In Cancer Therapy

cancers Review Plasma-Treated Solutions (PTS) in Cancer Therapy Hiromasa Tanaka 1,*,† , Sander Bekeschus 2,*,† , Dayun Yan 3,*,† , Masaru Hori 1, Michael Keidar 3 and Mounir Laroussi 4 1 Center for Low-Temperature Plasma Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; [email protected] 2 ZIK Plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany 3 Department of Mechanical and Aerospace Engineering, The George Washington University, Washington, DC 20052, USA; [email protected] 4 Plasma Engineering and Medicine Institute, Old Dominion University, Norfolk, VA 23508, USA; [email protected] * Correspondence: [email protected] (H.T.); [email protected] (S.B.); [email protected] (D.Y.) † Equally contributed as first authors. Simple Summary: Cold physical plasma is a partially ionized gas generating various reactive oxygen and nitrogen species (ROS/RNS) simultaneously. ROS/RNS have therapeutic effects when applied to cells and tissues either directly from the plasma or via exposure to solutions that have been treated beforehand using plasma processes. This review addresses the challenges and opportunities of plasma-treated solutions (PTSs) for cancer treatment. Abstract: Cold physical plasma is a partially ionized gas generating various reactive oxygen and nitrogen species (ROS/RNS) simultaneously. ROS/RNS have therapeutic effects when applied to cells and tissues either directly from the plasma or via exposure to solutions that have been treated Citation: Tanaka, H.; Bekeschus, S.; beforehand using plasma processes. This review addresses the challenges and opportunities of Yan, D.; Hori, M.; Keidar, M.; plasma-treated solutions (PTSs) for cancer treatment. These PTSs include plasma-treated cell culture Laroussi, M. Plasma-Treated Solutions (PTS) in Cancer Therapy. media in experimental research as well as clinically approved solutions such as saline and Ringer’s Cancers 2021, 13, 1737. https:// lactate, which, in principle, already qualify for testing in therapeutic settings. Several types of cancers doi.org/10.3390/cancers13071737 were found to succumb to the toxic action of PTSs, suggesting a broad mechanism of action based on the tumor-toxic activity of ROS/RNS stored in these solutions. Moreover, it is indicated that the Academic Editor: Pierre Busson PTS has immuno-stimulatory properties. Two different routes of application are currently envisaged in the clinical setting. One is direct injection into the bulk tumor, and the other is lavage in patients Received: 8 January 2021 suffering from peritoneal carcinomatosis adjuvant to standard chemotherapy. While many promising Accepted: 9 February 2021 results have been achieved so far, several obstacles, such as the standardized generation of large Published: 6 April 2021 volumes of sterile PTS, remain to be addressed. Publisher’s Note: MDPI stays neutral Keywords: cold physical plasma; low-temperature plasma; nonthermal plasma; oncology; PAM; with regard to jurisdictional claims in plasma-activated medium; plasma medicine; reactive oxygen species; reactive nitrogen species published maps and institutional affil- iations. 1. Introduction Cancer is a devastating condition, and the second leading cause of death in Western Copyright: © 2021 by the authors. countries [1]. Despite ongoing improvements in cancer therapy, novel research lines are Licensee MDPI, Basel, Switzerland. warranted to improve the clinical efficacy of cancer treatments. A recent development This article is an open access article distributed under the terms and in oncology is increasingly focusing on combination therapies that tackle tumor cells via conditions of the Creative Commons several mechanisms, either simultaneously or consecutively. While many therapeutic ap- Attribution (CC BY) license (https:// proaches focus on targeted therapies and immuno-therapies, promising research motivated creativecommons.org/licenses/by/ continuously tackling tumors on a much broader scale involving cancer metabolism and 4.0/). Cancers 2021, 13, 1737. https://doi.org/10.3390/cancers13071737 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x FOR PEER REVIEW 2 of 20 Cancers 2021, 13, 1737 2 of 19 and reactive oxygen and nitrogen species (ROS/RNS) and their associated redox signaling pathwaysreactive oxygen[2–4]. and nitrogen species (ROS/RNS) and their associated redox signaling pathwaysCold physical [2–4]. plasma, which also goes by low-temperature plasma or nonthermal plasma,Cold is a physical partially plasma, ionized which gas generating also goes bya multitude low-temperature of ROS/RNS plasma simultaneously. or nonthermal Moreplasma, than is two a partially decades ionized ago, it was gas generatingproposed that a multitude these ROS/RNS of ROS/RNS can be