Endosomes disruption

Plank C, Oberhauser B, Mechtler K, Koch C, Wagner E (1994) The influence of endosome-disruptive peptides on gene transfer using synthetic virus-like gene transfer systems. J Biol Chem 269 12918-12924... 

To bridge this gap, liposomal transfection efficiency can be dramatically enhanced by the inclusion of peptides into the complex without increasing immunogenicity. Peptides can be selected to assist lipofection at each key stage of the process complex formation, cell targeting and uptake, endosomal disruption, and nuclear targeting. The purpose of this chapter is... 

Other peptides containing histidines listed in Table 16.2, such as those of the histatin family (antimicrobial peptides), Sea Urchin (B18) and LAH4, strongly interact with phospholipid membranes and destabilize them. LAH4, which does not contain other cationic residues, exhibits a-helix and is more active in an acidic medium. These peptides could be putative endosome disrupting helpers that have not yet been used for polyfection. 

Lim YB, Kim SM, Suh H et al (2002) Biodegradable, endosome disruptive, and cationic network-type polymer as a highly efficient and nontoxic gene delivery carrier. Bioconjug Chem 13 952-957... 

Gotten, M., Wagner, E., Zatloukal, K., Phihips, S., Curiel, D.T., and Bimstiel, M.L. (1992). High-efficiency receptor-mediated delivery of small and large (48 kilobase) gene constructs using the endosome-disruption activity of defective or chemically inactivated adenovirus particles. Proc. Natl. Acad. Sci. USA 89, 6094 6098. 

Ov Integrins Regulate Adenovirus-Mediated Endosome Disruption. 482... 

Adenovims(es), 64, 65, 172-74, 381, 428-430 attachment receptors of, 476-478 double-stranded DNA viruses and, 172-174 human, 475-476 Adenovirus internalization cell integrins and, 478-482 signaling events and, 481 Adenovirus-mediated endosome disruption, a, integrins and, 482-482 AFM. See Atomic force microscopy (AFM) African horse sickness virus (AHSV), 71 Agrobacterium tumefaciens, 14, 26 AHSV. See African horse sickness virus (AHSV)... 

Mastrobattista E et al (2002) Functional characterization of an endosome-disruptive peptide and its application in cytosolic delivery of immunoliposome-entrapped proteins. J Biol Chem 277 27135-27143... 

Cationic lipids can destabilize a cellular membrane because of its intrinsic detergent property. Therefore, destabilization of endosomal and/or lysosomal membrane may be a contribution from the cationic lipids itself In the same context, it was shown that the cationic lipid/DOPE or cationic lipid/cholesterol liposome formulation exhibit surface anisotropies in terms of increased liposomal surface pH (161,162). The surface pH of the liposomal formulations exhibits at least two pH units higher than the pH of the solution at which they are made. Therefore, a liposomal solution made at physiological pH may in reality exhibit a surface pH > 9, which is detrimental for both the stability of endosome and activity of lysosomal enzymes. Endosomal disruptions were also done with fusogenic peptides, which promote pH-dependent fusion of small liposomes when associated with lipid bilayer. When these peptides were co-delivered with lipid/DNA complex, they imparted formidable endosomal disruption by changing its usual random coil conformation into amphipathic a-helix conformation at lower pH, resulting in consequent cytoplasmic delivery of DNA (163). 

More recently, a family of acid responsive polymers based on a-alkyl acrylic acids such as methacrylic acid (MAA), ethylacrylic acid (EAA), propylacrylic acid, and butylacrylic acid (BAA) and their copolymers with alkyl acrylates or methacrylates have been explored for their ability to disrupt membranes and their potential as endosomal disruption polymers. The key feature of these poly(a-alkyl acrylic acids) is that they switch from a hydrophilic to a hydrophobic character as they become protonated (pH sensitive), and the switch to a hydrophobic character has been shown to disrupt membranes [68, 69]. The polymer, PPAA, has been shown to be 15 times more effective than PEAA at membrane disruption and to have maximum hemolytic activity at pH < 6, which is in the range of endosomal pH [68, 285]. PPAA has been successfully been used to enhance lipolyplex-mediated gene transfer [286] in vitro and wound healing by altering extracellular matrix organization and greater vascularization in vivo [286]. 

Fig. 5 Schematic diagram of the siRNA delivery system. A cationic group is universal in all siRNA delivery systems to condense siRNA into nanosized complex. To release the siRNA from the endosome after endocytosis, an endosomal disrupting agent is also essential. PEG modification is also important to improve the pharmacokinetic profile of the complex, as well as to avoid the nonspecific uptake by RES. To achieve the targeted delivery to tumor cells, various ligands including antibody, antibody fragments, peptides, small molecules should be modified to the complex directly or via PEG as a linker...

Figure 6.3 Stimuli-responsive polymers and their intracellular mechanisms leading to transfection. (A) Cationic polymers containing bioreducible disulfide bonds (S-S) can form tight complexes with DNA, releasing it in the cytosol, due to reduction of disulfide bonds to two thiol groups. (B) Associated polyplexes can he dissociated in the cytosol by temperature decrease, leading to DNA release. (C) The endosomal escape can be promoted by pH-responsive polymers such as PEI that act as proton sponges, preventing the normal acidification of the endosomes the continuous influx of protons, counterions and water eventually leads to endosomal disruption and DNA release.

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