Development of new cold atmospheric plasma devices and approaches for cancer treatment Open Access
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Cold atmospheric plasma (CAP) treatment is a rapidly expanding and emerging technology for cancer treatment. However, direct CAP jet irradiation is limited to the skin or can be invoked as a supplement during surgery as it only causes cell death in the upper three to five cell layers. On the other hand, most cancers occur inside the body and plasma direct irradiation is not practical due to its high voltage, the formation of discharge in the organ, gas delivery and plasma probe volume. In this study, we focus on development of new cold atmospheric plasma devices and approaches for cancer treatment. Firstly, we reported indirect plasma treatment using CAP discharged in deionized (DI) water using three gases as carriers (argon (Ar), helium (He), and nitrogen (N2)). Plasma stimulated DI water was applied to human cancer cell lines, and MTT assay tests showed Ar plasma had the strongest effect on inducing apoptosis in cancer cells. The results also revealed that apoptosis efficiency was dependent on the plasma exposure time and on the levels of reactive oxygen and nitrogen species (ROS and RNS). Secondly, study on plasma-liquid interaction and formation self-organized patterns (SOP) at the plasma-liquid interface have revealed a nontrivial cancer-inhibiting capability of liquid media. After a short treatment at the stratified SOP plasma-liquid interface, the cancer inhibiting media demonstrate pronounced suppressing and apoptotic activities toward tumor cells. Furthermore, SOP interfacial discharge is capable to efficiently control the ROS and RNS concentrations in the cancer-inhibiting media. In particular, abnormal ROS/RNS ratios are not achievable in discharge since they do not form stratified thin-filament patterns. We also studied the effect of SOP discharge modes on ROS and RNS in He SOP plasma-activated media with different conductivity (saline solution and DI water), and employed them to the cancer cells. He SOP plasma discharge modes are also capable to efficiently control the ROS and RNS concentration in the plasma media contributing to the cytotoxic effect. Thirdly, to enhance efficiency and expand the applicability of the cold plasma method for brain tumors and reduce gas flow rate and size of the plasma jet, a novel micro-sized CAP (CAP) was developed and employed to target glioblastoma tumors in the murine brain. The direct and indirect effects of CAP on glioblastoma (U87MG-RedFluc) cancer cells in vitro were investigated and indicated that CAP-generated short- and long-lived species and radicals [i.e. hydroxyl radical (OH), hydrogen peroxide (H2O2), nitrite (NO2-), et al] with increasing tumor cell death in a dose-dependent fashion. Translation of these findings to an in vivo setting demonstrates that intracranial CAP is effective at preventing glioblastoma tumor growth in the mouse brain. The CAP device can be safely used in mice, resulting in suppression of tumor growth. These initial observations establish the CAP device as a potentially useful ablative therapy tool in the treatment of glioblastoma. Meanwhile, we also developed μCAP devices with 20 mm and 60mm length, and results showed that μCAP treatment with 60 mm length tube still has a strong effect on cancer therapy. Finally, we investigated plasma interaction with tissue via artificial tissue and molecular dynamics for understanding plasma interactions with tumors. CAP generated reactive oxygen and nitrogen species (ROS/RNS) reacted with artificial tissue system penetrating more than 1.5 mm in molecularly specific reactions. Our finds could be important for understanding the plasma-generated reactive species triggering cell-to-cell communication, and the potential in tackling challenges of plasma reacting with tumor.