Enhancing Triggered Release of Polar Cargo from ROS-Responsive Liposomes

Liposomes are promising nanocarriers because of their ability to encapsulate and deliver therapeutic cargo with wide-ranging physicochemical properties. However, liposome delivery could be improved by enhancing triggered release of cargo and particularly doing so in a manner that is selective toward diseased cells. Reactive oxygen species (ROS) provide exciting targets to explore as triggers for the development of stimuli-responsive liposomes due to substantial differences in ROS abundance between diseased versus healthy cells. While our group previously reported ROS-responsive liposomes using a synthetic lipid switch, polar cargo release was slow and limited using our original platform. Herein, we report an improved ROS-responsive lipid switch (2) containing an ROS-responsive boronate ester headgroup attached using an advanced self-immolative linker (SIL) bearing an electron-donating methoxy substituent to a lipid scaffold. Both hydrophobic and hydrophilic fluorescence-based dye release assays showed that liposome formulations including lipid switch 2 were initially stable but successfully released cargo when treated with hydrogen peroxide. Furthermore, dynamic light scattering (DLS) analysis was used to characterize changes in the size and dispersity of liposomes before and after treatment. Ultimately, lipid 2 enabled dramatically faster polar dye cargo release at a lower percentage of incorporation compared to our initial lipid switch. Such improvements increase the prospects of ROS-responsive liposomes for delivery applications.