The Effects of Imipramine Blue on Vascular Permeability in Glioblastomas

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DeHitta, Eleanor
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Glioblastoma (GBM), a form of glioma, is an aggressive form of human cancer with a median survival time of 14.6 months with after diagnosis. It is the most common and most aggressive form of brain cancer due to its invasive and angiogenic nature. Gliomas develop their vascularized networks through the process of angiogenesis, the development of blood vessels. In tumor development, angiogenesis is marked by a few hallmark characteristics: degradation of the basement membrane, recruitment of endothelial cells, and tube network formation among recently recruited endothelial cells to finalize the formation of a new blood vessel. Angiogenesis increases vascular permeability of blood vessels, which can ultimately progress from edema, to neurological deficits, to death. Anti-angiogenic therapies have been favored for reducing symptoms related with edema. Imipramine Blue (IB) is a novel compound used to treat gliomas. In vivo, it decreases invasion and prolongs survival. It is believed that IB’s ability to stop tumor cells from invading into neighboring areas also inhibits angiogenesis. If the tumor cells cannot move to create more blood vessels, then angiogenesis might also be inhibited. Additionally, it is believed that IB might stop the recruitment of endothelial cells, similar to how IB stops tumor cell invasion. This study investigated Imipramine Blue’s possible anti-angiogenic effects. In vitro, IB did not affect MMP-2 and MMP-9 activity in U87 and RT2A glioma cell lines (ANOVA). IB did not affect HUVEC invasion (p=0.08, two-pair, student’s t-test, α=0.05). In vivo, animals were treated with IB liposomes or plain liposomes, and vascular permeability was assessed using kinetic image analysis from MRI with the aid of contrast-enhancing dual-gadolinium liposomes. This method is useful for animal studies that want to investigate different variables from the same brain. No significant differences in endothelial transfer coefficients (KPS) were observed between treatment groups (two-sample student’s t-test, p = 0.3488), suggesting IB does not affect vascular permeability. In vitro and in vivo results suggest that IB does not have anti-angiogenic effects.
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