used simultaneously. for thera- peuticMore purposes. than two Early decades work ago, focused it was on proposed plasma-based that these disinfection ROS/RNS of biologically can be used contam- for ther- inatedapeutic surfaces purposes. and Earlyliquids work [5,6], focused which on wa plasma-baseds later transferred disinfection to the ofmedical biologically field and con- woundtaminated decontamination surfaces and liquids[7,8]. In [ 5addition,6], which to was decontamination later transferred, it was to the soon medical realized field that and plasma-derivedwound decontamination ROS/RNS also [7,8]. targ In additionet eukaryotic to decontamination, cells by cell-intrinsic it was mechanisms soon realized [9,10]. that Moreover,plasma-derived a recent ROS/RNS randomized also targetclinical eukaryotic trial found cells that by cell-intrinsicthe disinfection mechanisms properties [9 ,10of ]. plasmaMoreover, treatment a recent are randomized negligible clinicalin promoting trial found wound that thehealing disinfection in a cohort properties of diabetic of plasma pa- tientstreatment [11]. areAs ROS/RNS negligible infollow promoting hormetic wound responses healing in inbiology a cohort [12], of diabeticit seems patients natural [11to ]. investigateAs ROS/RNS exaggerated follow hormetic ROS/RNS responses exposure in biologyfrom cold [12 physical], it seems plasmas natural as to anticancer investigate exaggerated ROS/RNS exposure from cold physical plasmas as anticancer agents. Plasma- agents. Plasma-based cancer research started more than a decade ago with promising in based cancer research started more than a decade ago with promising in vitro [13–15] and vitro [13–15] and in vivo studies [16,17] and, ever since, has generated significant interest in vivo studies [16,17] and, ever since, has generated significant interest in experimental in experimental oncology [18,19] with the first promising results being obtained in pallia- oncology [18,19] with the first promising results being obtained in palliative cancer patients tive cancer patients in recent years [20,21]. in recent years [20,21]. While the direct application of cold physical plasma to cells and tissues is promising While the direct application of cold physical plasma to cells and tissues is promising and approved in European dermatology centers [22], an increasing need has emerged to and approved in European dermatology centers [22], an increasing need has emerged utilize the plasma-derived ROS/RNS more flexibly as putative injections. One way to to utilize the plasma-derived ROS/RNS more flexibly as putative injections. One way achieve this is the treatment of liquids or solutions with plasma devices [23,24]. In this to achieve this is the treatment of liquids or solutions with plasma devices [23,24]. In process, the plasma-derived ROS/RNS are delivered from the plasma gas phase into the this process, the plasma-derived ROS/RNS are delivered from the plasma gas phase into liquid phase (Figure 1). As most ROS/RNS are short-lived by virtue of their nature, this the liquid phase (Figure1). As most ROS/RNS are short-lived by virtue of their nature, comesthis comes at the atexpense the expense of their of deterioration their deterioration [25], yet [25 leaving], yet leaving a delicate a delicate mixture mixture of long- of livedlong-lived ROS/RNS ROS/RNS that might that even might recombine even recombine or react or with react short-lived with short-lived species speciesagain when again inwhen contact in contactwith cells with [26]. cells Since [26 ].the Since idea theof investigating idea of investigating these liquids these is liquids a future is aclinical future application,clinical application, two routes two have routes been have proposed been proposed so far. The so first far. involves The first the involves injection the into injection the bulkinto tumor, the bulk while tumor, the second while therelates second to the relates lavage to of the the lavage peritoneal of the cavity peritoneal in the cavitydisease in ofthe disseminated disease of disseminated peritoneal carcinomatosis, peritoneal carcinomatosis, currently tackled currently with HIPEC tackled and with PIPEC HIPEC ther- and apyPIPEC [27]. therapy [27]. FigureFigure 1. 1. DirectDirect plasma plasma treatment treatment exposes exposes the the biological biological ta targetrget such such as as in in vitro vitro cells cells or or in in vivo vivo or or ex ex vivo tissue directly to the plasma gas phase. Plasma-treated solution (PTS), in turn, is generated vivo tissue directly to the plasma gas phase. Plasma-treated solution (PTS), in turn, is generated by by exposing a solution to the plasma gas phase and subsequently

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