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.
Highlights
At least 23,000 patients are diagnosed with malignant primary brain or other CNS cancers in the United States each year, and nearly half of the patients develop high-grade glioma or glioblastoma multiforme (GBM) [1]
We recently reported that Focused ultrasound (FUS)-blood-brain barrier (BBB) opening combined with temozolomide administration can provide successful tumor progression control and survival improvement in glioma-bearing rats [23]
An exposure power level of 2 W induced a successful BBB opening effect, confirmed by Evans Blue (EB) dye staining in the exposed brain hemisphere
Summary
At least 23,000 patients are diagnosed with malignant primary brain or other CNS cancers in the United States each year, and nearly half of the patients develop high-grade glioma or glioblastoma multiforme (GBM) [1]. A phase-III randomized trial found that the prognosis of GBM patients remains poor after debulking surgery and radiation, with a median survival time of only 12 months [2]. TMZ is an alkylating agent of the imidazotetrazine series that possesses strong antineoplastic activity against high-grade glioma [4, 5]. Clinical trials have shown that the median survival in patients treated with radiation plus TMZ was limited to 3 to 4 months longer than that in patients treated by radiation alone, which is far from satisfactory [7, 8]
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