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The equivalence of different types of electric pulses for electrochemotherapy with cisplatin − an in vitro study

Maria Scuderi

Maria Scuderi

Faculty of Electrical Engineering, University of LjubljanaLjubljana, Slovenia
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Scuderi, Maria
, 
Janja Dermol-Cerne

Janja Dermol-Cerne

Faculty of Electrical Engineering, University of LjubljanaLjubljana, Slovenia
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Dermol-Cerne, Janja
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Janez Scancar

Janez Scancar

  • Department of Environmental Sciences, Jožef Stefan InstituteLjubljana, Slovenia
  • Jožef Stefan International Postgraduate SchoolLjubljana, Slovenia
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Scancar, Janez
, 
Stefan Markovic

Stefan Markovic

  • Department of Environmental Sciences, Jožef Stefan InstituteLjubljana, Slovenia
  • Jožef Stefan International Postgraduate SchoolLjubljana, Slovenia
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Markovic, Stefan
, 
Lea Rems

Lea Rems

Faculty of Electrical Engineering, University of LjubljanaLjubljana, Slovenia
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Rems, Lea
 und 
Damijan Miklavcic

Damijan Miklavcic

Faculty of Electrical Engineering, University of LjubljanaLjubljana, Slovenia
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Miklavcic, Damijan
  
21. Feb. 2024
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Artikel-Kategorie: Research Article
Online veröffentlicht: 21. Feb. 2024
Seitenbereich: 51 - 66
Eingereicht: 20. Nov. 2023
Akzeptiert: 05. Dez. 2023
DOI: https://doi.org/10.2478/raon-2024-0005
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© 2024 Maria Scuderi et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

FIGURE 1.

(A) 50 × 50 HF pulses. From left to right: 50 bursts were applied with a repetition frequency of 1 Hz; one burst with 200 μs total pulse on time and consisted of 50 bipolar pulses; one bipolar pulse of amplitude U consisted of a 2 μs long positive pulse, and a 2 μs long negative pulse (both of voltage U) with a 2 μs long interpulse delay. (B) 8 × 100 μs or 8 × 5 ms monopolar pulse of amplitude U and pulse duration of 100 μs or 5 ms were applied with a repetition frequency of 1 Hz
(A) 50 × 50 HF pulses. From left to right: 50 bursts were applied with a repetition frequency of 1 Hz; one burst with 200 μs total pulse on time and consisted of 50 bipolar pulses; one bipolar pulse of amplitude U consisted of a 2 μs long positive pulse, and a 2 μs long negative pulse (both of voltage U) with a 2 μs long interpulse delay. (B) 8 × 100 μs or 8 × 5 ms monopolar pulse of amplitude U and pulse duration of 100 μs or 5 ms were applied with a repetition frequency of 1 Hz

FIGURE 2.

Schematic of the model that describes electroporation and molecular transport. (A) The equivalent circuit, which considers electroporation (membrane pore/defect formation) to be a two-step process, as depicted in (B). The blue capacitance and resistance represent the intact cell membrane. When the electric field is applied, the cell membrane becomes permeable first to small ions, indicating the first porous state (N) of the membrane represented by green resistance. Then the membrane becomes permeable to small molecules, indicating the second porous state (M) of the membrane represented by magenta resistance. Reproduced from Sweeney et al.56 with permission.
Schematic of the model that describes electroporation and molecular transport. (A) The equivalent circuit, which considers electroporation (membrane pore/defect formation) to be a two-step process, as depicted in (B). The blue capacitance and resistance represent the intact cell membrane. When the electric field is applied, the cell membrane becomes permeable first to small ions, indicating the first porous state (N) of the membrane represented by green resistance. Then the membrane becomes permeable to small molecules, indicating the second porous state (M) of the membrane represented by magenta resistance. Reproduced from Sweeney et al.56 with permission.

FIGURE 3.

