Fig. 4

Combination ibrutinib with doxil impairs glioma model growth and prolongs survival. Treatment schema denoting repeat drug therapies, image timing, doxil blood/tissue concentrations and survival studies (a). Repeat ibrutinib with doxil therapy does no influence doxil plasma concentrations yet increases brain tumor doxil concentrations by approximately 32% (*p < 0.05) (b). Brain MRIs reflect additive ibrutinib effect of ibrutinib compared to vehicle (left panel) doxil alone (left middle panel), ibrutinib alone (right middle panel) or ibrutinib + doxil (right panel) as seen by statistically significant volumetric decrease as denoted via graphed values (*p < 0.05) (c). H/E staining demonstrates the lessened tumor size with doxil treatment alone and with combination therapy (d). 3kD dextran extravasation studies revealed ibrutinib can increase the blood-tumor barrier to larger agents, specifically within the peritumoral tissue region (*p < 0.01) (e). Co-staining of CD31/Claudin-5 on tumor, peritumoral and distant sites areas did not demonstrate any statistical differences in co-localized expression. (f). Prolonged survival seen with combination therapy with a median survival of 27 days versus 16 days for control therapy (****p < 0.0001) (*p < 0.05) (g)