Production of Designer Lipids Using “Click” Chemistries

Authors: 
Konetski, D., University of Colorado
Bowman, C. N., University of Colorado
Wang, C., University of Colorado
Worrell, B., University of Colorado
Gong, T., University of Colorado
Baranek, A., University of Colorado
Xi, W., University of California, Los Angeles
Liposomes have proven to be excellent drug delivery vehicles and as such have generated great interest in current research. However, in order for their utility to be realized, liposomes frequently require chemical modifications to the phospholipid structure. To this end, we demonstrate a simplified method for the synthesis of designer lipids through the use of a functionalized lysolipid to allow for integration of selected lipid tails. Using a variety of functionalities, we have established “click” based phospholipid formation chemistries such as Copper-catalyzed Azide-Alkyne Cycloaddition (CuAAC), thiol-Michael, and thiol-acrylate initiated upon the introduction of a range of catalysts including reducing agents, base, or light. This range in formation chemistries and initiation conditions allows for the incorporation of useful functional groups into the phospholipids with the high yield and mild conditions characteristic of “click” reactions without the new functionalities becoming compromised. Following formation, we have demonstrated this orthogonality through the inclusion of crosslinkable groups for enhanced stability. In addition, our thiol functionalized lysolipids are capable of formation via transthioesterification in a catalyst free environment, allowing for future lipid remodeling. Together, these new chemistries will open the door for simplified exploration of improved liposomal drug carriers without the need for labor-intensive chemical synthesis.
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