Cell survival (solid) and cell membrane permeability (dashed) as a function of the electric field when (A) 50 × 50 HF pulses; (B) 8 × 100 μs pulses; (C) 8 × 5 ms pulses are used. The chosen optimal electric fields are encircled. Each data point presents the mean ± standard deviation from 3–4 experiments. * = statistically significant differences from control (p < 0.05) performing one-way ANOVA if the normality test passed or otherwise ANOVA on ranks. The light blue, red, and green asterisks are related to survival experiments.
Cell survival (solid) and cell membrane permeability (dashed) as a function of the electric field when (A) 50 × 50 HF pulses; (B) 8 × 100 μs pulses; (C) 8 × 5 ms pulses are used. The chosen optimal electric fields are encircled. Each data point presents the mean ± standard deviation from 3–4 experiments. * = statistically significant differences from control (p < 0.05) performing one-way ANOVA if the normality test passed or otherwise ANOVA on ranks. The light blue, red, and green asterisks are related to survival experiments.

FIGURE 4.

Cytotoxicity of cisplatin (A) and cisplatin molecules per cell (B) at different concentrations of cisplatin at a fixed electric field: 1.4 kV/cm for 50 × 50 HF pulses, 1.2 kV/cm for 8 × 100 μs pulses and 0.6 kV/cm for 8 × 5 ms pulses. Each data point presents the mean ± standard deviation from 3–4 experiments. *= statistically significant differences from control (p < 0.05) performing twoway ANOVA test. The color of the asterisk corresponds to the line color for a specific type of tested pulse. Cell survival as a function of cisplatin molecules per cell in combination with electroporation (C) our experimental data and (D) experimental data replotted from Vižintin et al.52 with permission.
Cytotoxicity of cisplatin (A) and cisplatin molecules per cell (B) at different concentrations of cisplatin at a fixed electric field: 1.4 kV/cm for 50 × 50 HF pulses, 1.2 kV/cm for 8 × 100 μs pulses and 0.6 kV/cm for 8 × 5 ms pulses. Each data point presents the mean ± standard deviation from 3–4 experiments. *= statistically significant differences from control (p < 0.05) performing twoway ANOVA test. The color of the asterisk corresponds to the line color for a specific type of tested pulse. Cell survival as a function of cisplatin molecules per cell in combination with electroporation (C) our experimental data and (D) experimental data replotted from Vižintin et al.52 with permission.

FIGURE 5.

Comparison between the number of cisplatin molecules obtained experimentally (asterisks) and using the model (solid line) for (A) 50 × 50 HF pulses, (B) 8 × 100 μs pulses, (C) 8 × 5 ms pulses, (D) 1 × 200 ns pulses, and (E) 25 × 400 ns pulses. We used three different extracellular concentrations of cisplatin: 0 μM, 10 μM, 30 μM, and 50 μM.
Comparison between the number of cisplatin molecules obtained experimentally (asterisks) and using the model (solid line) for (A) 50 × 50 HF pulses, (B) 8 × 100 μs pulses, (C) 8 × 5 ms pulses, (D) 1 × 200 ns pulses, and (E) 25 × 400 ns pulses. We used three different extracellular concentrations of cisplatin: 0 μM, 10 μM, 30 μM, and 50 μM.

Model parameters

Parameter Symbol Value Reference
Electroporation threshold voltage U0 258 mV 56
Membrane thickness h 5 nm 56
Cell radius r 7.5 μm 56
Membrane time constant τRC 1 µs 56
Membrane permittivity ɛm 12 × 8.85 × 10−12 F/m 56
Solute radius ρs 0.58 nm 58
Defect radius ρd 0.8 nm 56
Solute radius/Defect radius λm = ρs/ρd 0.7250 56
Solute diffusivity D 1.670 × 10−9 m2/s 58,59
Parameter in N formation rate α 2 × 10−6 56
N relaxation rate β 4 × 10−8 56
Relative permeabilzed conductance γ 1 × 106 56
Parameter in M formation rate δ 1 × 10−3 56
M relaxation rate η 4 × 10−9 56
Permeability coefficient ξ 8.45 × 10−4 56
Electroporation medium conductivity σ 1.4 S/m *
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