Biodegradable lipids for the delivery of active agents

Abstract

The present invention relates to a cationic lipid having one or more biodegradable groups located in a lipidic moiety (e.g., a hydrophobic chain) of the cationic lipid. These cationic lipids may be incorporated into a lipid particle for delivering an active agent, such as a nucleic acid. The invention also relates to lipid particles comprising a neutral lipid, a lipid capable of reducing aggregation, a cationic lipid of the present invention, and optionally, a sterol. The lipid particle may further include a therapeutic agent such as a nucleic acid.

What is claimed is: 
     
         1 . A cationic lipid comprising a head group, two hydrophobic tails, and a central moiety to which the head group and the two hydrophobic tails are directly bonded, wherein
 (a) the central moiety is a central carbon or nitrogen atom; and   (b) each hydrophobic tail, independently, has the formula —R 12 -M 1 -R 13 , wherein R 12  is a C 4 -C 14  alkylene or C 4 -C 14  alkenylene, M 1  is —C(O)O— or —OC(O)—, and R 13  is a C 10 -C 20  alkyl, where
 (I) M 1  is separated from a terminus of the hydrophobic tail by from 6 to 12 carbon atoms; and 
 (II) the total carbon atom content of a tail having a branched alkyl R 13  is 21 to 26; 
   (c) at least one R 13  is a branched C 10 -C 20  alkyl where the branching occurs at the α-position relative to M 1 ; and   (d) the lipid has at least one protonatable group.   
     
     
         2 . The cationic lipid of  claim 1 , wherein the central moiety is a nitrogen atom. 
     
     
         3 . The cationic lipid of  claim 1 , wherein M 1  is —OC(O)—. 
     
     
         4 . The cationic lipid of  claim 1 , wherein M 1  is —C(O)O—. 
     
     
         5 . The cationic lipid of  claim 1 , wherein the chain length of —R 12 -M 1 -R 13  is at most 21 atoms from the first atom after the central moiety to a terminus of the tail. 
     
     
         6 . The cationic lipid of  claim 1 , having a pKa of from about 5 to about 7 when incorporated into a lipid particle. 
     
     
         7 . The cationic lipid of  claim 1 , wherein, in at least one hydrophobic tail,
 (i) R 12  is a C 5 -C 10  alkylene or C 5 -C 10  alkenylene;   (ii) the total number of carbon atoms between the central moiety and a terminus of the hydrophobic tail ranges from 15 to 20; and   (iii) M 1  is separated from a terminus of the hydrophobic tail by from 8 to 12 carbon atoms.   
     
     
         8 . The cationic lipid of  claim 1 , wherein at least one hydrophobic tail has the formula 
       
         
           
           
               
               
           
         
       
       where R 13  is a branched C 13 -C 17  alkyl where the branching occurs at the α-position relative to the —C(O)O— group, and the total carbon length of the tail from the first carbon after the central moiety to a terminus of the tail is at most 20. 
     
     
         9 . A cationic lipid comprising a head group, two hydrophobic tails, and a central moiety to which the head group and the two hydrophobic tails are directly bonded, wherein
 (a) the central moiety is a central carbon or nitrogen atom;   (b) each hydrophobic tail, independently, has the formula —R 12 -M 1 -R 13 , wherein R 12  is a C 4 -C 14  alkylene or C 4 -C 14  alkenylene, M 1  is —C(O)O— or —OC(O)—, and R 13  is a branched C 10 -C 20  alkyl where the branching occurs at the α-position relative to M 1 ;   (c) the total carbon atom content of the tail —R 12 -M 1 -R 13  is 21 to 26;   (d) M 1  is separated from a terminus of the hydrophobic tail by from 6 to 12 carbon atoms; and   (e) the lipid has at least one protonatable group.   
     
     
         10 . The cationic lipid of  claim 9 , wherein the central moiety is a nitrogen atom. 
     
     
         11 . The cationic lipid of  claim 9 , wherein M 1  is —OC(O)—. 
     
     
         12 . The cationic lipid of  claim 9 , wherein M 1  is —C(O)O—. 
     
     
         13 . The cationic lipid of  claim 9 , wherein the chain length of —R 12 -M 1 -R 13  is at most 21 atoms from the first atom after the central moiety to a terminus of the tail. 
     
     
         14 . The cationic lipid of  claim 9 , wherein the lipid has a pKa of from about 5 to about 7 when incorporated into a lipid particle. 
     
