Chemotherapy sensitization of glioblastoma by focused ultrasound-mediated delivery of therapeutic liposomes

Abstract In glioblastoma, the benefit from temozolomidechemotherapy is largely limited to a subgroup of patients (30–35%) with tumors exhibiting methylation of the promoter region of the O 6- methylguanine-DNA methyltransferase( MGMT ) gene. In order to allow more patients to benefit from this treatment, we explored magnetic resonance image-guided microbubble-enhanced low-intensity pulsed focused ultrasound (LIFU) to transiently open the blood-brain barrierand deliver a first-in-class liposome-loaded small molecule MGMT inactivator in mice bearing temozolomide-resistant gliomas. We demonstrate that a liposomal O 6 -(4-bromothenyl)guanine (O 6 BTG) derivative can efficiently target MGMT, thereby sensitizing murine and human glioma cells to temozolomidein vitro. Furthermore, we report that image-guided LIFU mediates the delivery of the stable liposomal MGMT inactivator in the tumor region resulting in potent MGMT depletion in vivo . Treatment with this new liposomal MGMT inactivator facilitated by LIFU-mediated blood-brain barrieropening reduced tumor growth and significantly prolonged survival of glioma-bearing mice, when combined with temozolomidechemotherapy. Exploring this novel combined approach in the clinic to treat glioblastoma patients with MGMT promoter-unmethylated tumors is warranted.