title: Increasing of Blood-Brain Tumor Barrier Permeability through Transcellular and Paracellular Pathways by Microbubble-Enhanced Diagnostic Ultrasound in a C6 Glioma Model.
abstract: Most of the anticancer agents cannot be efficiently delivered into the brain tumor because of the existence of blood-brain tumor barrier (BTB). The objective of this study was to explore the effect of microbubble-enhanced diagnostic ultrasound (MEUS) on the BTB permeability and the possible mechanism. Glioma-bearing rats were randomized into three groups as follows: the microbubble-enhanced continued diagnostic ultrasound (MECUS) group; the microbubble-enhanced intermittent diagnostic ultrasound (MEIUS) group and the control group. The gliomas were insonicated through the skull with a diagnostic ultrasound and injected with microbubbles through the tail veins. Evans Blue (EB) and dynamic contrast-enhanced-MRI were used to test changes in the BTB permeability. Confocal laser scanning microscopy was used to observe the deposition of the EB in the tumor tissues. The distribution and expression of junctional adhesion molecule-A (JAM-A) and calcium-activated potassium channels (KCachannels) were detected by a Western blot, qRT-PCR, and immunohistochemical staining. In the MEUS groups, the EB extravasation (11.0 ± 2.2 μg/g in MECUS group and 17.9 ± 2.3 μg/g in MEIUS group) exhibited a significant increase compared with the control group (5.3 ± 0.9 μg/g). The MEIUS group had more EB extravasation than the MECUS group. TheKtransvalue of the dynamic contrast-enhanced-MRI in the MEUS groups was higher than that of the control group and correlated strongly with the EB extravasation in the tumor (R2= 0.97). This showed that theKtransvalue might be a non-invasive method to evaluate the BTB permeability in rat glioma after microbubble-enhanced ultrasound treatment.Western blot, qRT-PCR and immunohistochemical staining revealed that MEUS increased theKCachannels expression and reduced JAM-A expression in glioma. This change was more obvious in the MEIUS group than in the MECUS group. The results demonstrated that MEUS effectively increased the BTB permeability in glioma. The mechanisms might involve the up-regulation ofKCachannels expression and affecting the formation of tight junctions in the BTB by a reduction of JAM-A expression. These findings might provide some new guidance for glioma drug therapy.
authors.affiliation: Department of Radiology, Research Institute of Surgery, Daping Hospital, Third Military Medical University Chongqing, China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Radiology, Research Institute of Surgery, Daping Hospital, Third Military Medical University Chongqing, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Radiology, Research Institute of Surgery, Daping Hospital, Third Military Medical University Chongqing, China.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Radiology, Research Institute of Surgery, Daping Hospital, Third Military Medical University Chongqing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Radiology, Research Institute of Surgery, Daping Hospital, Third Military Medical University Chongqing, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Radiology, Research Institute of Surgery, Daping Hospital, Third Military Medical University Chongqing, China.
authors.forename: Shunan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Radiology, Research Institute of Surgery, Daping Hospital, Third Military Medical University Chongqing, China.
authors.forename: Jingqin
authors.initials: J
authors.lastname: Fang
authors.affiliation: GE HealthCare Shanghai, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Cao
authors.affiliation: Four and the State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Third Military Medical University Chongqing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Ultrasound, Xinqiao Hospital, Third Military Medical University Chongqing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Radiology, Research Institute of Surgery, Daping Hospital, Third Military Medical UniversityChongqing, China; Chongqing Clinical Research Center for Imaging and Nuclear MedicineChongqing, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhang
keywords: blood-brain tumor barrier; diagnostic ultrasound; dynamic contrast-enhanced-MRI; glioma; permeability