Endosomal membrane destabilization

Fig. 1 Bioresponsive polyplexes. (a) Systemic circulation of shielded polyplexes in blood stream and attachment to cell surface receptor (b) endocytosis into endosomes, deshielding by cleavage of PEG linkers and activation of membrane-destabilizing component by acidic pH or other means (c) endosomal escape into cytosol (d) siRNA transfer to form a cytosolic RNA-induced silencing complex complex (e) cytosolic migration and intranuclear import of pDNA (/) presentation of pDNA in accessible form to the transcription machinery...

Fig. 3 Activation of membrane-destabilizing component by acidic pH, resulting in endosomal...

Yessine MA, Leroux JC (2004) Membrane-destabilizing polyanions interaction with lipid bilayers and endosomal escape of biomacromolecules. Adv Drug Deliv Rev 56 999-1021... 

As the ortho ester hydrolysis ensues, a lactonization process liberates a singlechain detergent like lipid to destabilize the endosomal membrane. 

Due to its ability to form inverted hexagonal phase, DOPE is believed to impart fusogenicity to lipoplexes, thus facilitating fusion followed by destabilization of the endosomal membrane, lipoplex escape from the endosomes, and eventually the DNA release. Indeed, inclusion of DOPE into lipoplexes was shown to enhance considerably the transfection activity of some of the cationic lipid carriers [35,120, 121]. For example, formulations of oxypropyl quaternary ammonium cationic lipids with 50 mol% DOPE have been reported to exhibit 2-5 times higher transfection activity in COS7 cells than formulations with pure cationic lipid (Fig. 29) [35]. Recently, a triple-bond dialkynoyl analog of DOPE has been... 

Plasmid/cationic carrier complexes have been proposed to internalize into the endosome and initiate the destabilization of endosomal membranes. This destabilization would induce diffusion of anionic lipids from the external layer of the endosomal membrane into the complexes and form charge neutralized ion pairs with the cationic lipids. Destabilization and/or fusion of the complex with the plasma membrane would permit the same anionic lipids to diffuse to the surface, as would fusion with the endosomal membrane. Release of the condensed DNA from the cationic lipid in the endosome is likely to generate a mechanical or osmotic stress that raptures the endosomal bilayer and releases DNA into the cytoplasm. In contrast, DNA release from complexes on the cell surface might be unable to stress the membrane to a degree sufficient to rapture. 

One of the bottlenecks to achieve gene or drug delivery to cells is the spatio-temporal release of the cargo to effect the correct task whereever and whenever it is supposed to. The aim of this chapter is to describe the synthesis and properties of lipids, which can form liposome complexes with DNA and to fall apart in slight acidic condition such as those encountered in the late endosome, thus destabilizing the liposome membrane and releasing their content. 

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