Design, Synthesis, and in Vitro Gene Delivery Efficacies of Novel Cholesterol-Based Gemini Cationic Lipids and Their Serum Compatibility:  A Structure−Activity Investigation

Abstract

Five cholesterol-based gemini cationic lipids, which differ in the length of the spacer [-(CH2)n-] chain between the head groups, have been synthesized. These lipids are useful as nonviral gene delivery agents, and all cholesterol-based gemini lipids (2a-2e) are better transfecting agents than their monomeric lipid counterpart 1. Transfection efficiency of all the gemini lipids except lipid 2a [-(CH2)3-] was maintained even when the serum was present during the transfection conditions as compared to the monomeric lipid 1, with which a dramatic decrease in transfection efficiency was observed. With the increase in spacer chain length from propanediyl [-(CH2)3-] to pentanediyl [-(CH2)5-], transfection efficiency increased both in the absence and presence of serum. However, transfection efficiency decreased with further increase in the length from the pentanediyl [-(CH2)5-] to the dodecanediyl [-(CH2)12-] spacer. Among these gemini lipids 2c showed the highest transfection activity, which was also greater than that of the commercially available formulation.

A Potential Targeting Gene Vector Based on Biotinylated Polyethyleneimine/Avidin Bioconjugates

“…Despite the high transfection efficacy of viral vectors, safety concerns have been raised in clinical trials. Non-viral vectors make a heterogeneous group of vehicles for gene transfer including cationic liposomes and polymers, which are considered to be less toxic, less immunogenic, and easier to handle than viral vectors, thus they are more attractive vectors for clinical applications (9)(10)(11)(12)(13). As the profound non-viral gene vector, polyethyleneimine (PEI) presents significantly high transfection capability in various cell cultures and in vivo gene transfer (14)(15)(16)(17).…”

Non-Viral Gene Delivery Systems Based on Cholesterol Cationic Lipids: Structure-Activity Relationships

“…Other gemini-surfactants were specially synthesized for the usage as nucleic acids carriers into the cells (Kirby et al, 2003;) and the effects of the nature of the spacer, hydrocarbon chains, and headgroups on the transfection activity of these compounds were studied in detail. Dimeric lipids 14a-k, differing in the length of the spacer and the type of the cationic headgroup, were synthesized, and the transfection activity of these compounds was compared with this parameter for the monomeric lipids 3d and 3e (Bajaj et al, 2007a;Biswas et al, 2011). Lipids formed different aggregates, depending on the structure of the cationic head.…”

Arginine-based cationic liposomes for efficient in vitro plasmid DNA delivery with low cytotoxicity

“…[31][32][33] Furthermore, a suitable spacer, in terms of length and nature, influences the gene delivery efficiency and serum compatibility of cationic liposomes. [34][35][36][37] Recently, we reported that the ionization states of the cationic head group influence the phase transition temperature, morphology, and transfection efficiency of the lysine-based cationic assemblies. 38 More specifically, lysine-based cationic assemblies with trifluoroacetic acid (TFA) salt as the counterion and a 3-hydrocarbon chain spacer between the lysine head group and the hydrophobic moiety showed the highest transfection efficiency in COS-7 cells.…”