Molecular Engineering as an Approach To Modulate Gene Delivery Efficiency of Peptide-Modified Gemini Surfactants

Abstract

The unique molecular structure confers the diquaternary ammonium gemini surfactants with enhanced nucleic acid complexation ability, bottom-up design flexibility, and relatively low cytotoxicity. To capitalize on their potential as gene delivery vectors, novel structural modifications should be explored. In this work, 22 novel peptide-modified gemini surfactants with various alkyl tails and peptide spacer modifications were evaluated. This work represents the first report of dendrimer-like gemini surfactants and first evaluation of the impact of incorporating a hydrocarbon linker into the peptide chain. Our aim was to establish a structure activity relationship of the peptide-modified gemini surfactants and to identify the fundamental architectural requirements needed for the ultimate gene delivery systems. In vitro assessment revealed that the highest transfection efficiency and lowest cytotoxicity were associated with the glycyl-lysine modified gemini surfactants having the hexadecyl tail, 16-7N(G-K)-16. In fact, it showed an 8-fold increase in secreted protein with 20% increase in cell viability relative to the first-generation unsubstituted gemini surfactants. Further increase in the size of the attached peptides resulted in a decrease in the transfection efficiency and cell viability. Whereas the incorporation of a hydrocarbon linker into the peptide chain decreased the transfection efficiency of compounds with dipeptides, it increased the transfection efficiency of compounds with larger peptide chains. Such an increase was more prominent with the incorporation of a longer hydrocarbon linker. We conclude that a balance between the hydrophilic and hydrophobic characteristics of the compound is necessary since it results in physicochemical parameters conducive to the gene delivery process.

Peptide-Based Drug Delivery Systems

“…Dendrimer-like Gemini surfactants have critical micelle concentration in the range of 45-107 µM. The authors tried to establish the structure activity relationship of the peptide-modified Gemini surfactants and to determine the fundamental conformational requirements compulsory for the gene delivery systems [144]. According to the in vitro tests, the highest transfection efficacy and minimal cytotoxicity were attributed to the Gly-Lys modified Gemini surfactants possessing the hexadecyl tail, C16-7N(Gly-Lys)-C16.…”

“…The authors reported that an increase in the size of the attached peptides led to a decrease in the transfection effectiveness and cell viability. In contrast, the incorporation of a hydrocarbon linker into the peptide chain reduced the transfection efficacy of substances with dipeptides [144]. A balance between the hydrophilic and hydrophobic characteristics of the compound is necessary since it results in physicochemical parameters conducive to the gene delivery process using intravenous administration.…”

Mass Spectrometric Detection and Characterization of Metabolites of Gemini Surfactants Used as Gene Delivery Vectors

“…These gemini surfactants have been successfully used in vitro and in vivo as nonviral gene delivery agents; 19−21 however, they vary among each other in terms of gene transfer efficiencies and toxicities. 22,23 As our main therapeutic use for gemini surfactants is topical application, particularly for the treatment of localized scleroderma, a connective tissue disease, the epidermal keratinocytes PAM 212 cells were selected for the evaluation of the biological fate of these three gemini surfactants. In fact, we have shown recently in an ex-vivo experiment that gemini surfactants localized mainly in the skin with minimal penetration of skin tissues to enter the compartment representing the circulation.…”

“…The three gemini surfactants belong to different structural families; 16-3-16 is a conventional gemini surfactant with two quaternary amines in the head groups, whereas 16­(Py)-S-2-S-(Py)­16 contains two pyridine moieties in the head groups, and 16-7N­(GK)-16 is a glycyl-lysine di-peptide substituted gemini surfactant (Figure b–d). These gemini surfactants have been successfully used in vitro and in vivo as nonviral gene delivery agents; − however, they vary among each other in terms of gene transfer efficiencies and toxicities. , …”

Trehalose-based Siamese twin amphiphiles with tunable self-assembling, DNA nanocomplexing and gene delivery properties

“…Compound 6, featuring a rigid triazole moiety connecting the disaccharide core and the cationic arms, afforded stable homogeneous nanospheres of 15 nm diameter (TEM) in aqueous media, a typical behavior of ''conical'' surfactants. 12 In the presence of pDNA, morula-like nanoplexes of 120-140 nm diameter were formed, suggesting that interaction of the intact vector nanospheres with the polyphosphate chain drives compaction of the plasmid ( Fig. 3A and B; left panel).…”