Novel lipids and compositions for the delivery of therapeutics

Abstract

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure (I) wherein R 1 and R 2 are each independently for each occurrence optionally substituted C 10 -C 30 alkyl, optionally substituted C 10 -C 30 alkenyl, optionally substituted C 10 -C 30 alkynyl, optionally substituted C 10 -C 30 acyl, or -linker-ligand; R 3 is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, ω-aminoalkyls, ω-(substituted)aminoalkyls, ω-phosphoalkyls, ω-thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; E is O, S, N(Q), C(O), N(Q)C(O), C(O)N(Q), (Q)N(CO)O, O(CO)N(Q), S(O), NS(O)2N(Q), S(O)2, N(Q)S(O)2, SS, O═N, aryl, heteroaryl, cyclic or heterocycle; and, Q is H, alkyl, ω-aminoalkyl, ω-(substituted)aminoalky, ω-phosphoalkyl or ω-thiophosphoalkyl.

1 . A lipid having the structure 
       
         
           
           
               
               
           
         
         or a salt or isomer thereof, 
         wherein: 
         R 1  and R 2  are each independently for each occurrence optionally substituted C 10 -C 30  alkyl, optionally substituted C 10 -C 30  alkenyl, optionally substituted C 10 -C 30  alkynyl, or optionally substituted C 10 -C 30  acyl; 
         R 3  is H, optionally substituted C 1 -C 10  alkyl, optionally substituted C 2 -C 10  alkenyl, optionally substituted C 2 -C 10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, ω-aminoalkyls, ω-(substituted)aminoalkyls, ω-phosphoalkyls, ω-thiophosphoalkyls, optionally substituted polyethylene glycol, optionally substituted mPEG, heteroaryl, or heterocycle; 
         E is O, S, N(Q), C(O), N(Q)C(O), C(O)N(Q), (Q)N(CO)O, O(CO)N(Q), S(O), NS(O) 2 N(Q), S(O) 2 , N(Q)S(O) 2 , SS, O═N, aryl, heteroaryl, cyclic or heterocycle; and, 
         Q is H, alkyl, ω-aminoalkyl, ω-(substituted)aminoalky, ω-phosphoalkyl or ω-thiophosphoalkyl. 
       
     
     
         2 . A lipid having the structure 
       
         
           
           
               
               
           
         
         or a salt or isomer thereof, 
         wherein, 
         E is O, S, N(Q), C(O), N(Q)C(O), C(O)N(Q), (Q)N(CO)O, O(CO)N(Q), S(O), NS(O) 2 N(Q), S(O) 2 , N(Q)S(O) 2 , SS, O═N, aryl, heteroaryl, cyclic or heterocycle; 
         Q is H, alkyl, ω-aminoalkyl, ω-(substituted)aminoalky, ω-phosphoalkyl or ω-thiophosphoalkyl; 
         R 1  and R 2  and R x  are each independently for each occurrence H, optionally substituted C 1 -C 10  alkyl, optionally substituted C 10 -C 30  alkyl, optionally substituted C 10 -C 30  alkenyl, optionally substituted C 10 -C 30  alkynyl, or optionally substituted C 10 -C 30  acyl, provided that at least one of R 1 , R 2  and R x  is not H; 
         R 3  is H, optionally substituted C 1 -C 10  alkyl, optionally substituted C 2 -C 10  alkenyl, optionally substituted C 2 -C 10  alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, ω-aminoalkyls, ω-(substituted)aminoalkyls, ω-phosphoalkyls, ω-thiophosphoalkyls, optionally substituted polyethylene glycol, optionally substituted mPEG, heteroaryl, or heterocycle; 
         n is 0, 1, 2, or 3. 
       
     
     
         3 . A lipid particle comprising the lipid of  claim 2 , or a salt or isomer thereof. 
     
     
         4 . A lipid particle comprising the lipid of  claim 1 , or a salt or isomer thereof. 
     
     
         5 . The lipid particle of  claim 3 , wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation. 
     
     
         6 . The lipid particle of  claim 5 , wherein the lipid particle consists essentially of
 a. a lipid of  claim 2 , or a salt or isomer thereof;   b. a neutral lipid selected from DSPC, DPPC, POPC, DOPE and SM;   c. sterol; and   d. PEG-DMG or PEG-DMA,   in a molar ratio of about 20-60% lipid of claim  2 :5-25% neutral lipid:25-55% sterol:0.5-15% PEG-DMG or PEG-DMA.   
     
     
         7 . The lipid particle of  claim 3 , further comprising a therapeutic agent. 
     
     
         8 . The lipid particle of  claim 7 , wherein the therapeutic agent is a nucleic acid. 
     
     
         9 . The lipid particle of  claim 8 , wherein the nucleic acid is a plasmid. 
     
     
         10 . The lipid particle of  claim 8 , wherein the nucleic acid is an immunostimulatory oligonucleotide. 
     
     
         11 . (canceled) 
     
     
         12 . The lipid particle of  claim 8 , wherein the nucleic acid is an siRNA. 
     
     
         13 . A pharmaceutical composition comprising a lipid particle of  claim 7  and a pharmaceutically acceptable excipient, carrier, or diluent. 
     
     
         14 . A method of modulating the expression of a target gene in a cell, comprising providing to a cell the lipid particle of  claim 7 . 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . A method of treating a disease or disorder characterized by overexpression of a polypeptide in a subject, comprising providing to the subject the pharmaceutical composition of  claim 13 , wherein the therapeutic agent is selected from an siRNA, a microRNA, an antisense oligonucleotide, and a plasmid capable of expressing an siRNA, a microRNA, or an antisense oligonucleotide, and wherein the siRNA, microRNA, or antisense RNA comprises a polynucleotide that specifically binds to a polynucleotide that encodes the polypeptide, or a complement thereof. 
     
     
         18 . A method of treating a disease or disorder characterized by underexpression of a polypeptide in a subject, comprising providing to the subject the pharmaceutical composition of  claim 13 , wherein the therapeutic agent is a plasmid that encodes the polypeptide or a functional variant or fragment thereof. 
     
     
         19 . A method of inducing an immune response in a subject, comprising providing to the subject the pharmaceutical composition of  claim 13 , wherein the therapeutic agent is an immunostimulatory oligonucleotide. 
     
     
         20 . (canceled) 
     
     
         21 . A vaccine comprising the lipid particle of  claim 7 . 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . The lipid of  claim 1 , or a salt or isomer thereof, wherein E is N(Q). 
     
     
         27 . The lipid of  claim 2 , or a salt or isomer thereof, wherein E is N(Q). 
     
     
         28 . The lipid particle of  claim 7 , wherein the therapeutic agent is mRNA.