Abstract Cold atmospheric plasma,as a new technology to efficiently generate exogenous reactive species, has great potential to become a safe and effective new method for cancer treatment. However, the direct plasma treatment of biological objects has several inherent limitations including shallow penetration depth and short effective time, which makes it difficult to completely release the application potential ofplasmas.Plasma-activated solutions (PAS), an indirect application form of cold atmospheric plasma,have the advantages of relatively long effective time, strong penetration ability, and large action range, which have been widely employed for emerging cancer therapies in recent years. In this paper,recent research advances in the plasma systems for preparing PAS, in vitro anticancer effects and biological mechanisms of PAS, and in vivo anticancer application and biosafety of PAS have been reviewed in detail. Firstly, the preparation and regulation processes of PAS are summarized in terms of plasma discharge types, solutions types and activation methods. For the preparation of PAS in biomedical applications, the types of plasma include dielectric barrier discharge plasma, plasma jet, gliding arc discharge plasma and high-frequency (microwave, radiofrequency) discharge plasma; the types of solutions include deionized water, normal saline, phosphate buffer saline and cell culture medium; the activation methods include direct plasma activation and indirect plasma activation depending on whether plasma is in contact with solutions.The type of plasma discharge devices, the initial environment provided by different solutions and the choice of activation methods all determine the activation efficiency of plasma and affect the composition of reactive species in PAS. Secondly, the in vitro anticancer research status of PAS is reviewed. In the PAS-enabled cancer treatment, cancer cells are generally treated by the plasma-activated cell culture medium or cell culture medium mixed with a volume of PAS. The in vitro anticancer cell models, including cancer cells, drug-resistant cancer cells and 3D tumor spheroids, are compared to fully evaluate the inactivation effect of PAS on cancer cells in different states. Further attempts to understand the PAS anticancer mechanisms are initialized: Cancer cells usually show higher levels of endogenous reactive oxygen species compared with normal cells, and the selective anticancer effects of PAS are achieved by supplying low-dose exogenous reactive species to cancer cells, which makes cancer cells to achieve the lethal threshold faster than normal cells. Finally, the in vivo anticancer research status of PAS is reviewed. At present, the in vivo anticancer ways using PAS mainly include the pericarcinomatous tissue injection and intraluminal perfusion. The former is mainly selected for the treatment of solid tumors located in deep tissues, and intraluminal perfusion is mainly used for the treatment of tumor tissues located in the cavity (such as the peritoneal cavity, bladder, etc.). In addition, the long-term biosafety of PAS in mice has been confirmed, but there are no reports about the biosafety of PAS in clinical applications. The researches of PAS cancer treatment are in the ascendant, and much work remains to be accomplished, including the exploration of insightful anticancer mechanisms, further improvements of anticancer effects, the expansion oftherapeutic scope and the optimization of combined therapies. This paper summarizes recent progresses in the PAS-enabled cancer therapy, and the corresponding theory and methods can provide an important reference for other medical application studies (such as infectious disease treatment).
Zhang Hao,Zhang Jishen,Xu Dehui等. Advances of Plasma-Activated Solutions for Cancer Therapy[J]. Transactions of China Electrotechnical Society, 2023, 38(zk1): 231-246.
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