Zinc Triggered Release of Encapsulated Cargo from Liposomes via a Synthetic Lipid Switch.

Liposomes are effective nanocarriers due to their ability to encapsulate and deliver a wide variety of therapeutics. However, therapeutic potential would be improved by enhanced control over the release of drug cargo. Zinc ions provide exciting new targets for stimuli-responsive lipid design due to their overly abundant concentrations associated with diseased cells. Herein, we report zinc-triggered release of liposomal contents exploiting synthetic lipid switches designed to undergo conformational changes in the presence of this ion. Initially, Nile red leakage assays were conducted that validated successful dose-dependent triggering of release using zinc-responsive lipids (ZRLs). In addition, dynamic light scattering and confocal microscopy experiments showed that zinc treatment led to morphological changes in lipid nanoparticles only when ZRLs were present in formulations. Next, zinc-binding experiments conducted in a solution (NMR, MS) or membrane (zeta potential) context confirmed ZRL-Zn complexation. Finally, polar cargo release from liposomes was achieved. The results from these wide-ranging experiments using four different compounds indicated that zinc-responsive properties varied based on ZRL structure, providing insights into the structural requirements for activity. This work has established zinc-responsive liposomal platforms toward the development of clinical triggered release formulations.

Calcium-Responsive Liposomes via a Synthetic Lipid Switch.

Liposomal drug delivery would benefit from enhanced control over content release. Here, we report a novel avenue for triggering release driven by chemical composition using liposomes sensitized to calcium-a target chosen due to its key roles in biology and disease. To demonstrate this principle, we synthesized calcium-responsive lipid switch 1, designed to undergo conformational changes upon calcium binding. The conformational change perturbs membrane integrity, thereby promoting cargo release. This was shown through fluorescence-based release assays via dose-dependent response depending on the percentage of 1 in liposomes, with minimal background leakage in controls. DLS experiments indicated dramatic changes in particle size upon treatment of liposomes containing 1 with calcium. In a comparison of ten naturally occurring metal cations, calcium provided the greatest release. Finally, STEM images showed significant changes in liposome morphology upon treatment of liposomes containing 1 with calcium. These results showcase lipid switches driven by molecular recognition principles as an exciting avenue for controlling membrane properties.