Liposome Targeting and Triggered Release Driven by Reactive Oxygen Species

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Project Summary Liposomes are supramolecular lipid assemblies that are highly effective at entrapping, delivering, and enhancing the pharmacokinetic properties of a variety of drug cargo with poor performance in the absence of a nanocarrier. However, achieving both liposome targeting and spatiotemporal control over release with high diseased-cell specificity remains a significant challenge that must be overcome to optimize drug potency and minimize off-target effects. Our approach to surmount these issues entails the development of “smart” liposomes that respond to overly abundant reactive oxygen species (ROS) to localize drug delivery to diseased cells. To this end, we have pioneered the development of ROS-responsive liposomes designed to selectively trigger therapeutic cargo release in the presence of upregulated ROS. These liposomes harness synthetic lipid switches in which oxidative cleavage of caging groups leads to lipid decomposition that destabilizes the liposome membrane to trigger content release. Herein, we propose to develop next-generation ROS-directed liposomes that will mark a significant technological advance toward clinical viability. The proposed work will achieve this goal by developing liposomes that include both activatable cell-targeting groups and lipid switches that exhibit ROS-responsive properties. First, we will maximize payload release through the development of advanced immolating lipid structures that facilitate complete liposome breakdown upon oxidation by ROS (Aim 1). These structures will exploit programmed intramolecular reactions that degrade ROS-responsive lipid switches into non-liposome-forming small molecules. Second, we will develop a series of caged cell-penetrating peptide- (CPP-)lipid conjugates that will activate cell targeting and entry only following ROS oxidation (Aim 2). These compounds will exploit the exceptional cell delivery properties of CPPs while solving their primary drawback of poor selectivity. Finally, ROS-responsive lipid switches and activatable targeting groups, both separately and in combination, will undergo comprehensive liposome release and cellular delivery evaluations to identify optimal structures and formulations that maximize therapeutic delivery and diseased-cell specificity (Aim 3). These studies are expected to culminate in new clinically effective liposomal technology as “smart” carriers exhibiting diseased cell specificity and optimized release properties.