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

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 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 barrier and 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 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.

Investigating the Mechanism of Cyclodextrins in the Treatment of Niemann‐Pick Disease Type C Using Crosslinked 2‐Hydroxypropyl‐β‐cyclodextrin

“…The limited brain delivery and penetration was addressed employing MRIg-FUS, which has been shown to enhance the deposition of different drugs in various organs [56][57][58] while being well tolerated by animals [59][60][61][62][63] and humans. [64,65] Moreover, MRIg-FUS showed therapeutic efficacy per se on phosphorylated Tau and amyloid plaques.…”

“…The rats were i.v. injected with 2.4 mL kg −1 of microbubbles (600 µL min −1 injection speed) 30 s before the beginning of the FUS sequence, which lasted for 3 min with fixed parameters during the whole session (length: 10 ms pulse; sequence: 1 Hz pulse repetition frequency; acoustic pressure emitted: 0.9 MPa; estimated pressure in situ: 0.4-0.5 MPa; duty cycle: 1%; mechanical index: 0.7; expected thermal index: ≈0) and was adapted from a protocol described by Papachristodoulou et al [58] Twenty min after FUS sequence, rats were i.v. injected with 75 µL per animal of gadolinium-DOTA (Guerbet, Paris, France) and T1-weighted MR images were acquired to confirm BBB opening.…”

Elucidating the mechanism of cyclodextrins in the treatment of Niemann-Pick Disease Type C using crosslinked 2-hydroxypropyl-β-cyclodextrin

“…The limited brain delivery and penetration was addressed employing MRIg-FUS, which has been shown to enhance the deposition of different drugs in various organs [57][58][59] while being well tolerated by animals [60][61][62][63] and humans [64,65]. Moreover, MRIg-FUS showed therapeutic efficacy per se on phosphorylated Tau and amyloid plaques [66,67].…”

“…The rats were i.v. injected with 2.4 mL kg -1 of microbubbles (600 µL/min injection speed) 30 s before the beginning of the FUS sequence, which lasted for 3 min (Length: 5-10 ms pulse; Sequence: 1 Hz pulse repetition frequency; Pressure in situ: 0.4-0.5 mPa) and was adapted from a protocol described by Papachristodoulou et al [59]. Twenty min after FUS sequence, rats were i.v.…”

O6-Methylguanine-DNA Methyltransferase (MGMT): Challenges and New Opportunities in Glioma Chemotherapy

“…The dose-limiting toxicity of O 6 -BTG was myelosuppression (78). Papachristodoulou et al reported that a liposomal O 6 BTG can efficiently target MGMT, thereby sensitizing murine and human glioma cells to TMZ in vitro and magnetic resonance image-guided microbubbleenhanced low-intensity pulsed focused ultrasound mediates the delivery of the stable liposomal MGMT inactivator into the tumor region resulting in complete MGMT depletion in vivo (79).…”