IMG-35. Targeted blood-nerve-barrier opening for the delivery of MEK inhibitor selumetinib in peripheral nerve sheath tumours using focused ultrasound

Neurofibromatosis-1 (NF1) is a genetic disorder affecting 1 in 2500 births and is characterized by the development of multiple peripheral nerve sheath tumours (PNSTs). Treatment involves surgical resection and radiation therapy however both are invasive and associated with morbidity, pain, neurological complications, and long-term risks associated with ionizing radiation. Clinical trials in NF1 patients have identified selumetinib as a promising chemotherapeutic as it can reduce tumour size and inhibit tumour progression. However, only 68% of patients showed a partial response with 10% discontinuing treatment due to toxicities; adverse events occur in 50% of patients. Focused ultrasound (FUS) is a non-invasive, non-ionizing technique that uses ultrasonic waves to manipulate deep tissue without affecting overlying or surrounding structures. Through stable cavitation of intravenous microbubbles, FUS can disrupt the blood-nerve-barrier (BNB) and could offer a novel strategy in targeted selumetinib delivery to PNSTs, enabling lower systemic doses and reducing off-target toxicities. We first wanted to confirm the feasibility of non-invasive BNB disruption in the sciatic nerve. In an acute experiment with 6 C57BL/6J mice, the right sciatic nerve was sonicated at 0.3 MPa. Evan’s blue dye penetration suggested successful BNB disruption. Half the animals were sacrificed immediately and both the right and left sciatic nerves were collected. The other half were kept for acute clinical assessments at 24 hours post FUS. No change in hind limb function was observed with a slight reduction in avoiding response, however further studies are required to elucidate these changes. The sciatic nerves were collected after. H&E stains were performed on the nerves to assess for tissue damage. Based on images taken, there was no evidence of tissue damage between the sonicated and un-sonicated nerves. This suggests this technique may be feasible. Future work will be to perform FUS in a tumour model with and without drug.