Pharmacodynamic and therapeutic investigation of focused ultrasound-induced blood-brain barrier opening for enhanced temozolomide delivery in glioma treatment

• Published in: PloS one 2014-12, Vol.9 (12), p.e114311-e114311
• Main Authors: Liu, Hao-Li, Huang, Chiung-Yin, Chen, Ju-Yu, Wang, Hay-Yan Jack, Chen, Pin-Yuan, Wei, Kuo-Chen
• Format: Article
• Language: English
• Subjects: Animal tissues; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain cancer; Brain tumors; Cancer therapies; Capillaries - drug effects; Capillaries - pathology; Capillary Permeability; Cell Line, Tumor; Chemical compounds; Chemotherapy; Dacarbazine - administration & dosage; Dacarbazine - analogs & derivatives; Dacarbazine - metabolism; Dacarbazine - pharmacology; Dacarbazine - therapeutic use; Development and progression; Drug Delivery Systems - methods; Drug dosages; Drug therapy; Electrical engineering; Exposure; Glioma; Glioma - blood supply; Glioma - drug therapy; Glioma - metabolism; Glioma - pathology; Glioma cells; Gliomas; Health aspects; Histology; Humans; Magnetic resonance imaging; Male; Medical prognosis; Medicine and Health Sciences; Mice; Microbubbles; Neurosurgery; Permeability; Pharmacodynamics; Pharmacology; Plasma; Research and Analysis Methods; Survival; Survival Analysis; Temozolomide; Tight Junctions - drug effects; Tight Junctions - metabolism; Tumor Burden - drug effects; Tumors; Ultrasonic imaging; Ultrasonics; Ultrasound; Volumetric analysis; Xenograft Model Antitumor Assays
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0114311

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.