Novel cyclic cationic lipids and methods of use

Abstract

The present invention provides compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel 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. In addition, the compositions and methods of the present invention are less toxic and provide a greater therapeutic index compared to compositions and methods previously known in the art.

1 . A cationic lipid of Formula III having the following structure: 
       
         
           
           
               
               
           
         
         or salts thereof, wherein:
 R 1  and R 2  are either the same or different and are independently hydrogen (H) or an optionally substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, or R 1  and R 2  may join to form an optionally substituted heterocyclic ring; 
 R 3  is either absent or is hydrogen (H) or a C 1 -C 6  alkyl to provide a quaternary amine; 
 R 4  and R 5  are either the same or different and are independently an optionally substituted C 10 -C 24  alkyl, C 10 -C 24  alkenyl, C 10 -C 24  alkynyl, or C 10 -C 24  acyl, wherein at least one of R 4  and R 5  comprises at least one optionally substituted cyclic alkyl group; 
 X is O, S, N(R 6 ), C(O), C(O)O, OC(O), C(O)N(R 6 ), N(R 6 )C(O), OC(O)N(R 6 ), N(R 6 )C(O)O, C(O)S, C(S)O, S(O), S(O)(O), C(S), or an optionally substituted heterocyclic ring, wherein R 6  is hydrogen (H) or an optionally substituted C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 2 -C 10  alkynyl; and 
 Y is either absent or is an optionally substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
 
       
     
     
         2 - 16 . (canceled) 
     
     
         17 . A cationic lipid of Formula I having the following structure: 
       
         
           
           
               
               
           
         
         or salts thereof, wherein:
 R 1  and R 2  are either the same or different and are independently hydrogen (H) or an optionally substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, or R 1  and R 2  may join to form an optionally substituted heterocyclic ring; 
 R 3  is either absent or is hydrogen (H) or a C 1 -C 6  alkyl to provide a quaternary amine; 
 R 4  and R 5  are either the same or different and are independently an optionally substituted C 10 -C 24  alkyl, C 10 -C 24  alkenyl, C 10 -C 24  alkynyl, or C 10 -C 24  acyl, wherein at least one of R 4  and R 5  comprises at least one optionally substituted cyclic alkyl group; 
 X and Y are either the same or different and are independently O, S, N(R 6 ), C(O), C(O)O, OC(O), C(O)N(R 6 ), N(R 6 )C(O), OC(O)N(R 6 ), N(R 6 )C(O)O, C(O)S, C(S)O, S(O), S(O)(O), C(S), or an optionally substituted heterocyclic ring, wherein R 6  is hydrogen (H) or an optionally substituted C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 2 -C 10  alkynyl; and 
 Z is either absent or is an optionally substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
 
       
     
     
         18 - 33 . (canceled) 
     
     
         34 . A cationic lipid of Formula II having the following structure: 
       
         
           
           
               
               
           
         
         or salts thereof, wherein:
 R 1  and R 2  are either the same or different and are independently an optionally substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, or R 1  and R 2  may join to form an optionally substituted heterocyclic ring; 
 R 3  is either absent or is hydrogen (H) or a C 1 -C 6  alkyl to provide a quaternary amine; 
 R 4  and R 5  are either the same or different and are independently an optionally substituted C 10 -C 24  alkyl, C 10 -C 24  alkenyl, C 10 -C 24  alkynyl, or C 10 -C 24  acyl, wherein at least one of R 4  and R 5  comprises at least one optionally substituted cyclic alkyl group; 
 m, n, and p are either the same or different and are independently either 0, 1, or 2, with the proviso that m, n, and p are not simultaneously 0; 
 X and Y are either the same or different and are independently O, S, N(R 6 ), C(O), C(O)O, OC(O), C(O)N(R 6 ), N(R 6 )C(O), OC(O)N(R 6 ), N(R 6 )C(O)O, C(O)S, C(S)O, S(O), S(O)(O), C(S), wherein R 6  is hydrogen (H) or an optionally substituted C 1 -C 10  alkyl, C 2 -C 10  alkenyl, or C 2 -C 10  alkynyl; and 
 Z is either absent or is an optionally substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
 
       
     
     
         35 - 49 . (canceled) 
     
     
         50 . A lipid particle comprising a cationic lipid of  claim 1 . 
     
     
         51 - 57 . (canceled) 
     
     
         58 . The lipid particle of  claim 50 , wherein the particle further comprises a therapeutic agent. 
     
     
         59 - 66 . (canceled) 
     
     
         67 . A pharmaceutical composition comprising a lipid particle of  claim 50 , and a pharmaceutically acceptable carrier. 
     
     
         68 . A method for introducing a therapeutic agent into a cell, the method comprising:
 contacting the cell with a lipid particle of  claim 58 .   
     
     
         69 . (canceled) 
     
     
         70 . A method for the in vivo delivery of a therapeutic agent, the method comprising:
 administering to a mammal a lipid particle of  claim 58 .   
     
     
         71 - 72 . (canceled) 
     
     
         73 . 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 58 .   
     
     
         74 - 75 . (canceled) 
     
     
         76 . A lipid particle comprising a cationic lipid of  claim 17 . 
     
     
         77 . The lipid particle of  claim 76 , wherein the particle further comprises a therapeutic agent. 
     
     
         78 . A pharmaceutical composition comprising a lipid particle of  claim 76 , and a pharmaceutically acceptable carrier. 
     
     
         79 . A method for introducing a therapeutic agent into a cell, the method comprising contacting the cell with a lipid particle of  claim 77 . 
     
     
         80 . A method for the in vivo delivery of a therapeutic agent, the method comprising administering to a mammal a lipid particle of  claim 77 . 
     
     
         81 . 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 77 . 
     
     
         82 . A lipid particle comprising a cationic lipid of  claim 34 . 
     
     
         83 . The lipid particle of  claim 82 , wherein the particle further comprises a therapeutic agent. 
     
     
         84 . A pharmaceutical composition comprising a lipid particle of  claim 82 , and a pharmaceutically acceptable carrier. 
     
     
         85 . A method for introducing a therapeutic agent into a cell, the method comprising contacting the cell with a lipid particle of  claim 83 . 
     
     
         86 . A method for the in vivo delivery of a therapeutic agent, the method comprising administering to a mammal a lipid particle of  claim 83 . 
     
     
         87 . 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 83 .