Background In electrochemotherapy (ECT), chemotherapeutics are first administered, followed by short 100 μs monopolar pulses. However, these pulses cause pain and muscle contractions. It is thus necessary to administer muscle relaxants, general anesthesia and synchronize pulses with the heart rhythm of the patient, which makes the treatment more complex. It was suggested in ablation with irreversible electroporation, that bursts of short high-frequency bipolar pulses could alleviate these problems. Therefore, we designed our study to verify if it is possible to use high-frequency bipolar pulses (HF-EP pulses) in electrochemotherapy. Materials and methods We performed in vitro experiments on mouse skin melanoma (B16-F1) cells by adding 1–330 μM cisplatin and delivering either (a) eight 100 μs long monopolar pulses, 0.4–1.2 kV/cm, 1 Hz (ECT pulses) or (b) eight bursts at 1 Hz, consisting of 50 bipolar pulses. One bipolar pulse consisted of a series of 1 μs long positive and 1 μs long negative pulse (0.5–5 kV/cm) with a 1 μs delay in-between. Results With both types of pulses, the combination of electric pulses and cisplatin was more efficient in killing cells than cisplatin or electric pulses only. However, we needed to apply a higher electric field in HF-EP (3 kV/cm) than in ECT (1.2 kV/cm) to obtain comparable cytotoxicity. Conclusions It is possible to use HF-EP in electrochemotherapy; however, at the expense of applying higher electric fields than in classical ECT. The results obtained, nevertheless, offer an evidence that HF-EP could be used in electrochemotherapy with potentially alleviated muscle contractions and pain.

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Electroporation is a biophysical phenomenon involving an increase in cell membrane permeability to molecules after a high-pulsed electric field is applied to the tissue. Currently, electroporation is being developed for non-thermal ablation of cardiac tissue to treat arrhythmias. Cardiomyocytes have been shown to be more affected by electroporation when oriented with their long axis parallel to the applied electric field. However, recent studies demonstrate that the preferentially affected orientation depends on the pulse parameters. To gain better insight into the influence of cell orientation on electroporation with different pulse parameters, we developed a time-dependent nonlinear numerical model where we calculated the induced transmembrane voltage and pores creation in the membrane due to electroporation. The numerical results show that the onset of electroporation is observed at lower electric field strengths for cells oriented parallel to the electric field for pulse durations ≥10 µs, and cells oriented perpendicular for pulse durations ~100 ns. For pulses of ~1 µs duration, electroporation is not very sensitive to cell orientation. Interestingly, as the electric field strength increases beyond the onset of electroporation, perpendicular cells become more affected irrespective of pulse duration. The results obtained using the developed time-dependent nonlinear model are corroborated by in vitro experimental measurements. Our study will contribute to the process of further development and optimization of pulsed-field ablation and gene therapy in cardiac treatments.

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