Pharmacodynamic Therapeutic Investigation of Focused Ultrasound-induced Blood-Brain Barrier Opening for Enhanced Temozolomide Delivery in Glioma Treatment
Journal
PLoS ONE
Journal Volume
9
Journal Issue
12
Pages
e114311
Date Issued
2014
Author(s)
Abstract
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. Copyright: © 2014 Liu et al.
SDGs
Other Subjects
temozolomide; antineoplastic agent; dacarbazine; temozolomide; animal experiment; animal model; animal tissue; Article; blood brain barrier; controlled study; drug accumulation; drug blood level; drug brain level; drug degradation; drug efficacy; drug uptake; focused ultrasound; glioma; glioma cell; human; human cell; male; microbubble; mouse; nonhuman; pharmacodynamics; therapy effect; tumor growth; ultrasound therapy; ultrasound transducer; analogs and derivatives; animal; blood brain barrier; capillary; capillary permeability; drug delivery system; drug effects; drug screening; glioma; metabolism; pathology; procedures; survival; tight junction; tumor cell line; tumor volume; ultrasound; vascularization; Animalia; Mus musculus; Animals; Antineoplastic Agents; Blood-Brain Barrier; Capillaries; Capillary Permeability; Cell Line, Tumor; Dacarbazine; Drug Delivery Systems; Glioma; Humans; Male; Mice; Microbubbles; Survival Analysis; Tight Junctions; Tumor Burden; Ultrasonics; Xenograft Model Antitumor Assays
Type
journal article