Cellular uptake mechanisms and potential therapeutic utility of peptidic cell delivery vectors: progress 2001-2006

Cell delivery vectors (CDVs) are short amphipathic and cationic peptides and peptide derivatives, usually containing multiple lysine and arginine residues. They possess inherent membrane activity and can be conjugated or complexed with large impermeable macromolecules and even microscopic particles to facilitate cell entry. Various mechanisms have been proposed but it is now becoming clear that the main port of entry into cells of such CDV constructs involves adsorptive-mediated endocytosis rather than direct penetration of the plasma membrane. It is still unclear, however, how and to what extent CDV constructs are capable of exiting endosomal compartments and reaching their intended cellular site of action, usually the cytosol or the nucleus. Furthermore, although many CDVs can mediate cellular uptake of their cargo and appear comparatively non-toxic to cells in tissue culture, the utility of CDVs for in vivo applications remains poorly understood. Whatever the mechanisms of cell entry and disposition, the overriding question as far as potential pharmacological application of CDV conjugates is concerned is whether or not a therapeutic margin can be achieved by their administration. Such a margin will only result if the intracellular concentration in the target tissues necessary to elicit the biological effect of the CDV cargo can be achieved at systemic CDV exposure levels that are non-toxic to both target and bystander cells. It is proposed that the focus of CDV research now be shifted from mechanistic in vitro studies with labeled but otherwise unconjugated CDVs to in vivo pharmacological and toxicological studies using CDV-derivatized and other cationized forms of inherently non-permeable macromolecules of true therapeutic interest.