Calcium‐Responsive Liposomes via a Synthetic Lipid Switch

Abstract

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.

Lipid Switches: Stimuli‐Responsive Liposomes through Conformational Isomerism Driven by Molecular Recognition

“…Our group is interested in lipid switches for liposome release, and our initial report described calcium-responsive liposomes. [23] This trigger was selected since calcium is ak ey regulator of biological signaling processes that are aberrant in disease. In particular,c ells infected with malaria plasmodia undergo dramatici ncreases in calcium concentrations.…”

Exploration of trans‐2‐(azaarylsulfanyl)‐cyclohexanols as potential pH‐triggered conformational switches

“…Conformational or mechanical molecular switches are molecular systems able to perform a directed change in the relative orientation of their parts under external stimulus (light, radiation, electric field, metal complex formation, pH change, etc). They play a central role in a design of controllable compounds, molecular machinery, and intelligent materials with a variety of possible applications including drug release, new sensor techniques, or information storage and transmission . The cyclohexane‐based molecular systems provide an efficient prototype for such switches .…”

Easy access to a carbohydrate-based template for stimuli-responsive surfactants

“…This challenge has led to the development of stimuli-responsive surfactants: amphiphilic molecules that can alter their properties upon an external stimulus [6]. The intelligent surfactants are not passive but designed to undergo a molecular change when it is triggered with either a change in the pH value [7,8], upon light irradiation [9] or in the presence of metal ions [10,11]. Common for all of the systems is that the hydrophilic head group can undergo a conformational change upon an external stimulus.…”