Thioether Choline Phosphate Liposomes for Reactive Oxygen Species-Trigger Drug Release

Though the exciting advancements in liposome formulations composed of phosphorylcholine (PC) lipid bilayers for antitumor therapy, their clinical efficacy is hindered by the challenge of triggering cargo release. Zwitterionic choline phosphate (CP) liposomes, with reversed charge orientation, possessed improved bioorthogonality and drug accumulations than that of phosphorylcholine. Here, we report the synthesis of five CP-typed lipids with different carbon chain lengths and ROS-responsive thioether moieties. These lipids self-assemble into CP liposomes capable of efficiently encapsulating doxorubicin (DOX) at a high drug loading capacity (approximately 7.6 wt % for DOX/12S-CPs). Compared to PC liposomes, our findings demonstrate that CP liposomes exhibit excellent stability under physiological conditions while rapidly triggering DOX release in a simulated high oxidation tumor environment. Furthermore, the experimental results in vitro and in vivo reveal the preferential localization of CP liposomes at the tumor site and their enhanced internalization by tumor cells compared to PC liposomes. Consequently, DOX/S-CPs exhibit superior tumor inhibition effects when compared to free DOX or DOX/HSPCs. In summary, our study highlights the potential of thioether-modified CP liposomes as highly efficient formulations for controlled drug release in cancer therapy.