Abstract
The activation of Toll-like receptors (TLR) by natural or synthetic ligands results in cytokine secretion and increased phagocytosis by macrophages and cytolytic activity by natural killer (NK) cells. So,wedeveloped a stable, efficient, and nontoxic cationic nanoemulsion (CNE) suitable for TLR ligand oligonucleotide (ssRNA) delivery. The nanoemulsion is based on squalene, cationic lipid 1,2-dioleoyl-sn-glycero-3-trimethylammoniumpropane (DOTAP), helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), tween 80, and poloxamer 188. Factorial design was used to investigate the influence of of tween 80 and poloxamer 188 on particle size, single strand RNA (ssRNA) binding %, Interferon (INF α induction). Results showed that by increasing the poloxamer 188 and/or tween 80, the particle size decreased.The influence of tween 80 and poloxamer 188 concentrations on the particle surface on ssRNA binding efficiency is evident. Although most of the formulations showed a high binding efficiency of ssRNA, only two formulations produced high amount of INF α. Interestingly that in both formulations either poloxamer 188 is present (F3) or tween 80 is present (F4) but where both together in one formulation, the INF α production decreased relatively. In conclusion, cationic nanoemulsion could be a promising drug delivery system for nucleic acids (DNA/RNA) in cancer and viral immunotherapy.
Highlights
Recent molecular biological studies have clarified the function of Toll-like receptors (TLRs) in microbial infection
Ten and 12 functional TLRs have been identified in humans and mice, respectively (Kawai and Akira, 2010).TLR-1,2, -4, -5 and -6 are located on the cell surfaces, while TLR-3, -7/8 and -9, as depicted in Fig. 1, are located in the endosomal compartments with their ligand-binding domains facing the lumen of the vesicle (Akira et al, 2006)
TLRs are expressed on different immune subsets, especially monocytes, dendritic cells (DCs) and macrophages
Summary
Recent molecular biological studies have clarified the function of Toll-like receptors (TLRs) in microbial infection. Cationic liposomes showed aggregation upon mixing with DNA in presence of serum and the optimal transfection activity could be obtained without serum. This article aims to develop a stable, efficient, and nontoxic cationic nanoemulsion suitable forTLR ligand oligonucleotide (ssRNA) delivery (Fig. 2).The nanoemulsion approach is based on squalene which has been manufactured at large scale and has been used in a commercially approved product as an oil phase. Among many non-ionic surfactants, the inclusionof Tween 80 and the Brij series which have PEG moieties increased the stability of DOTAP emulsions. They helped to maintain structure and transfection activities during the process of complex formation with DNA under high salt conditions such as PBS (Tae et al, 2002). Factorial design was used to investigate the influence of of tween 80 and poloxamer 188 on particle size, ssRNA binding %, INF α induction
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