Photo-Enhanced Aqueous Solubilization of Azobenzene-Incorporated Lipids

Lipids, including fatty acids and phospholipids, play crucial roles in biological systems and are widely utilized in pharmaceutical and biomedical applications. However, their inherent hydrophobicity poses significant challenges for formulation and administration. In this study, we aimed to enhance the aqueous solubility of lipidic compounds by leveraging light-responsive molecular design. We synthesized azo-lipids by incorporating azobenzene units into a fatty acid and phosphatidylcholine, hypothesizing that light-induced trans-cis isomerization would improve solubility. The synthesized compounds exhibited reversible photoisomerization upon alternating UV (365 nm) and visible light irradiation, as confirmed by UV-vis spectroscopy and reverse-phase HPLC. The solubilization of these azo-lipids was quantified under UV-unirradiated and irradiated conditions. Azobenzene-incorporated phosphatidylcholine 2 exhibited a drastic increase in solubilization from 2.030 to 1008 µM (496-fold) after UV irradiation. This significant improvement was attributed to efficient photoisomerization and molecular bending in the cis, cis conformation, reducing intermolecular interactions. Our findings suggest that this on-demand aqueous solubilization strategy offers a novel approach for improving the handling, storage, and potential therapeutic administration of lipid-based compounds.