Investigating bolalipids as solubilizing agents for poorly soluble drugs: Effects of alkyl chain length on solubilization and cytotoxicity

Synthetic single-chain bolalipids with symmetrical headgroups have shown potential in various pharmaceutical applications, such as the stabilization of liposome bilayers. Despite their amphiphilic character, synthetic bolalipids have not yet been investigated for their suitability as solubilizing agents for poorly soluble drug compounds. In this study, three synthetic single-chain bolalipids with increasing alkyl chain lengths (C22, C24 and C26) were investigated. All three bolalipids were able to achieve an increased solubility of the model drug, mefenamic acid, by approximately 180% in a pH 7.4 buffer compared to only a 102–105% increase achieved by sodium dodecyl sulfate (SDS) or the non-ionic surfactant pegylated hydroxystearate (PEG-HS). Subsequently, interfacial activity of bolalipids and their ability to destabilize liposomal bilayers were investigated. The C22 bolalipid exhibited a consistently lower interfacial activity, which was consistent with its significantly lower cytotoxicity in the macrophage-like cell line, J774. A1, compared to C24 and C26 counterparts. The mean IC50 values of the bolalipids tested (0.035–0.093 mM) were approximately 4–100-fold lower than that of SDS (0.401 mM) or PEG-HS (0.922 mM), with the mechanism of toxicity linked to increased cell membrane permeability, as is expected for surfactants. In summary, evidence from this study shows that decreasing the length of the bolalipid alkyl linker from C26 to C22 resulted in a significantly decreased cytotoxicity with no loss in drug solubilization efficiency.