Additive effect of low-frequency ultrasound and endothelial monocyte-activating polypeptide II on blood–tumor barrier in rats with brain glioma

Brain glioma is a malignant tumor which needs surgery followed by chemotherapy. Low-frequency ultrasound (LFU) and Optison could open blood–tumor barrier (BTB) selectively and noninvasively and thus increase the permeability of BTB. Endothelial monocyte-activating polypeptide II (EMAP-II) induces cytoskeletal remodeling in endothelial cells. In this study, we asked whether LFU, Optison, and/or EMAP-II used in combination have additive effects on increasing the permeability of BTB by tight junction (TJ)-associated protein-dependent manner and thus help understand the possible mechanisms for TJ-based drug delivery to the central nervous system through BTB. Evans Blue assay was used to measure the permeability of BTB in rat model of C6 glioma. The mRNA and protein levels of TJ-associated proteins, claudin-5, occludin, and ZO-1, were determined. Results showed that Evans blue content significantly increased and the mRNA and protein levels of claudin-5, occludin, and ZO-1 significantly reduced after the treatment in groups treated with EMAP-II and LFU combined with or without Optison (LFU + EMAP-II and LFU + Optison + EMAP-II groups) and in the group treated with LFU and Optison (LFU + Optison group). In conclusion, LFU and EMAP-II used in combination have additive effects on increasing the permeability of BTB and remodeling of TJ-associated proteins.