title: Pharmacodynamic and therapeutic investigation of focused ultrasound-induced blood-brain barrier opening for enhanced temozolomide delivery in glioma treatment.
abstract: 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.
authors.affiliation: Department of Electrical Engineering, Chang-Gung University, Taoyuan, Taiwan; Healthy Aging Research Center, Chang-Gung University, Taoyuan, Taiwan.
authors.forename: Hao-Li
authors.initials: HL
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Chang-Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Chiung-Yin
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Department of Electrical Engineering, Chang-Gung University, Taoyuan, Taiwan.
authors.forename: Ju-Yu
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
authors.forename: Hay-Yan Jack
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Chang-Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Pin-Yuan
authors.initials: PY
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Chang-Gung Memorial Hospital, Linkou, Taiwan.
authors.forename: Kuo-Chen
authors.initials: KC
authors.lastname: Wei
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D045423:Microbubbles; D016019:Survival Analysis; D000077204:Temozolomide; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D014465:Ultrasonics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003606:Dacarbazine; D000077204:Temozolomide