title: Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study.
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.
authors.affiliation: Department of Neurosurgery, Chang-Gung University and Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Kuo-Chen
authors.initials: KC
authors.lastname: Wei
authors.forename: Po-Chun
authors.initials: PC
authors.lastname: Chu
authors.forename: Hay-Yan Jack
authors.initials: HY
authors.lastname: Wang
authors.forename: Chiung-Yin
authors.initials: CY
authors.lastname: Huang
authors.forename: Pin-Yuan
authors.initials: PY
authors.lastname: Chen
authors.forename: Hong-Chieh
authors.initials: HC
authors.lastname: Tsai
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Lu
authors.forename: Pei-Yun
authors.initials: PY
authors.lastname: Lee
authors.forename: I-Chou
authors.initials: IC
authors.lastname: Tseng
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Feng
authors.forename: Peng-Wei
authors.initials: PW
authors.lastname: Hsu
authors.forename: Tzu-Chen
authors.initials: TC
authors.lastname: Yen
authors.forename: Hao-Li
authors.initials: HL
authors.lastname: Liu
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000528:radiation effects*; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005909:Glioblastoma / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D013016:Sound; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide