Abstract
Cell permeabilization by electric pulses (EP), or electroporation, is widely used for intracellular delivery of drugs and plasmids, as well as for tumour and tissue ablation. We found that cells pre-treated with 100-μs EP develop delayed hypersensitivity to subsequent EP applications. Sensitizing B16 and CHO cells by splitting a single train of eight 100-μs EP into two trains of four EP each (with 5-min. interval) decreased the LD50 1.5–2 times. Sensitization profoundly enhanced the electroporation-assisted uptake of bleomycin, a cell-impermeable cytotoxic agent accepted for killing tumours by electrochemotherapy. EP exposures that were not lethal per se caused cell death in the presence of bleomycin and proportionally to its concentration. Sensitizing cells by a split-dose EP exposure increased bleomycin-mediated lethality to the same extent as a 10-fold increase in bleomycin concentration when using a single EP dose. Likewise, sensitization by a split-dose EP exposure (without changing the overall dose, pulse number, or amplitude) enhanced the electroporative uptake of propidium up to fivefold. Enhancement of the electroporative uptake appears a key mechanism of electrosensitization and may benefit electrochemotherapy and numerous applications that employ EP for cell permeabilization.
Highlights
Electropermeabilization by intense electric pulses (EP), commonly known as electroporation is a well-established physical method of disrupting cell membrane, to kill cells or to facilitate the uptake of membrane-impermeable substances without cell killing [1,2,3,4]
We found that cells subjected to electroporation develop delayed sensitization to EP, and that the cytotoxic effect can be markedly increased by splitting a single EP treatment into two fractions [19]
We show that a split-dose delivery of 100-ls EP efficiently caused electrosensitization in melanoma and epithelial cell models, and that the sensitized cells responded to EP by profoundly higher electroporative uptake of bleomycin
Summary
Electropermeabilization by intense electric pulses (EP), commonly known as electroporation is a well-established physical method of disrupting cell membrane, to kill cells or to facilitate the uptake of membrane-impermeable substances without cell killing [1,2,3,4]. We found that cells subjected to electroporation develop delayed sensitization to EP, and that the cytotoxic effect can be markedly increased by splitting a single EP treatment into two fractions [19]. The mechanism responsible for the phenomenon of sensitization has not been understood
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