ABSTRACT
Among non-viral systems, cationic lipids are the most efficient systems for gene delivery. Although their efficiency was shown to be lower than that of viral particles, they display higher transfection efficiency as compared to polymers and peptide-based systems. Their relatively higher efficiency is the result of the development of various generations of cationic lipids obtained by chemical modification of the different chemical entities in the cationic lipid, as well as the development of different formulations. Thus, along the different cationic lipid generations, the transfection efficiency in vitro was improved by three orders of magnitude. The high efficiency of some of these cationic lipids can be rationalized in terms of their ability to form virus-like particles. Cationic lipids possess two elements that are crucial for efficient gene delivery: a cationic headgroup to condense DNA and a lipid moiety as fusogenic group for improved penetration into the host cell. The nature of each of these elements will have a significant effect on gene transfer. For example, the presence of double-lipid chains as a fusiogenic group and the introduction of spermine as a cationic entity instead of the originally applied quaternary ammonium salts, confer a compacted state of the DNA, resulting in well defined virus-like particles arranged as multilamellar bilayers which enclose the DNA between the lipid bilayers. In various approaches, other elements were introduced into the cationic lipids. For example, fluorescent probes were included by co-for-mulation with fluorescently labeled DOPE or by direct labeling of cationic lipids, allowing intracellular trafficking studies of cationic lipid/DNA complexes. Alternatively, targeting molecules were introduced allowing cell or tissue-specific gene delivery. Finally, efforts were invested to modulate the stability of the self-assembling system between the cationic lipid and the DNA. In different works, chemical groups were introduced as ‘modulating switches’ for a controlled formation and/or disruption of the non-viral complexes to obtain improved transgene expression.
