Abstract
The effectiveness of electrochemotherapy (ECT) in local eradication of tumours in human and veterinary medicine has been proven. ECT consists of increasing the uptake of cytotoxic drugs by means of pulsed electric fields (PEFs) that transiently permeabilise the cell membrane. Still, this tumour treatment includes some drawbacks that are linked to the characteristics of the intense electric pulses (EPs) used. Meanwhile, the emerging field of cancer therapies that are based on the application of non-thermal plasmas (NTP) has recently garnered interest because of their potentialities as rich sources of reactive species. In this work, we investigated the potential capabilities of the combined application of indirect NTP treatment and microsecond PEFs (µsPEFs) to outperform in vitro cell electropermeabilisation, the basis of ECT. Thus, phosphate-buffered saline (PBS) was plasma-treated (pPBS) and used afterwards to explore the effects of its combination with µsPEFs. Analysis of two different cell lines (DC-3F Chinese hamster lung fibroblasts and malignant B16-F10 murine melanoma cells), by flow cytometry, revealed that this combination resulted in significant increases of the level of cell membrane electropermeabilisation, even at very low electric field amplitude. The B16-F10 cells were more sensitive to the combined treatment than DC-3F cells. Importantly, the percentage of permeabilised cells reached values similar to those of cells exposed to classical electroporation field amplitude (1100 V/cm) when the cells were treated with pPBS before and after being exposed only to very low PEF amplitude (600 V/cm). Although the level of permeabilisation of the cells that are treated by the pPBS and the PEFs at 600 V/cm is lower than the level reached after the exposure to µsPEFs alone at 1100 V/cm, the combined treatment opens the possibility to reduce the amplitude of the EPs used in ECT, potentially allowing for a novel ECT with reduced side-effects.
Highlights
Electrochemotherapy (ECT) is a non-thermal, safe, and efficient tumour treatment [1,2,3,4] that is currently used in more than 150 clinics in the European Union and abroad, together with its applicationCancers 2020, 12, 219; doi:10.3390/cancers12010219 www.mdpi.com/journal/cancersCancers 2020, 12, 219 in veterinary oncology for treatment of metastases as well as primary tumours [5,6]
We tested the cytotoxic effect of phosphate-buffered saline (PBS) was plasma-treated (pPBS) alone to define favourable initial conditions under which cells would not be excessively harmed by the pPBS prior to the assessment of the effect of the combined treatment
The first assay combining pPBS produced at +7 kV and μsPEF with an amplitude of 1100 V/cm was performed in DC-3F fibroblasts
Summary
Electrochemotherapy (ECT) is a non-thermal, safe, and efficient tumour treatment [1,2,3,4] that is currently used in more than 150 clinics in the European Union and abroad, together with its applicationCancers 2020, 12, 219; doi:10.3390/cancers12010219 www.mdpi.com/journal/cancersCancers 2020, 12, 219 in veterinary oncology for treatment of metastases as well as primary tumours [5,6]. The applied EPs create a transient transmembrane potential difference that causes changes in the cell membrane structure and transiently permeabilise its phospholipid bilayer [7] This biophysical process, which is named reversible electroporation or reversible electropermeabilisation, allows for the penetration of the chemotherapeutic agent inside the cell to generate irreversible DNA damages. One of the main drawbacks of ECT application are muscles contraction with discomfort sensations associated with repeated electrical stimulation, mainly linked to the characteristics of the high-amplitude electric pulses used. These EPs depolarise the neurons in the treated area and can, generate action potentials, either in the musculo-excitatory nerves or in the sensory nerves, imposing the use of at least a local anaesthesia during the treatment [9]
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