pH-sensitive PEG lipids containing orthoester linkers: new potential tools for nonviral gene delivery

In vitro and in vivo effects of polyethylene glycol (PEG)-modified lipid in DOTAP/cholesterol-mediated gene transfection

“…16 The rapid clearance from the system of intravenously injected DOTAP/chol-based lipoplexes have been reported, 13,42 and since our gene therapy strategy is aimed at the systemic treatment of subcutaneous xenograft tumors 14 and eventually disseminated SCLC, in this study we sought to stabilize and increase the circulation time of DOTAP/ chol-based lipoplexes that have been modified with different amounts of PEG-lipid, ie, without abolishing the eminent ability to transfect cells. 43,44 Several other works have reported the effect of PEGylation of lipoplexes made from DOTAP or other cationic lipid and with DOPE as the helper lipid, 25,26,[45][46][47] and we discuss these in relation to our findings with PEGylation of DOTAP/chol-based lipoplexes further below.…”

“…Similarly, a size stabilizing effect exist when more than 4-5 moL% of a mono-alkyl-or cholesteryl-anchored PEG-lipid is incorporated into lipoplexes at neutral charge ratio. 47 The biophysical basis of this difference may rely on the surface density of PEG-lipid that in less than 5% allow for a mushroom-structured PEG-lipids where PEG-polymers do not interact. 23,24 However, upon lipoplexing where negatively charged DNA is added, PEG-lipids may interdigit with PEG of other particles and hence favor aggregation.…”

The Polyethyleneglycol Dilemma: Advantage and Disadvantage of PEGylation of Liposomes for Systemic Genes and Nucleic Acids Delivery to Tumors

“…Intracellular environments with a low pH in endosomes/lysosomes are employed as triggers of PEG cleavage. [97][98][99][100][101][102] Szoka and colleagues constructed pHsensitive PEG lipids containing an orthoester linkage, and a transfection experiment showed greater luciferase expression of pH-sensitive lipoplexes as compared with stable PEGylated ones. 97) In addition to the pH gradient, an intracellular reducing environment and enzymes are considered alternative stimulating triggers.…”

Recent Advances in Endogenous and Exogenous Stimuli-Responsive Nanocarriers for Drug Delivery and Therapeutics

“…pH-Sensitive polyethylene glycol (PEG) lipids containing an acid cleavable linkage have been developed, which increased the activity of cargos of liposomes in comparison with stable PEGylated lipids. [13][14][15] Polymer based nanoparticles composed of pH-sensitive linkages have been also reported. [16][17][18] Walker et al demonstrated successful gene delivery using pH-sensitive polyplexes with pH-labile hydrazone linkages between the PEG and polycation for in vitro and in vivo use.…”