Focused Ultrasound-Induced Blood–Brain Barrier Opening to Enhance Temozolomide Delivery for Glioblastoma Treatment: A Preclinical Study

• Published in: PloS one Vol. 8; no. 3; p. e58995
• Main Authors: Wei, Kuo-Chen, Chu, Po-Chun, Wang, Hay-Yan Jack, Huang, Chiung-Yin, Chen, Pin-Yuan, Tsai, Hong-Chieh, Lu, Yu-Jen, Lee, Pei-Yun, Tseng, I-Chou, Feng, Li-Ying, Hsu, Peng-Wei, Yen, Tzu-Chen, Liu, Hao-Li
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.03.2013; Public Library of Science (PLoS)
• Subjects: Animal tissues; Animals; Antineoplastic Agents, Alkylating - pharmacokinetics; Antineoplastic Agents, Alkylating - therapeutic use; Biology; Blood-brain barrier; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - radiation effects; Brain; Brain - pathology; Brain cancer; Brain Neoplasms - diagnosis; Brain Neoplasms - drug therapy; Brain Neoplasms - mortality; Brain research; Brain tumors; Cancer therapies; Cell Line, Tumor; Cerebrospinal fluid; Chemotherapy; Clinical trials; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacokinetics; Dacarbazine - therapeutic use; Development and progression; Disease Models, Animal; Drug Evaluation, Preclinical; Dyes; Electrical engineering; Engineering; Glioblastoma; Glioblastoma - diagnosis; Glioblastoma - drug therapy; Glioblastoma - mortality; Glioblastoma multiforme; Glioblastomas; Glioma cells; Health aspects; Histology; Magnetic resonance; Magnetic Resonance Imaging; Male; Medical imaging; Medicine; Molecular weight; Neuroimaging; Neurosurgery; NMR; Nuclear magnetic resonance; Parenchyma; Permeability; Rats; Sound; Spectrophotometry; Survival; Temozolomide; Tumors; Ultrasonic imaging; Ultrasound; United States > US; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0058995

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.