Cationic Serine-Based Gemini Surfactant:Monoolein Aggregates as Viable and Efficacious Agents for DNA Complexation and Compaction: A Cytotoxicity and Physicochemical Assessment
2024
Isabel S. Oliveira | Sandra G. Silva | Andreia C. Gomes | M. Elisabete C. D. Real Oliveira | M. Luísa C. do Vale | Eduardo F. Marques
Cationic gemini surfactants have emerged as potential gene delivery agents as they can co-assemble with DNA due to a strong electrostatic association. Commonly, DNA complexation is enhanced by the inclusion of a helper lipid (HL), which also plays a key role in transfection efficiency. The formation of lipoplexes, used as non-viral vectors for transfection, through electrostatic and hydrophobic interactions is affected by various physicochemical parameters, such as cationic surfactant:HL molar ratio, (+/−) charge ratio, and the morphological structure of the lipoplexes. Herein, we investigated the DNA complexation ability of mixtures of serine-based gemini surfactants, (nSer)<sub>2</sub>N5, and monoolein (MO) as a helper lipid. The micelle-forming serine surfactants contain long lipophilic chains (12 to 18 C atoms) and a five CH<sub>2</sub> spacer, both linked to the nitrogen atoms of the serine residues by amine linkages. The (nSer)<sub>2</sub>N5:MO aggregates are non-cytotoxic up to 35–90 µM, depending on surfactant and surfactant/MO mixing ratio, and in general, higher MO content and longer surfactant chain length tend to promote higher cell viability. All systems efficaciously complex DNA, but the (18Ser)<sub>2</sub>N5:MO one clearly stands as the best-performing one. Incorporating MO into the serine surfactant system affects the morphology and size distribution of the formed mixed aggregates. In the low concentration regime, gemini–MO systems aggregate in the form of vesicles, while at high concentrations the formation of a lamellar liquid crystalline phase is observed. This suggests that lipoplexes might share a similar bilayer-based structure.
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