Synthesis of a novel archaeal tetraether-type lipid containing a diorthoester group as a helper lipid for gene delivery

Abstract

International audienceAs an alternative to recombinant virus, synthetic carriers are widely developed for providing efficient and safe DNA delivery. To reach the nucleus where nucleic acid (NA) constructs are transcripted, chemical complexes have to overcome serious cellular traps such as endosomal escape and intracellular trafficking. Here, the design and the multi-step synthesis of a stabilizing tetraether lipid analogue of archaeal counterparts containing a diorthoester moiety in the middle of the bridging chain were described. The key step involved a double coupling reaction between two diether alcohols and a diketene acetal. Under aqueous acidic conditions, the diorthoester function of the tetraether lipid can be hydrolysed to yield two monopolar diether lipids. Applied to gene delivery in association with a cationic lipid, this new helper bipolar tetraether lipid led to lipid-DNA complexes with sizes and potential zeta values depending on the charge ratios (+/-). In addition, preliminary in vitro transfection assays supported the interest of these novel bipolar lipid-based lipoplex formulations compared to standard Lipofectamine-based formulations. © 2016 Elsevier Ltd. All rights reserved

Liposomal nanoparticles based on steroids and isoprenoids for nonviral gene delivery

“…These lipids could improve the gene transfection ability by providing LipoNPs as well as their DNA‐complexes with some additional rigidity, facilitating cellular uptake via endocytosis and reorganization of the membranes to inverted hexagonal phases during transfection (Gall et al, 2014; Picquet et al., 2005). The previous lipid was also modified with bridging diorthoester moiety in tetraether lipid (Figure 21, 285 ) instead of cyclopentane ring which introduced further pH sensitivity in their LipoNPs and yielded two monopolar diether lipids in acidic pH (Barbeau et al, 2016).…”

Hemiacetal-linked pH-sensitive PEG-lipids for non-viral gene delivery

“…34 Introduction of pH-sensitive linkers to PEG-lipids, one of the most common strategies, allows PEGylated CL-DNAs to cleave and shed the PEG chain inside the endosome due to the lower endosomal pH, leaving the CL-DNA membrane free to fuse with the endosome membrane, permitting the content to escape to the cytosol. 46,47 Ortho esters, 41,48,49 imines, 41,50 hydrazones, 40 and acetals 51,52 are among the most commonly used pH-sensitive linkages. Acetals can be expected to provide enough sensitivity to respond to the pH variations encountered within endosomes.…”

Thiol-Triggered Release of Intraliposomal Content from Liposomes Made of Extremophile-Inspired Tetraether Lipids

“…To incorporate stimuli-responsive functionality into GcGTPC–CH lipids, here we chose to integrate a disulfide linker near the polar headgroups of the lipid (Figure ) with the hypothesis that the relatively small addition of the disulfide outside of the hydrophobic core would not perturb membrane packing of the lipid, whereas cleavable linkers that typically involve an addition of bulky aromatic groups or heteroatoms could affect lipid organization within the membrane. − Incorporation of the disulfides near the polar lipid headgroups, rather than within the hydrophobic portion of the lipid, would also presumably facilitate access of free thiols to the disulfide bond for triggered response of the lipid. In this work, we show that this lipid can form serum stable liposomes without the need for mixing with other lipids and exhibits accelerated release of encapsulated cargo in the presence of thiols.…”