Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study.
Authors: Wei KC, Chu PC, Wang HY, Huang CY, Chen PY, Tsai HC, Lu YJ, Lee PY, Tseng IC, Feng LY, Hsu PW, Yen TC, Liu HL
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.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To evaluate whether MRI-monitored focused ultrasound–induced blood–brain barrier disruption enhances temozolomide delivery and improves therapeutic outcomes in a rat glioblastoma model.
Animal model / Human subject
Rat, Fisher, None, None
Disease model
Glioblastoma Multiforme (GBM)
MRI or image guidance method
MRI-monitored
Cargo name and characteristics
Temozolomide (TMZ), small-molecule alkylating chemotherapeutic agent
Outcomes and Safety
Summary of Outcomes
MRI‑monitored, microbubble‑assisted focused ultrasound (500 kHz transducer; two exposures during the 5‑day TMZ regimen) transiently opened the BBB (Evans Blue +3.8× in normal and +2.1× in tumor tissue), increased TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced 7‑day tumor progression from 24.03 to 5.06, and modestly extended median survival from 20 to 23 days with histologic evidence of tumor shrinkage. Successful FUS parameters reported: MRI‑guided, microbubble‑assisted FUS at 500 kHz using the two‑exposure protocol described.
Duration of biological effect
3 days
Safety-related matter
No overt systemic adverse effects were reported, but histology of successfully treated FUS-enhanced animals showed tiny areas of gliosis with chronic inflammatory cell infiltration; the authors also cautioned that their current protocol could induce off-target tissue damage from high local TMZ levels and that additional physiological, immunological and biodistribution data are needed to conclusively demonstrate safety.
Brain Region
Ultrasound Parameters
Focal Characteristics
Focal depth: None; Focal length: None; Aperture size: None
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