Chapter 1 │ Page 17 The therapeutic e ects of NTP are primarily attributed to the generation of a large number of reactive species. These ROS/RNS interact with the exposed cancer cells, triggering direct cytotoxic e ects and initiating downstream signaling events. The resulting oxidative stress activates cellular stress responses, ultimately leading to cancer cell death [68-71]. The particular vulnerability of cancer cells to NTPinduced oxidative stress is hypothesized to originate from their fundamentally altered characteristics, including a reprogrammed cellular metabolism and increased redox balance, which may render them more susceptible to further oxidative damage [56, 57]. These intrinsic di erences between malignant and healthy cells form the basis of the ongoing research e orts to delineate NTP’s potential selectivity for cancer cells. However, early studies often struggled with experimental inconsistencies, such a culturing cancerous and non-cancerous cells in di erent media or comparing cells from unrelated tissue origins [72-74]. To address this, our lab conducted a comprehensive analysis under standardized and comparable conditions, and observed a slight selectivity at lower NTP intensities in specific models (glioblastoma and melanoma) [75]. Given the fact that this e ect disappeared at higher intensities whereby normal cells were equally killed, these findings suggest that an optimal treatment window may exist, but further validation in complex models like patient-derived organoids (PDOs) and in vivo is essential to confirm true treatment selectivity. However, encouragingly, the first clinical case study in HNSCC patients reported no significant acute adverse e ects [76, 77], supporting NTP’s potential as a selective therapy. Two main types of NTP devices are commonly used in biomedical applications: (i) a dielectric barrier discharge (DBD), in which the plasma is directly generated between one electrode and the target tissue, and (ii) a plasma jet, in which plasma is generated in a pen-like applicator and a flow of feed gas directs the ROS/RNS onto the target [78]. Notably, the kINPen® MED plasma jet received clinical approval
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