Micro-sized cold atmospheric plasma (uCAP) has been developed to expand the applications of CAP in cancer therapy. In this paper, uCAP devices with different nozzle lengths were applied to investigate effects on both brain (glioblastoma U87) and breast (MDA-MB-231) cancer cells. Various diagnostic techniques were employed to evaluate the parameters of uCAP devices with different lengths such as potential distribution, electron density, and optical emission spectroscopy. The generation of short- and long-lived species (such as hydroxyl radical (.OH), superoxide (O2-), hydrogen peroxide (H2O2), nitrite (NO2-), et al) were studied. These data revealed that uCAP treatment with a 20 mm length tube has a stronger effect than that of the 60 mm tube due to the synergetic effects of reactive species and free radicals. Reactive species generated by uCAP enhanced tumor cell death in a dose-dependent fashion and was not specific with regards to tumor cell type.
Cold atmospheric plasma (CAP) has been proposed as a novel therapeutic method for anticancer treatment, which can be applied to living tissues and cells 1,2 . CAP is a partially ionized gas that contain charge particles, reactive oxygen and nitrogen species (ROS and RNS), excited atoms, free radicals, UV photons, electric field, etc 3,4 . ROS and RNS, combined or independently, are well known to initiate different signaling pathways in cells and to promote oxidative stress 5,6 . Plasmainduced biological effects include damage lips, proteins, DNA, and induce apoptosis through plasma-generated ROS and RNS [7][8][9][10] . Moreover, many studies have reported both in vivo and vitro that plasma is a possible adjunct treatment in oncology as well as killing achieved for various types of cancers such as glioblastoma, breast cancer, bladder carcinoma, cervical carcinoma, skin carcinoma, pancreatic carcinoma, lung carcinoma, colon carcinoma, gastric carcinoma, melanoma and hepatocellular carcinoma [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] .
In plasma medicine, jet plasma, corona discharge, and dielectric barrier discharge (DBD) have been used 28 . These types of plasma can be directly applied to skin cancers, while they are not applicable for more systemic cancer treatment. Some studies investigated the plasma device in the micro-sized to conduct the plasma species to the living animals 29 . However, their device just applied to xenografts tumors not systemic cancer treatment. Moreover, delivery of the plasma species is crucial to suppress tumor growth and assess efficiency of micro-sized plasma device.
Hence, this study aims to design micro-sized cold atmospheric plasma devices with different lengths of nozzle in order to enhance delivery of reactive species and evaluate the efficiency of these devices on cancer therapy. Fig. 1 shows the potential applications of µCAP for brain and breast tumors in the future.
Fig. 2 depicts the schematic of the experiment setup including high voltage power (Fig. 2a) and 𝜇CAP devices (Fig. 2b). The high voltage power includes DC input, Trigger signal + MOSFET (switch), and the secondary output. In this work, the DC input was set at 5 V, square wave signal was obtained from the control unit (upper left in Fig. 2a), and a high voltage wave was obtained from the square wave signal through the transformer (upper right in Fig. 2a). The 𝜇CAP devices consist of a two-electrode (copper) assembly with a central powered electrode (1 mm in diameter) and a grounded outer electrode wrapped around the outside of a quartz tube (10 mm) as shown in Fig. 2b. The electrodes were connected to the secondary output of the high voltage transformer.
The peak-peak voltage was approximately 8 kV and the frequency of the discharge was around 16 kHz (upper right in Fig. 2a). The secondary output of high voltage transformer was connected to the first input. At the end of a quartz tube, a 275 ± 5 𝜇m inner diameter capillary tube (stainless steel) with 20 or 60 mm length was attached and insulated by epoxy. The feed gas for this study was industrial purity helium, which was injected into the quartz tube with a 0.2 L/min gas flow rate. Longer tube (60 mm) is needed to access deeper tumors in brain and breast. In this study, we are accessing effect of length to understand limitation of depth.
In this study, we are assessing the effect of tube length to understand limitation of depth. For instance, it is believed that a longer tube (60 mm) is needed to access deeper tumors in brain and breast. UV-visible-NIR, a range of wavelength 200-850 nm, was investigated on plasma to detect various RNS and ROS (nitrogen [N 2 ], nitric oxide [-NO], nitrogen cation [N +2 ], atomic oxygen
[O], and hydroxyl radicals [-OH]). The optical probe was placed at distance of 1.0 cm in front of the plasma jet nozzle. Data were then collected with an integration time of 100 ms.
A fluorimetric hydrogen peroxide assay Kit (Sigma-Aldrich) was used for measuring the amount of H 2 O 2 , according to the manufacturer’s protocol. Briefly, 50 µl of standard curve, control, and experimental samples were added to 96-well flat-bottom black plates, and then 50 µl of Master Mix was added to each of well. The plates were incubated for 20 min at room temperature protected from light and fluorescence was measured by a Synergy H1 Hybrid Multi-Mode Microplate Reader at Ex/Em: 540/590 nm. RNS level were determined by using a Griess Reagent System (Promega Corporation) according to the instructions provided by the manufacturer. Briefly, 50 µl of samples and 50 µl of the provided Sulfanilamide Solution were added to 96-well flat-bottom plates and incubated for 5-10 minutes at room temperature. Subsequently, 50 µl of the NED solution was added to each well and incubated at room temperature for 5-10 minutes. The absorbance was measured at 540 nm by Synergy H1 Hybrid Multi-Mode Microplate Reader. U87 and MDA-MB-231 cells were plat
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