Abstract
The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment.
Highlights
At least 18,000 patients are diagnosed with malignant primary brain tumors in the United States each year and more than half of them have glioblastoma multiform (GBM), making it the most common malignant brain tumor in adults [1]
Evans blue (EB) dye leakage was used to illustrate that focused ultrasound (FUS) was effective at local disruption of the intact blood-brain barrier (BBB) in normal rats as viewed from the top of the brain (Fig. 3(a)) and in dissected brain sections (Fig. 3(b))
When enhanced by FUS, EB deposition in the brain tumor region further increased by 2.1 fold (7.9261.36 mM), but did not reach statistical significance (p = 0.09)
Summary
At least 18,000 patients are diagnosed with malignant primary brain tumors in the United States each year and more than half of them have glioblastoma multiform (GBM), making it the most common malignant brain tumor in adults [1]. The most common approach to identify GBM in-vivo is based on detecting the leakage of dye into regions where the tumor has caused breakdown of the blood-brain barrier (BBB) using contrast enhanced magnetic resonance imaging (MRI), computed tomography (CT) or nuclear imaging. Such contrast-enhanced areas only partially represent the tumor-cell distribution and autopsy studies have demonstrated glioblastoma cells at great distances from the enhancing regions of tumors [2,3]. Permeability does not necessarily correlate with tumor histology, size, or anatomical location
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