Enhancing Delivery and Efficacy of Panobinostat for Diffuse Midline Glioma through Focused Ultrasound-Mediated Blood-Brain Barrier Opening

Diffuse midline gliomas (DMG) are one of the most prevalent and deadliest brainstem tumors among children. DMGs present a challenge for chemotherapy due in part to their maintaining of the blood-brain barrier (BBB). Focused ultrasound (FUS) in combination with microbubbles (MBs) has shown potential in opening the BBB (BBBO), enabling larger chemotherapeutic agents to access brain tissue. An illustrative case is panobinostat, an in vitro candidate displaying promise against DIPG but hindered clinical efficacy due to limited BBB penetration. This study aimed to exploit FUS/MBs to open the BBB, increasing the accumulation of panobinostat in the tumor. Mice were implanted with a patient-derived thalamic DMG cell line, BT245. Employing MRI guidance, FUS/MB intervention (1.5 MHz, 0.492 MPa PNP, 1 Hz PRF, 10 ms PL, 3 minutes duration) along with intravenous injection of MBs (25 µL/kg) were precisely targeted at the tumor site. When panobinostat (10 mg/kg) was administered alongside FUS/MB treatment, a threefold rise in tumor panobinostat concentration occurred, with negligible elevation in cortical tissue. In mice receiving three weekly treatment sessions, the combined approach led to a 71% reduction in tumor volumes (p = 0.01). Notably, FUS/MB treatment extended mean survival from 21 to 31.5 days (p < 0.0001). This investigation underscores the potential of FUS-mediated BBBO to enhance the delivery of panobinostat to orthotopic DMG tumors, resulting in robust therapeutic effects and prolonged survival rates.