DDEL-05. BLOOD-BRAIN BARRIER DISRUPTION AND ENHANCED RADIOSENSITIZERS EXTRAVASATION UPON FOCUSED ULTRASOUND FOR TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA

Poor prognosis of diffuse midline glioma, including diffuse intrinsic pontine glioma (DIPG), reflects the low efficacy of current treatment strategies, mainly due to (1) a largely intact blood-brain barrier (BBB) and (2) the proficiency of tumour tissues to upregulate multiple DNA repair genes, resulting into radio-resistance. In vitro studies showed therapeutic benefit by combining radiotherapy and radiosensitizers, while pre-clinical and clinical studies evidenced safe and transient opening of the BBB using microbubble mediated focused ultrasound (FUS). Previously, we demonstrated the enhanced extravasation of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor in the mouse pons. Local drug delivery was applied using an in-house built X-ray image-guided FUS system with a 1 MHz mono-element transducer delivering a tone-burst pulse with a mechanical index of 0.4. Tissue/blood drug concentrations were analysed by LC-MS/MS, 30 minutes after intraperitoneal injection of 10 mg/kg olaparib. The FUS system allowed for precise treatment of the pons, proven by local extravasation of Evans Blue-conjugated albumin. A significant 5.1 fold median increase was observed in absolute concentrations in the pons after FUS intervention compared to the control and a 4.9 fold increase of the median tissue-blood ratio (*p<0.05). No significant differences were detected in brain regions outside the ultrasound focus and other organs, confirming the local intervention. With this, the 299 nM equivalent olaparib concentration found in the pons will facilitate PARP inhibition in future murine patient-derived xenograft tumour models, thus leading to a greater therapeutic effect when in combination with radiotherapy treatment of DIPG.