Acoustic cluster therapy mediated enhancement of [68Ga]Ga-PSMA-617 in a murine glioblastoma multiforme model verified by simultaneous PET/MRI

Purpose Targeted radioligand therapy (TRT) shows promise for treating glioblastoma multiforme (GBM), but its effectiveness is limited by insufficient and heterogeneous tumor uptake. Prostate-specific membrane antigen (PSMA) is being clinically explored as a target in GBM however, low and variable expression restricts effective radioligand delivery. Acoustic Cluster Therapy (ACT) is an ultrasound-mediated platform for targeted therapeutic enhancement that transiently increases vascular permeability to enhance accumulation of co-administered agents. Here, we investigate whether ACT improves the delivery of the PSMA-targeted radioligand [ 68 Ga]Ga-PSMA-617 in a GBM mouse model. Results Three weeks after orthotopic implantation of GL261 cells in C57BL/6JRj mice (n = 19, female, 8 weeks, 20.1 ± 0.9 g; tumor volume 0.07 ± 0.02 cm 3 ), dynamic [ 68 Ga]Ga-PSMA-617 PET/MRI was performed to evaluate the effect of ACT on radioligand delivery. A cross-over design was used with baseline treatment (saline + ultrasound) on day 21 followed by experimental treatment (PS101 microclusters + ultrasound) 24 h later. Additional controls included perfluorobutane microbubbles with ultrasound, PS101 microclusters without ultrasound, and repeated baseline procedures. A dedicated ultrasound sequence was applied before i.v. injection of 5.9 ± 1.6 MBq [ 68 Ga]Ga-PSMA-617. Pharmacokinetic analyses were performed using 1-tissue and 2-tissue compartment models and Logan analysis. ACT increased the accumulation of [ 68 Ga]Ga-PSMA-617 in the tumor by approximately two-fold and resulted in an increased V T and cumulative activity (103–217%) within the tumor region. Gadolinium-enhanced MRI in six healthy mice (female, 8 weeks, 24.1 ± 0.9 g) demonstrated increased contrast following ACT, indicating a transient ACT-mediated increase in BBB permeability. Exploratory correlation analyses further demonstrate associations between tumor size and baseline V T , indicating that baseline vascular permeability and BBB status influence tracer availability and the response to ACT. Conclusions ACT increased tumor accumulation of [ 68 Ga]Ga-PSMA-617 by approximately two-fold. Pharmacokinetic modeling and longitudinal MRI suggest that this effect is primarily driven by ACT-induced increases in vascular permeability across the blood–brain barrier, enhancing radioligand delivery and availability in the brain parenchyma rather than increased receptor-mediated binding. ACT-induced enhancement was most pronounced in tumors with lower baseline tracer accessibility, indicating that the vascular state of the tumor microenvironment strongly influences radioligand delivery. While these findings suggest an increased radioactive burden in the tumor, dedicated therapeutic studies using therapeutic radionuclides will be required to understand the implications ACT may have for dosimetry and therapeutic outcomes in TRT.