An Imidazolium‐Based Lipid Analogue as a Gene Transfer Agent

Abstract

A dicationic imidazolium salt is described and investigated towards its application for gene transfer. The polar head group and the long alkyl chains in the backbone contribute to a lipid‐like behavior, while an alkyl ammonium group provides the ability for crucial electrostatic interaction for the transfection process. Detailed biophysical studies regarding its impact on biological membrane models and the propensity of vesicle fusion are presented. Fluorescence spectroscopy, atomic force microscopy and confocal fluorescence microscopy show that the imidazolium salt leads to negligible changes in lipid packing, while displaying distinct vesicle fusion properties. Cell culture experiments reveal that mixed liposomes containing the novel imidazolium salt can serve as plasmid DNA delivery vehicles. In contrast, a structurally similar imidazolium salt without a second positive charge showed no ability to support DNA transfection into cultured cells. Thus, we introduce a novel and variable structural motif for cationic lipids, expanding the field of lipofection agents.

1,3 Dialkylated Imidazolium Ionic Liquid Causes Interdigitated Domains in a Phospholipid Membrane

“…After numerous studies on the effects of ILs on various microorganisms and human cells, it can be inferred that they significantly alter the membrane morphology, leading to cell lysis. ,, One of the essential features of ILs is their selective interaction with a membrane which qualifies them to use as a therapeutic agent. For example, the double-chained imidazolium-based ILs can form giant unilamellar vesicles and a lamellar phase which can be used as a gene delivery vector with higher transfection efficiency. , In a study by Bakshi et al, it has been shown that out of many ILs and different cells, the long-chain imidazolium-based ILs inhibit the growth of the cancerous liver cell . For the future pharmaceutical applications of these ILs, the mechanism of their interactions with lipid membranes and the respective microscopic organization of the molecules are vital.…”

Squeezing Out Interfacial Solvation: The Role of Hydrogen-Bonding in the Structural and Orientational Freedom of Molecular Self-Assembly

“…To address this problem, much effort has been devoted to the synthesis of lipid analogues with improved material and structural properties, including stability. These include alkylated imidazolium compounds − and amphiphilic polymers. ,,− Biomimetic membranes containing amphiphilic siloxane-based polymer groups have been shown to be significantly more robust than phospholipid bilayer membranes. In this regard, we previously described a single-chain lipid analogue based on a methylimidazolium cationic headgroup (MIM + ) covalently tethered to a monodisperse, hydrophobic dimethylsiloxane oligomer (ODMS) (Figure top). − This robust amphiphilic oligomer is capable of self-assembly into monolayers with tunable structural motifs at the oil–aqueous interface over a wide concentration range.…”

Bipolar Imidazolium-Based Lipid Analogues for Artificial Archaeosomes

“…Their amphiphilic nature and the highly polar heterocycle are susceptible to electrostatic interactions with various biomacromolecules, especially with lipid membranes. Using molecular hybridization as a strategy for the development of medicinal agents, the Glorius group and partners have designed and synthesized several backbone alkylated imidazolium lipids that differ in the chain length of the two alkyl chains and the structure of their cationic headgroup. − Depending on the features of their structure, different effects upon partitioning into phospholipid model biomembranes have recently been reported. − A distinct advantage of the imidazolium salts is the ease with which structural changes can be made to achieve desired biophysical properties such as solubility, lipophilicity, and fusogenic power. − Considering this tunable platform, we envisioned the design of archaea-like bolaamphiphiles, where two imidazolium salts are connected by an alkyl chain. The planarity and charge of the imidazolium group should ensure membrane integration, while the alkyl chain should provide chemical, temperature, and pressure robustness.…”

“…We started with a single-component lipid membrane composed of DPPC, which exhibits lamellar phases with two major phase transitions with increasing temperature, a gel-to-gel pretransition, and a gel-to-fluid chain melting (main) transition . Because the existence of lipid domains of different lipid composition, sterol content and fluidity seem to be important for many membrane-associated biological processes, such as signaling, exo- and endocytosis, and virus uptake, − also a five-component anionic lipid mixture of DPPC:DPPG:DOPC:DOPG:cholesterol (45:5:20:5:25), which mimics a natural eukaryotic plasma membrane composition, was evaluated (DPPG: 1,2-dipalmitoyl- sn -glycero-3-phospho-(1′- rac -glycerol); DOPC: 1,2-dioleoyl- sn -glycero-3-phosphocholine; DOPG: 1,2-dioleoyl- sn -glycero-3-phospho-(1′- rac -glycerol)). , The five-component phospholipid (5C-PL) membrane system containing cholesterol shows the coexistence of raft-like liquid-ordered (l o ) domains and more fluid, liquid-disordered (l d ) domains containing mostly DOPC and DOPG at ambient temperature. , Next to recording structural changes over a wide temperature range up to about 90 °C, also selected pressure-dependent studies were performed to be able to evaluate changes in phase state upon compression of the lipid system.…”