaging. Post-contrast tumor T2 relaxation times were 33.14 ms in the FMX group and 22.47 ms in the FMX+FUS group. Tumor transverse relaxation rate change showed a 2.6-fold increase under FUS conditions relative to the non-FUS group, demonstrating enhanced nanoparticle transport across a transiently permeabilized BBB. Pressure thresholds were identified for FMX delivery to normal brain versus tumor tissue, with a lower estimated threshold in tumor tissue than in healthy brain (0.224 MPa vs. 0.265 MPa), highlighting a pressure window for selective nanoparticle transport. Histopathological evaluation of H&E-stained normal brain and tumor sections showed no significant increase in detectable acute structural tissue damage. Our findings establish a quantitative and clinically translatable framework for spatially controlled FUS-enhanced delivery of clinically relevant nanoparticle formulations to brain tumors, advancing targeted delivery strategies for neuro-oncologic applications.