Synthesis, Properties, and Biomedical Application of Dicationic Gemini Surfactants with Dodecane Spacer and Carbamate Fragments

A synthesis procedure and aggregation properties of a new homologous series of dicationic gemini surfactants with a dodecane spacer and two carbamate fragments (N,N'-dialkyl-N,N' -bis(2-(ethylcarbamoyloxy)ethyl)-N,N'-dimethyldodecan-1,6-diammonium dibromide, n-12-n(Et), where n = 10, 12, 14) were comprehensively described. The critical micelle concentrations of gemini surfactants were obtained using tensiometry, conductometry, spectrophotometry, and fluorimetry. The thermodynamic parameters of adsorption and micellization, i.e., maximum surface excess (Amax), the surface area per surfactant molecule (A(min)), degree of counterion binding (beta, and Gibbs free energy of micellization (Delta G(mic)), were calculated. Functional activity of the surfactants, including the solubilizing capacity toward Orange OT and indomethacin, incorporation into the lipid bilayer, minimum inhibitory concentration, and minimum bactericidal and fungicidal concentrations, was determined. Synthesized gemini surfactants were further used for the modification of liposomes dual-loaded with alpha-tocopherol and donepezil hydrochloride for intranasal treatment of Alzheimer's disease. The obtained liposomes have high stability (more than 5 months), a significant positive charge (approximately + 40 mV), and a high degree of encapsulation efficiency toward rhodamine B, alpha-tocopherol, and donepezil hydrochloride. Korsmeyer-Peppas, Higuchi, and first-order kinetic models were used to process the in vitro release curves of donepezil hydrochloride. Intranasal administration of liposomes loaded with ff-tocopherol and donepezil hydrochloride for 21 days prevented memory impairment and decreased the number of Afi plaques by 37.6%, 40.5%, and 72.6% in the entorhinal cortex, DG, and CA1 areas of the hippocampus of the brain of transgenic mice with Alzheimer's disease model (APP/PS1) compared with untreated animals.

Automated summary

The synthesis procedure and properties of a new series of dicationic gemini surfactants with a dodecane spacer and two carbamate fragments were comprehensively described. The critical micelle concentrations of the surfactants were determined, and their functional activities were evaluated. The synthesized surfactants were used for the modification of liposomes for the treatment of Alzheimer's disease, showing promising results in preventing memory impairment and reducing plaques in a transgenic mouse model.