Low temperature plasmas as emerging cancer therapeutics: the state of play and thoughts for the future

Abstract

The field of plasma medicine has seen substantial advances over the last decade, with applications developed for bacterial sterilisation, wound healing and cancer treatment. Low temperature plasmas (LTPs) are particularly suited for medical purposes since they are operated in the laboratory at atmospheric pressure and room temperature, providing a rich source of reactive oxygen and nitrogen species (RONS). A great deal of research has been conducted into the role of reactive species in both the growth and treatment of cancer, where long-established radio- and chemo-therapies exploit their ability to induce potent cytopathic effects. In addition to producing a plethora of RONS, LTPs can also create strong electroporative fields. From an application perspective, it has been shown that LTPs can be applied precisely to a small target area. On this basis, LTPs have been proposed as a promising future strategy to accurately and effectively control and eradicate tumours. This review aims to evaluate the current state of the literature in the field of plasma oncology and highlight the potential for the use of LTPs in combination therapy. We also present novel data on the effect of LTPs on cancer stem cells, and speculatively outline how LTPs could circumvent treatment resistance encountered with existing therapeutics.

Keywords: Cancer stem cells; Combination therapy; Focal therapy; Low temperature plasma; Reactive species.

Fig. 1

Schematic representation of low temperature plasma formation and application. Gas flow is ignited by high voltage applied across ring electrodes. The core plasma propagates from the end of the tube and is applied into a bulk tumour, causing DNA damage through the formation of reactive oxygen and nitrogen species. Note: this diagram is not to scale; in the accompanying image, the dimensions of central quartz glass tube are 70 × 6 mm. Elements of this figure are modified from Hirst et al. [6]

Fig. 2

An illustrative representation of the multi-phase transfer of plasma species towards a biological sample. The main components of the plasma phase, including ions, photons and neutral species, are shown, leading to the creation of various RONS across the plasma-liquid interface and their propagation towards and diffusion through an arbitrary tissue layer. In addition, approximate timescales governing various phenomena across the plasma-liquid phases and biological interaction are outlined

Fig. 3

LTP induces DNA damage in cancer stem cells. Prostate cancer stem cells (SC), transit amplifying (TA) and committed basal (CB) cells were cultured and fractionated [106, 107] from a Gleason grade 9 metastatic tumour, and treated as described in Hirst et al. [17]. Statistical analysis of plasma treatments was calculated using Mann–Whitney test against untreated samples and showed P < 0.0001 significance, unless otherwise indicated (**P < 0.01, ****P < 0.0001)

Fig. 4

Illustration of LTP treatment of a tumour. In the proposed approach, the LTP probe is inserted under needle guidance into the core of the tumour. The plasma is then ignited, creating short-lived reactive species (red dots) that induce DNA damage, necrosis and potentially electroporative effects to cells in the immediate vicinity. The diffusion of longer-lived species (blue dots) to the tumour periphery is shown, contributing to apoptotic and plasma-induced bystander effects. Proposed cellular effects and responses are estimated based on their proximity to the plasma source. Gas extraction is also indicated through a co-axial configuration in the LTP probe. Elements of this figure are adapted from Hirst et al. [17]