Thioether Phosphatidylcholine Liposomes: A Novel ROS-Responsive Platform for Drug Delivery

Liposomes are the most valuable nanocarriers in clinical use because of their biocompatibility, biodegradation, and effective encapsulation of hydrophilic or hydrophobic drugs. However, their applications are limited by the structure and functions of the most common phospholipids used as the main component of the liposomes. In this work, novel series of thioether phosphatidylcholines (S-PCs) and S-PC-based liposomes (S-LPs) were developed for reactive oxygen species (ROS)-responsive drug release. First of all, S-PCs with different chain lengths were synthesized by a combination of click reaction and heterogeneous esterification. Differential scanning calorimetry studies indicated that S-PCs had different phase transition temperatures depending on their chain lengths. Their critical aggregation concentrations were measured by the fluorescence probe technique indicating the self-assembly ability. After that, S-PC-based stealth liposomes (S-LPs) containing DSPE-PEG₂₀₀₀ and cholesterol were prepared via a classic thin-film method. Doxorubicin (DOX) as a model drug was loaded in the stealth liposomes (DOX/S-LPs) by using the ammonium sulfate gradient method with high encapsulation efficiency. DOX/S-LPs were characterized by dynamic light scattering (DLS), transmission electron microscope (TEM), and cryogenic TEM, confirming their spherical structure with the bilayer thickness of about 4 nm. The ROS sensitivity of S-PCs and S-LPs was carefully evaluated in the presence of H₂O₂ by means of mass spectrometry, DLS, TEM, and ultraviolet spectroscopy and release study. The results indicated the significant structural change of S-LPs after H₂O₂ treatment, which demonstrated that S-LPs possessed an efficient ROS-triggered disintegration because of thioether oxidation of S-PCs. Finally, in vitro and in vivo anticancer efficiency assays revealed the improved drug potency of DOX/S-LPs, which can be attributed to ROS-triggered destruction of S-LPs after the uptake by tumor cells followed by rapid release of DOX. All together, as alternatives of traditional phosphatidylcholines, S-PC-based stealth liposomes are promising ROS-responsive carriers for the controlled delivery of drugs.