Long chain arginine esters: A new class of cationic detergents for preparation of hydrophobic ion-paired complexes

The ability of stoichiometric amounts (based on charged groups) of ionic de tergents to bind to oppositely charged ionic compounds has been recently re viewed. These hydrophobic ion-paired (HIP) complexes display altered solubi lity properties. Most of the work to date on HIP complexes has focused on b asic drugs and anionic detergents. It would be extremely useful to extend t his approach to acidic compounds, including DNA and RNA. However, most cati onic detergents are relatively toxic. It is hypothesized that detergents co nstructed from naturally occurring or well tolerated components, coupled by labile linkages, will be less toxic and still able to form strong HIP comp lexes. This study describes the synthesis and characterization of long chai n alkyl esters of arginine. This class of cationic detergents, which have n ot been reported previously, are less cytotoxic than alkyltrimethylammonium detergents, possibly making them more acceptable in drug delivery applicat ions. These arginine esters exhibit detergent-like properties. For example, the dodecyl ester of arginine has a critical micelle concentration of 0.07 mM, while being approximately 5-10 fold less toxic than tetradecyltrimethy lammonium bromide. The arginine dodecyl ester forms stable HIP complexes wi th plasmid DNA. The complex is sufficiently stable to allow some modest lev el of transfection with Cos-7 cells in a time- and concentration-dependent fashion. This work demonstrates that arginine-based cationic detergents are effective ion-pairing agents, appear to be less toxic than alkyltrimethyla mmonium compounds, and form stable complexes with DNA.