How to overcome a cell's protective barrier to enable delivery of therapies

The function of cell membrane is to maintain the stability of a cell's interior by regulating the amounts and types of molecules entering or leaving the cell.

Professor Damijan Miklavcic at the Faculty of Electrical Engineering,...
Professor Damijan Miklavcic at the Faculty of Electrical Engineering, University of Ljubljana, Slovenia

However, sometimes we need to deliver drugs into the cell, which cannot pass through its membrane. Electroporation is an efficient technique to overcome the membrane barrier and allow entry to the cell. When a cell is exposed to an electric field, transmembrane voltage is induced on the cell membrane (Figure 1) and the resulting high electric field strength in the cell membrane leads to its increased permeability. Up to now the most plausible theory for this is that lipids in the membrane are rearranged to form aqueous nano-scale pores - a phenomenon referred to as electroporation.

Induced transmembrane voltage depends on the cell radius, applied electric field strength and orientation of the electric field. By applying an electric field of adequate strength and duration, the membrane returns into its normal state after exposure to the electric field ends - electroporation is reversible. However, too high electric field strength, or too long an exposure to the electric field leads to cell death, in which case  electroporation is irreversible. The reversibility is a function of electrical parameters, such as the voltage applied, pulse duration, number, shape and repetition rate; as well as of other conditions such as cell type and development stage, pulsing buffer, temperature and electrode material.

Using reversible electroporation, both small and large molecules can be introduced into cells, proteins can be inserted into the cell membrane and cells can be fused. However, Irreversible electroporation can be used for nonthermal food and water preservation. Due to its efficiency, electroporation has found its application in biochemistry, molecular biology and medicine for genetic manipulation of mammalian cells, plant cells, bacteria and yeast; preparation of hybridoma and monoclonal antibodies, as well as for in-vitro and in-vivo drug delivery.

In vitro electroporation has been used in the laboratories for decades and has become a standard laboratory procedure. Medical applications are still in their earlier stage of development. Nevertheless, clinical relevance has already been shown in oncology as an efficient method for local treatment of solid tumours by introducing cytotoxic drugs into malignant cells, thus potentiating their cytotoxic effect (http://www.cliniporator.com). Moreover, as a physical method of gene delivery with high efficiency, electroporation holds great promises for gene therapy and DNA vaccination. In the future electroporation might become the delivery method of choice for many applications of gene therapy in treating of cancer, metabolic disorders and other genetic diseases.

Further reading
Neumann E, Kakorin S, Toensing K. Fundamentals of electroporative delivery of drugs and genes. Bioelectrochemistry and Bioenergetics 48: 3-16, 1999. In this paper the discussion is focused on the chemical-structural aspects of membrane electroporation and cell deformation, as well as the fundamentals of transport through electroporated membrane patches.

Golzio M, Rols MP, Teissié J. In vitro and in vivo electric field-mediated permeabilisation, gene transfer, and expression. Methods 33(2): 126-135, 2004. The present paper describes the factors controlling electropermeabilisation to small molecules (<4 kDa) and the processes supporting DNA transfer in vitro. The description of in vitro events brings the attention of the reader to the processes occurring before, during, and after electropulsation of DNA and cells. Developments for the in vivo processes are reported and potential clinical applications described.

Mir LM. Therapeutic perspectives of in vivo cell electropermeabilisation. Bioelectrochemistry 53: 1-10, 2001. This review gives an overview of the therapeutic perspectives of cell electroporation in vivo, in particular of the antitumour electrochemotherapy i.e. the combination of a cytotoxic nonpermeant drug with permeabilising electric pulses delivered to the tumours and of in vivo DNA electrotransfer for gene therapy.

Sersa G, Stabuc B, Cemazar M, Miklavcic D, Rudolf Z. Clinical experience in malignant melanoma patients. Clin. Canc. Res. 6: 863-867, 2000. This Phase II clinical study demonstrates the high effectiveness of electrochemotherapy with cisplatin on malignant melanoma nodules. The advantages of this therapy, such as its simplicity, the short duration of treatment sessions, low cisplatin doses and insignificant side effects, are emphasized.

Puc M, Corovic S, Flisar K, Petkovsek M, Nastran J, Miklavcic D. Techniques of signal generation required for electropermeabilisation. Survey of electropermeabilisation devices. Bioelectrochemistry 64: 113-124, 2004. The authors of this paper compare most commonly used techniques of signal generation required for electroporation. In addition, an overview of commercially available electroporators and electroporation systems is presented.


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