Trialkyl cationic lipids and methods of use thereof

Abstract

The present invention provides compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel, trialkyl, cationic lipids and nucleic acid-lipid particles that provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo. The compositions of the present invention are highly potent, thereby allowing effective knock-down of a specific target protein at relatively low doses.

1 . A lipid having a structural Formula (I):
   X-A-Y—Z;   (I)
   
       or salts thereof, wherein:
 X is alkylamino; 
 A is C 1  to C 6  optionally substituted alkyl, wherein said C 1  to C 6  optionally substituted alkyl can be saturated or unsaturated, and wherein A may or may not be present; 
 Y is selected from the group consisting of ketal, ester, optionally substituted carbamate, ether, and optionally substituted amide; and 
 Z is a hydrophobic moiety consisting of three alkyl chains wherein each of the alkyl chains has a length of from C 8  to C 11 , wherein each of the three alkyl chains can independently be saturated or unsaturated, and wherein each of the three alkyl chains is optionally substituted. 
 
     
     
         2 . The lipid of  claim 1 , wherein each of the alkyl chains has a length of from C 9  to C 10 . 
     
     
         3 . The lipid of  claim 1 , wherein at least one of the alkyl chains has a double bond. 
     
     
         4 . The lipid of  claim 1 , wherein at least one of the alkyl chains has a cis double bond. 
     
     
         5 . (canceled) 
     
     
         6 . The lipid of  claim 1 , wherein X is selected from the group consisting of dimethylamino, diethylamino and ethylmethylamino. 
     
     
         7 . (canceled) 
     
     
         8 . The lipid of  claim 1 , wherein Y is an ester or ketal. 
     
     
         9 . The lipid of  claim 1 , wherein Y is an optionally substituted carbamate. 
     
     
         10 . The lipid of  claim 1 , wherein Y is an ether. 
     
     
         11 . The lipid of  claim 1 , wherein Y is an optionally substituted amide. 
     
     
         12 . The lipid of  claim 1 , wherein Z has the formula: 
       
         
           
           
               
               
           
         
         wherein, R 1 , R 2 , and R 3  are each independently selected from the group consisting of C 8  to C 11  alkyl, wherein each of R 1 , R 2 , and R 3  can independently be saturated or unsaturated, and wherein each of R 1 , R 2 , and R 3  is optionally substituted. 
       
     
     
         13 . The lipid of  claim 1 , wherein the lipid is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . A lipid particle comprising a lipid of  claim 1 . 
     
     
         15 . The lipid particle of  claim 14 , wherein the particle further comprises a non-cationic lipid. 
     
     
         16 - 18 . (canceled) 
     
     
         19 . The lipid particle of  claim 14 , wherein the particle further comprises a conjugated lipid that inhibits aggregation of particles. 
     
     
         20 - 21 . (canceled) 
     
     
         22 . The lipid particle of  claim 14 , wherein the particle further comprises a therapeutic agent. 
     
     
         23 . The lipid particle of  claim 22 , wherein the therapeutic agent is siRNA or mRNA. 
     
     
         24 - 30 . (canceled) 
     
     
         31 . A pharmaceutical composition comprising a lipid particle of  claim 14  and a pharmaceutically acceptable carrier. 
     
     
         32 . A method for introducing a therapeutic agent into a cell, the method comprising:
 contacting the cell with a lipid particle of  claim 14 .   
     
     
         33 . (canceled) 
     
     
         34 . A method for the in vivo delivery of a therapeutic agent, the method comprising:
 administering to a mammal a lipid particle of  claim 14 .   
     
     
         35 - 36 . (canceled) 
     
     
         37 . A method for treating a disease or disorder in a mammal in need thereof, the method comprising:
 administering to the mammal a therapeutically effective amount of a lipid particle of  claim 14 .   
     
     
         38 - 39 . (canceled)