Lipid nanoparticles (LNPs) can be used to package and deliver molecular payloads to cells, including small molecules and nucleic acids. The effectiveness of LNP formation and transfection efficiency is dependent on a variety of factors that stem from the lipid structures. For example, lipids containing cationic head groups interact with the negatively charged phosphate backbone of DNA and RNA, leading to LNPs containing both of the desired components. Factors such as LNP size, charge, transition temperature, and pKa are dependent on the structures of the hydrophilic head groups and hydrophobic tails of the constituent lipids. With each new class of lipids, a new structure-function relationship must be determined. We are interested in building triazine-based lipids using cyanuric chloride as the starting material; the ability to substitute each of its three chlorine atoms one at a time makes it a powerful template upon which to create a library of lipids. A few studies have shown that triazine-based lipids can transfect cells with nucleic acids, but none of the lipids have contained esters as part of their hydrophobic tails. The integration of hydrolyzable esters into synthetic lipids typically decreases the cytotoxicity of the corresponding LNPs. We have developed two similar classes of triazine-based lipids where late-stage functionalization with readily available fatty acids can lead to a diverse collection of hydrophobic tails. Details about the syntheses will be presented.

Toward the synthesis of a library of triazine-based, biodegradable, cationic lipids

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