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

J Control Release. 2019 Feb 10;295:130-139. doi: 10.1016/j.jconrel.2018.12.009. Epub 2018 Dec 8.

Abstract

In glioblastoma, the benefit from temozolomide chemotherapy is largely limited to a subgroup of patients (30-35%) with tumors exhibiting methylation of the promoter region of the O6-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 barrier and deliver a first-in-class liposome-loaded small molecule MGMT inactivator in mice bearing temozolomide-resistant gliomas. We demonstrate that a liposomal O6-(4-bromothenyl)guanine (O6BTG) derivative can efficiently target MGMT, thereby sensitizing murine and human glioma cells to temozolomide in 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 barrier opening reduced tumor growth and significantly prolonged survival of glioma-bearing mice, when combined with temozolomide chemotherapy. Exploring this novel combined approach in the clinic to treat glioblastoma patients with MGMT promoter-unmethylated tumors is warranted.

Keywords: Focused ultrasound; Glioblastoma; Image-guided targeting; Liposomes; Methylguanine-DNA methyltransferase inactivation; Temozolomide resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / administration & dosage*
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Brain Neoplasms / diagnostic imaging
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Cell Line, Tumor
  • Dacarbazine / administration & dosage*
  • Dacarbazine / therapeutic use
  • Drug Delivery Systems / methods
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / therapeutic use
  • Glioblastoma / diagnostic imaging
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Guanine / administration & dosage
  • Guanine / analogs & derivatives*
  • Guanine / therapeutic use
  • Liposomes / administration & dosage*
  • Liposomes / therapeutic use
  • Magnetic Resonance Imaging / methods
  • Mice
  • O(6)-Methylguanine-DNA Methyltransferase / antagonists & inhibitors
  • O(6)-Methylguanine-DNA Methyltransferase / metabolism
  • Ultrasonic Waves

Substances

  • Antineoplastic Agents, Alkylating
  • Enzyme Inhibitors
  • Liposomes
  • O(6)-(4-bromothenyl)guanine
  • Guanine
  • Dacarbazine
  • O(6)-Methylguanine-DNA Methyltransferase