Cationic amphiphiles of cholesterol

Abstract

A stable aqueous dispersion which comprises a cationic lipid which is a molecule which comprises a cholesterol-derived lipophilic group, a linker bond which is hydrolyzable by cellular enzymes and relatively resistant to base-catalyzed hydrolysis, a spacer arm and a cationic amino group, and an appropriate co-lipid. The invention also includes the cationic lipids and mammalian plasmid DNA or other cells in admixture with the aqueous dispersion.

We claim:  
     
         1 . A stable aqueous dispersion of mixed lipids which dispersion comprises a cationic lipid of a structure which comprises a lipophilic group derived from cholesterol, a linker bond selected from the group consisting of carboxy amide and carbamoyl, a spacer arm having from 1 to 20 carbon atoms in a branched or unbranched linear alkyl chain, and a cationic amino group selected from the group consisting of primary, secondary, tertiary and quaternary amino groups, and a co-lipid which is a neutral phospholipid.  
     
     
         2 . The dispersion of  claim 1  wherein the co-lipid is selected from the group consisting of phosphatidylcholine and phosphatidylethanolamine.  
     
     
         3 . The dispersion of  claim 2  wherein the phosphatidylethanolamine is dioleoylphosphatidylethanolamine.  
     
     
         4 . The dispersion of  claim 1  wherein the cationic lipid is selected from the group consisting of cholesteryl-3β-carboxamidoethylenetrimethylammonium iodide, cholesteryl-3β-carboxyamidoethylenamine, cholesteryl-3β-oxysuccinamidoethylenetrimethylammonium iodide, 3β[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol, and 3β-[N-(polyethyleneimine)-carbamoyl]cholesterol.  
     
     
         5 . The dispersion of  claim 4  wherein the cationic lipid is 3β[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol.  
     
     
         6 . The dispersion of  claim 1  wherein the cationic lipid is 3β[N′,N′-dimethyl aminomethane)-carbamoyl]cholesterol Gi and the co-lipid is dioleoylphosphatidylethanolamine.  
     
     
         7 . The dispersion of  claim 1  which is in distilled water, normal saline or buffered saline.  
     
     
         8 . The dispersion of  claim 1  which contains from 20% to 50% of the cationic lipid.  
     
     
         9 . The dispersion of  claim 1  wherein the particles in the aqueous dispersion have an average diameter of-about 150 nm.  
     
     
         10 . A cationic lipid of a structure which comprises a lipophilic group derived from cholesterol, a linker bond selected from the group consisting of carboxy amide and carbamoyl, a spacer arm having from 1 to 20 carbon atoms in a branched or unbranched linear alkyl chain, and a cationic amino group selected from the group consisting of primary, secondary, tertiary and quaternary amino groups.  
     
     
         11 . The cationic lipid of  claim 10  which is selected from the group consisting of cholesteryl-3β-carboxamidoethylenetrimethylamionium iodide, cholesteryl-3β-carboxyamidoethylenamine, cholesteryl-3β-oxysuccinamidoethylenetrimethylammonium iodide, 3β[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol, and 3β-[N-(polyethyleneimine)-carbamoyl]cholesterol.  
     
     
         12 . The cationic lipid of  claim 11  which is 3β[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol.  
     
     
         13 . The mixture of the dispersion of  claim 1  with mammalian plasmid DNA.  
     
     
         14 . The mixture of  claim 13  wherein the cationic lipid is selected from the group consisting of cholesteryl-3β-carboxamidoethylenetrimethylammonium iodide, cholesteryl-3β-carboxyamidoethylenamine, cholesteryl-3β-oxysuccinamidoethylenetrimethylammonium iodide, 3β[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol, and 3β-[N-(polyethyleneimine)-carbamoyl]cholesterol.  
     
     
         15 . The mixture of  claim 14  where the cationic lipid is 3β[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol.