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... 

One primary factor that led to the selection of the DS for the SBE-P-CD was the need to economically produce a bulk that is safe for parenteral administration. The safety of the bulk required that it be devoid of any residual P-CD and that the SBE-P-CD exhibit no systemic toxicity. The most economical approach to the elimination of the unreacted P-CD was to derivatize all of the parent CD, a feat accomplished by reaching a DS of approximately 6.5 (SBE7-P-CD). A preliminary evaluation of the potential safety of the SBE7-P-CDs was demonstrated by its minimal involvement in membrane destabilization (20). 

A few caveats are in order as to what defines a lead. Firstly, a lead is more than just a compound that shows a defined level of activity in a primary screen. The screen must have been validated usually this will be by obtaining the expected responses from pharmacological standards or known drugs. Any reasons for false positives must be understood. Certain substances such as chemically reactive or unstable compounds, protein denaturants, membrane destabilizing agents or uncouplers of oxidative phosphorylation will record as active in a great variety of screens. These must be recognized and eliminated by suitable secondary procedures. 

Membrane destabilization can be simultaneously monitored by using propidium iodide. This non fluorescent and poorly permeant small molecule enters into the cells only upon membrane permeabilization/ destabilization and becomes fluorescent upon binding to DNA in the nucleus. In the presence of melittin, cells are also rapidly (200 s) red-labeled upon peptide induced membrane permeabilization (Figure 16.4D). It can be seen that the diffusion of propidium iodide inside the cells is correlated with the leak of EGFP. The results show that melittin induces the formation of pores in the plasma membranes allowing the passage of... 

Table 16.5 Peptide inducing DNA condensation and membrane destabilization...

Non-clathrin-coated pit internalization can occur through smooth imagination of 150-300 nm vesicles or via potocytosis. This pathway has been shown to be involved in the transport of folate and other small molecules into the cytoplasm. Plasmids are taken up by muscles through the T-tubules system and caveolae via potocytosis. Muscle cells appear to take up plasmids through the T-tubule system and caveolae via potocytosis. Apart from coated or uncoated pit pathways, cells may also take up plasmid/cationic carrier complexes via plasma membrane destabilization. Particles greater than 200 nm in diameter are not... 

Other functional liposomes are mainly stimuli-responsive liposomes. The pH-sensitive liposomes contain pH-sensitive lipids such as l,2-dioleoyl-vn-3-phosphatidylethanolamine (DOPE) showing an inverted hexagonal configuration in a low-pH environment and release entrapped drugs in the low-pH environment of tumor tissues due to liposomal membrane destabilization [89], Temperature-sensitive liposomes are prepared from special lipids such as DPPC whose phase transition temperature (Tc = 41°C) is proper to perform clinical anticancer therapy. When up to Tc, the fluidity of liposomal membranes increases sharply, followed by... 

Selection of an optimal CPP for delivering a specific cargo into a particular cell type, especially in vivo, is not necessarily a trivial task. Until now there are relatively few studies devoted to the comparison of the cellular delivery efficiency of different CPPs and the correlation to their side effects such as cytotoxicity and membrane destabilizing properties. Comparative data of the delivery efficiency of CPPs in vivo are even more scarce. 

Fujii, G. To fuse or not to fuse the effect of electrostatic interactions, hydrophobic forces and structural amphilicity on protein-mediated membrane destabilization. Adv. Drug Deliv. Rew. 1999, 38, 257-277. 

The cellular membrane is a hydrophobic barrier that surrounds the cytoplasm of every cell and is involved in complex cellular processes, such as signaling and transport, which are essential to maintain the normal life cycle of a cell major components of this cellular membrane are lipids, proteins, peptides, and carbohydrates. Peptides that interact with cellular membranes are referred to as membrane-active peptides and can be broadly divided into three major classes antimicrobial, cell-penetrating, and fusogenic peptides. Any of these may have variable lengths, hydrophobicities, and secondary structures, but they often exhibit similar effects on membranes. For example, some antimicrobial peptides have cell-penetrating properties, and vice versa [23,24] these peptides usually cause some degree of membrane destabilization. 

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