Cationic peg-lipids and methods of use

Abstract

The present invention provides cationic-polymer-lipid conjugates (CPLs) such as distal cationic-poly(ethylene glycol)-lipid conjugates which can be incorporated into conventional and stealth liposomes or other lipid-based formulation for enhancing cellular uptake. The CPLs of the present invention comprise a lipid moiety; a hydrophilic polymer; and a polycationic moiety. Method of increasing intracellular delivery of nucleic acids are also provided.

1 . A compound having the general structure of Formula I:  
       A-W-Y  I  
       wherein: 
 A is a lipid moiety;  
 W is a hydrophilic polymer; and  
 Y is a polycationic moiety.  
 
     
     
         2 . The compound according to  claim 1 , wherein said hydrophilic polymer is non-immunogenic or weakly immunogenic.  
     
     
         3 . The compound according to  claim 1 , wherein W is a polymer selected from the group consisting of PEG, polyamide, polylactic acid, polyglycolic acid, polylactic acid/polyglycolic acid copolymers and combinations thereof, said polymer having a molecular weight of about 250 to about 7000 daltons.  
     
     
         4 . The compound according to  claim 1 , wherein Y comprises a least one basic amino acid or derivative thereof.  
     
     
         5 . The compound according to  claim 1 , wherein Y has at least 4 positive charges at a selected pH.  
     
     
         6 . The compound according to  claim 1 , wherein Y has at least 8 positive charges at a selected pH.  
     
     
         7 . The compound according to  claim 4 , wherein Y comprises an amino acid selected from the group consisting of lysine, arginine, asparagine, glutamine, derivatives thereof and combinations thereof.  
     
     
         8 . The compound according to  claim 2 , wherein 
 A is a member selected from the group consisting of a diacylglycerolyl moiety, a dialkylglycerolyl moiety, a N—N-dialkylamino moiety, a 1,2-diacyloxy-3-aminopropane moiety and a 1,2,dialkyl-3-aminopropane moiey.    
     
     
         9 . The compound according to  claim 3 , wherein W is PEG.  
     
     
         10 . The compound according to  claim 3 , wherein W is a polyamide polymer.  
     
     
         11 . The compound according to  claim 3 , wherein W has a molecular weight of about 250 to about 2000 daltons.  
     
     
         12 . The compound according to  claim 9 , having the general structure of Formula II:  
       
         
           
           
               
               
           
         
       
       wherein 
 X is a member selected from the group consisting of a single bond and a functional group covalently attaching said lipid moiety A to at least one ethylene oxide unit;  
 Z is a member selected from the group consisting of a single bond and a functional group covalently attaching at least one ethylene oxide unit to the polycationic moiety Y; and  
 n is an integer having a value of between about 6 and about 50.  
 
     
     
         13 . The compound according to  claim 12 , wherein X is a member selected from the group consisting of a single bond, phosphatidylethanolamino, phosphatidylethanolamido, phosphoro, phospho, phosphoethanolamino, phosphoethanolamido, carbonyl, carbamate, carboxyl, carbonate, amido, thioamido, oxygen, sulfur and NR, wherein R is a hydrogen or alkyl group.  
     
     
         14 . The compound according to  claim 12 , wherein Z is a member selected from the group consisting of a single bond, phosphatidylethanolamino, phosphatidylethanolamido, phosphoro, phospho, phosphoethanolamino, phosphoethanolamido, carbonyl, carbamate, carboxyl, carbonate, amido, thioamido, oxygen, sulfur and NR, wherein R is a hydrogen or alkyl group.  
     
     
         15 . The compound according to  claim 12 , wherein 
 A is a diacylglycerolyl moiety;    X is phosphoethanolamido;    Z is NR, wherein R is a hydrogen atom; and    Y comprises about 1 to about 10 basic amino acids or derivatives thereof.    
     
     
         16 . The compound according to  claim 15 , where A is a diacylglycerolyl moiety having 2 fatty acyl chains, wherein each acyl chain is independently between 2 and 30 carbons in length and is either saturated or has vary degrees of saturation.  
     
     
         17 . The compound according to  claim 15 , wherein Y comprises an amino acid selected from the group consisting of lysine, arginine, glutamine, derivatives thereof and combinations thereof.  
     
     
         18 . The compound according to  claim 15 , wherein 
 A is a diacylglycerolyl moiety having 2 fatty acyl chains, wherein each acyl chain is a saturated C-18 carbon chain; and    Y is a cationic group comprising 4 lysine residues or derivatives thereof.    
     
     
         19 - 54 . (canceled)