title: Facilitation of electroporative drug uptake and cell killing by electrosensitization.
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 LD(50)  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.
authors.affiliation: Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, USA. opakhomo@odu.edu
authors.forename: Olga N
authors.initials: ON
authors.lastname: Pakhomova
authors.forename: Betsy W
authors.initials: BW
authors.lastname: Gregory
authors.forename: Andrei G
authors.initials: AG
authors.lastname: Pakhomov
mesh_terms: D000818:Animals; D001692:Biological Transport; D001761:Bleomycin / Q000378:metabolism* / Q000494:pharmacology; D016466:CHO Cells; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003603:Cytotoxins / Q000378:metabolism* / Q000494:pharmacology; D018274:Electroporation / Q000379:methods*; D008546:Melanoma, Experimental; D051379:Mice; D011419:Propidium / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D003603:Cytotoxins; D001761:Bleomycin; D011419:Propidium