Cell Electropermeabilization and Cellular Uptake of Small Molecules: The Electrochemotherapy Concept
The cell membrane is an impassable barrier for small hydrophilic molecules, termed nonpermeant, that are too hydrophilic for diffusing through the plasma membrane, and moreover are not recognized and internalized by a transporter, channel, or receptor sy
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Cell Electropermeabilization and Cellular Uptake of Small Molecules: The Electrochemotherapy Concept Aude Silve and Lluis M. Mir
Abstract The cell membrane is an impassable barrier for small hydrophilic molecules, termed n onpermeant, that are too hydrophilic for diffusing through the plasma membrane, and moreover are not recognized and internalized by a transporter, channel, or receptor system. Reversible cell electropermeabilization allows the cellular uptake of these nonpermeant small molecules. Studies demonstrating that bleomycin is a nonpermeant anticancer drug possessing a very high intrinsic cytotoxicity (the toxicity displayed when the drug has no biological barrier separating it from its target) have lead to the development of the electrochemotherapy concept. Indeed, cell electropermeabilization can increase bleomycin toxicity several thousand-fold in vitro and about thousand-fold in vivo. At the dosages used, bleomycin selectively kills the dividing cells by a mitotic cell death process. The physico-chemical bases reported in this chapter give light to the interesting aspects of the electrochemotherapy revealed and/or confirmed by the clinical trials, in particular, its efficacy and safety. Keywords Electrochemotherapy • Bleomycin • Cisplatin • Electroporation • Electropermeabilization • Nonpermeant molecules • Low-permeant molecules • Intrinsic activity • Vascular lock • Molecular transport across membranes • Mitotic cell death • Cell death • Antitumor treatment • Electropermeabilization monitoring • Drug vectorization • Targeting
Introduction In pharmacology, most of the current drugs are molecules that act on receptors or on molecules located at the cell surface. However, in the specific case of anticancer pharmacology, the classical cytotoxic drugs have their targets located inside cells. The control of transport across the plasma membrane is of the highest importance in cell physiology and homeostasis. On the one hand, internalization of metabolites necessary for cell function (e.g., sugars, amino acids, cofactors, ions) is mediated and precisely controlled by membrane transporters or channels. On the other hand, there is no mechanism for a controlled crossing of the cell
.M. Mir () L Univ Paris-Sud, Unité Mixte de Recherche (UMR) 8203, Institut Gustave-Roussy, 114 rue E. Vaillant, 94805 Villejuif, France and Centre Nationale de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8203, Institut Gustave-Roussy, 114 rue E. Vaillant, 94805 Villejuif, France e-mail: [email protected] S.T. Kee et al. (eds.), Clinical Aspects of Electroporation, DOI 10.1007/978-1-4419-8363-3_6, © Springer Science+Business Media, LLC 2011
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membrane in the case of macromolecules and small xenobiotic molecules like most of the anticancer cytotoxic drugs. Using this knowledge, important factors to consider are: –– Only plasma membrane crossing, either at the cell surface or in structures like the caveolae, results in direct access to the cell cytosol and the nucleosol; that i
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