Synthetic Lipid Switches for Controlling Liposome Assembly and Release

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Non-Technical SummaryLiposomes represent promising molecular carriers for enhancing the delivery of therapeutic agents due to their ability to encapsulate a wide range of cargo and deliver these contents to cells in a manner that limits side effects. While great advancements have been made to improve delivery properties using liposomes, several challenges remain. In particular, the ability to control the location and time of the release of encapsulated contents has been a longstanding obstacle. In this project, a novel paradigm for controlled release from liposomes is being pursued by which the discharge of cargo is caused by specific biological molecules that are overexpressed in and around diseased cells. Toward this end, designer liposomes composed of synthetic lipids will be developed that undergo changes in assembly properties in the presence of biological species to cause the release of contents. This project will result in fundamental scientific progress by advancing the ability to manipulate the assembly properties of liposomes and to program changes in these properties that occur in response to different chemical and biological conditions. This work will also advance national health as it will culminate in new technology aimed at improving the therapeutic properties of liposomes.Technical SummaryLiposomes exhibit many favorable attributes as they are biocompatible nanocarriers that can encapsulate both hydrophobic and hydrophilic molecular cargo. As such, there has been significant interest in developing designer liposomes by which their self-assembly properties can be controlled. Of particular interest is the ability to trigger the release of encapsulated contents when in the presence of different stimuli. In this project, novel strategies are proposed for triggering release from liposomes driven by binding interactions with chemical species. Toward this end, switchable lipids will be developed that are designed to undergo conformational changes that destabilize membrane properties and trigger content release upon the formation of binding interactions with target molecules. This research will investigate how the design of synthetic lipid analogs can be used to modulate the supramolecular properties of liposomes. In particular, switchable lipid analogs will be developed that contain molecular recognition groups embedded within their structures for the binding of target molecules. These lipids are designed such that they will initially form stable membrane bilayers. However, upon the formation of host-guest binding interactions with target molecules, these lipids are envisaged to undergo conformational changes that destabilize the liposome membrane, thereby altering lipid packing and self-assembly properties, and triggering the release of contents. The research performed during this project will entail comprehensive efforts for the design, synthesis and assessment of these switchable lipids to evaluate and optimize controlled release properties. Initial studies will be focused on understanding the fundamental release properties of liposomes containing these lipids. Subsequently, the ability of these designer liposomes to infiltrate cells and deliver encapsulated cargo with different properties will be evaluated. In this way, the proposed studies provide innovative approaches for modulating the self-assembly properties of lipid-based nanomaterials.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.