INTRACRANIAL TARGETING OF GLIOBLASTOMA MULTIFORME WITH COLD ATMOSPHERIC PLASMA

Glioblastoma multiforme (GBM) is a highly malignant aggressive neoplasm of the primary central nervous system characterized by rapid growth, extensive angiogenesis, and resistance to current therapies. The median survival is limited to 16-19 months after diagnosis. In this context, GBM treatment strategies remain largely palliative despite the advancement of multi-modal therapies. Thus, it is necessary to develop novel tools that can target proliferating tumor cells and enhance existing therapies. Conventional lasers in medical devices are based on the thermal interaction with tissues, which lead to necrosis and permanent tissue damage. In contrast, cold atmospheric plasma (CAP) has recently emerged as a novel therapeutic approach for targeting of cancerous tissue. Indeed, recent findings suggest that CAP jet interactions with tissue may allow for cell death without necrosis. However, studies to date have been limited primarily to subcutaneous implantation of tumors. While beneficial, this approach does not replicate the complex environment of the brain (i.e. GBM). Here, we developed a novel approach to target CAP to intracranial GBM tumors. This new device, termed μCAP, consists of a Pyrex syringe through which CAP, employing helium gas, is supplied via the implanted endoscopic cannula. We first performed a set of experiments to test the influence of μCAP on normal brain parenchyma. Female athymic Foxn1nu nude mice underwent intracranial μCAP injection to the frontal lobe (15s total). Helium alone was administered as a control. Histological examination (Nissl staining) of the frontal lobe 7 days later revealed a similar number of apoptotic cells surrounding the injection site between μCAP and control treated animals (9±3 vs. 6±1 apoptotic cells/µm2, control vs. μCAP, n=2-3, p\u3e0.05). Similarly, no evidence of glia infiltration at the injection site was apparent. Next, nude mice underwent implantation of U87 glioblastoma cells (105 cells) into the frontal lobe and were simultaneously instrumented with a custom endoscopic cannula. Tumors were allowed to develop for 7 days and mice were then treated intracranially with μCAP (15s total) or helium control. Using in vivo bioluminescence imaging (Figure), the tumor volume in control animals increased nearly 1000% over the course of a week, whereas μCAP treated tumor volumes remained at baseline levels (day 7: 1035±773 vs. 172±107 radiance %baseline, control vs. μCAP, n=3, p\u3e0.05). These findings indicate that CAP has a minimal effect on healthy brain tissue, and further provide the first evidence for the potential of CAP to inhibit intracranial GBM tumor growth