Electroporation for Electrochemotherapy and Gene Therapy

The theoretical understanding of the phenomenon of electroporation is crucial for planning and optimization of protocols for drug and/or gene delivery. In the last four decades, a number of tentative theoretical descriptions of this phenomenon have been proposed, assuming either deformation of membrane lipids,1–3 their phase transition,4 breakdown of interfaces between the lipid domains,5 or denaturation of membrane proteins.6 However, each of these former descriptions has serious flaws,7 and today, there is broad consensus that electroporation is best described as the formation of aqueous pores in the lipid bilayer.8–11 This also clarifies the prevalent choice of the term electroporation, as opposed to the broader term of electropermeabilization, which is also applicable to all the alternative explanations of the phenomenon. The theory of electroporation is largely based on thermodynamics and describes the initial stage of pore formation by penetration of water molecules into the lipid bilayer of the membrane, forming unstable structures termed water wires or water fingers. This subsequently causes the adjacent lipids to reorient with their polar heads toward these structures, forming metastable aqueous pores. Both the theory and molecular dynamics simulations suggest that small unstable pores are forming and closing within nanoseconds even in the absence of an external electric field, but an exposure of the membrane to an electric field reduces the energy required for penetration of water into the bilayer. As such exposure starts, the external field infiltrates the membrane so that the membrane CONTENTS