Pharmacodynamic and therapeutic investigation of focused ultrasound-induced blood-brain barrier opening for enhanced temozolomide delivery in glioma treatment.

Authors: Liu HL, Huang CY, Chen JY, Wang HY, Chen PY, Wei KC

Focused ultrasound (FUS) exposure with the presence of microbubbles has been shown to transiently open the blood-brain barrier (BBB), and thus has potential to enhance the delivery of various kinds of therapeutic agents into brain tumors. The purpose of this study was to assess the preclinical therapeutic efficacy of FUS-BBB opening for enhanced temozolomide (TMZ) delivery in glioma treatment. FUS exposure with microbubbles was delivered to open the BBB of nude mice that were either normal or implanted with U87 human glioma cells. Different TMZ dose regimens were tested, ranging from 2.5 to 25 mg/kg. Plasma and brain samples were obtained at different time-points ranging from 0.5 to 4 hours, and the TMZ concentration within samples was quantitated via a developed LC-MS/MS procedure. Tumor progression was followed with T2-MRI, and animal survival and brain tissue histology were conducted. Results demonstrated that FUS-BBB opening caused the local TMZ accumulation in the brain to increase from 6.98 to 19 ng/mg. TMZ degradation time in the tumor core was found to increase from 1.02 to 1.56 hours. Improved tumor progression and animal survival were found at different TMZ doses (up to 15% and 30%, respectively). In conclusion, this study provides preclinical evidence that FUS-BBB opening increases the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting the potential for clinical application to improve current brain tumor treatment.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To assess whether focused ultrasound-induced blood-brain barrier opening enhances temozolomide delivery and therapeutic efficacy in a preclinical glioma model.

Animal model / Human subject Mouse (nude mice/athymic nude), age not specified, sex not specified

Disease model glioma

Targeted brain region(s) Glioma (Brain Tumor, Tumor Core)

Cargo name and characteristics Temozolomide (TMZ), a small-molecule alkylating chemotherapeutic agent; systemically administered to mice at doses of 2.5–25 mg/kg; brain/tumor concentrations measured by LC-MS/MS to assess FUS-BBB enhanced delivery.

Outcomes and Safety

Summary of Outcomes Transcranial focused ultrasound (FUS) BBB opening with microbubbles (2 W) increased local temozolomide (TMZ) accumulation in brain/tumor (~2.7-fold in brain), prolonged TMZ retention in tumor (degradation time from ~1.02 to ~1.56 h), slowed tumor progression and improved animal survival (notably enhancing low-dose TMZ efficacy and producing near-complete tumor suppression with high-dose TMZ). Successful FUS parameter tested: 2 W exposure (5 W produced wider BBB opening with RBC extravasation and tissue damage and was therefore not selected).

Duration of biological effect 1.56 hours

Safety-related matter FUS at 2 W induced BBB opening without pathological changes to CNS cells and was chosen for subsequent experiments for safety; at a higher exposure (5 W) there was RBC extravasation in exposed regions indicating tissue injury. FUS-BBB opening alone did not adversely affect animal survival (median survival similar to control).

Brain Region

Ultrasound Parameters

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

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