Using molecular dynamics simulations, this study investigates the effects of UV-induced trans-to-cis photoisomerization of azobenzene-derivatized phosphatidylcholine (azoPC) lipids on lipid membranes. Doxorubicin intercalation is enhanced by photoisomerization, which also increases lipid diffusivity and decreases membrane packing density. The design of lipid-based systems for targeted drug delivery and biological applications is advanced by these discoveries.

Abstract

Photoswitchable lipids, in particular azobenzene-derivatized phosphatidylcholine (azoPC) lipids, offer a unique mechanism for reversible modification of membrane properties upon exposure to ultraviolet (UV) radiation. Using all-atom molecular dynamics simulations, we investigate how UV irradiation-induced trans-to-cis photoisomerization (TCPI) of AzoPC lipid affects the structure and dynamics of a lipid membrane composed of dipalmitoylphosphatidylcholine (DPPC) and cholesterol with a composition similar to that of DOXIL®. Structural and dynamic analyses of two states of the membrane, ‘dark’ state (containing cis-azoPC lipid) and ‘bright’ state (containing 85% cis-azoPC and 15% trans-azoPC lipids) reveal that TCPI reduces membrane packing density and increases lipid diffusivity. We have demonstrated enhanced intercalation of doxorubicin (DOX), an anticancer drug, in the ‘bright’ state of the membrane compared to that in the ‘dark’ state. This study – which elucidates the complex interplay between lipid composition, photoswitching and lipid-drug interactions – contributes to the design of lipid-based systems for targeted drug delivery and biomedical applications.