     
         15 . The cationic lipid of  claim 9 , wherein in at least one hydrophobic tail,
 (i) R 12  is a C 5 -C 10  alkylene or C 5 -C 10  alkenylene;   (ii) the total number of carbon atoms between the central moiety and a terminus of the hydrophobic tail ranges from 15 to 20; and   (iii) M 1  is separated from a terminus of the hydrophobic tail by from 8 to 12 carbon.   
     
     
         16 . The cationic lipid of  claim 9 , wherein the at least one hydrophobic tail has the formula 
       
         
           
           
               
               
           
         
       
       where R 13  is a branched C 13 -C 17  alkyl where the branching occurs at the α-position relative to the —C(O)O— group, and the total carbon length of the tail from the first carbon after the central moiety to a terminus of the tail is at most 20. 
     
     
         17 . A method for delivering a nucleic acid comprising administering to a subject a lipid particle comprising a nucleic acid, a cationic lipid, a neutral lipid, a PEG-lipid, and a sterol, wherein
 the cationic lipid comprises a head group, two hydrophobic tails, and a central moiety to which the head group and the two hydrophobic tails are directly bonded, wherein   (a) the central moiety is a central carbon or nitrogen atom;   (b) each hydrophobic tail, independently, has the formula —R 12 -M 1 -R 13 , wherein R 12  is a C 4 -C 14  alkylene or C 4 -C 14  alkenylene, M 1  is —C(O)O— or —OC(O)—, and R 13  is a C 10 -C 20  alkyl, where
 (I) M 1  is separated from a terminus of the hydrophobic tail by from 6 to 12 carbon atoms; and 
 (II) the total carbon atom content of a tail having a branched alkyl R 13  is 21 to 26; 
   (c) at least one R 13  is a branched C 10 -C 20  alkyl where the branching occurs at the α-position relative to the M 1 ; and   (d) the lipid has at least one protonatable group.   
     
     
         18 . The method of  claim 17 , wherein the central moiety is a nitrogen atom. 
     
     
         19 . The method of  claim 17 , wherein the chain length of —R 12 -M 1 -R 13  is at most 21 atoms from the first atom after the central moiety to a terminus of the tail. 
     
     
         20 . The method of  claim 17 , wherein in at least one hydrophobic tail,
 (i) R 12  is a C 5 -C 10  alkylene or C 5 -C 10  alkenylene;   (ii) the total number of carbon atoms between the central moiety and a terminus of the hydrophobic tail ranges from 15 to 20; and   (iii) M 1  is separated from a terminus of the hydrophobic tail by from 8 to 12 carbon.   
     
     
         21 . The method of  claim 17 , wherein the cationic lipid comprises a head group, two hydrophobic tails, and a central moiety to which the head group and the two hydrophobic tails are directly bonded, wherein
 the central moiety is a central carbon or nitrogen atom;   each hydrophobic tail, independently, has the formula —R 12 -M 1 -R 13 , wherein R 12  is a C 4 -C 14  alkylene or C 4 -C 14  alkenylene, M 1  is —C(O)O— or —OC(O)—, and R 13  is a branched C 10 -C 20  alkyl where the branching occurs at the α-position relative to the M 1 ,   the total carbon atom content of the tail —R 12 -M 1 -R 13  is 21 to 26, and   M 1  is separated from a terminus of the hydrophobic tail by from 6 to 12 carbon atoms;   wherein the lipid has at least one protonatable group.   
     
     
         22 . The method of  claim 21 , wherein the central moiety is a nitrogen atom. 
     
     
         23 . The method of  claim 21 , wherein in each hydrophobic tail,
 (i) R 12  is a C 5 -C 10  alkylene or C 5 -C 10  alkenylene;   (ii) the total number of carbon atoms between the central moiety and a terminus of the hydrophobic tail ranges from 15 to 20; and   (iii) M 1  is separated from a terminus of the hydrophobic tail by from 8 to 12 carbon.   
     
     
         24 . The method of  claim 17 , wherein the lipid particle comprises
 the nucleic acid,   35-65 mol % of the cationic lipid,   3-12 mol % of distearoylphosphatidylcholine (DSPC),   15-45 mol % cholesterol, and   0.5-10 mol % of the PEG-modified lipid,   wherein the mol % is based on 100% total moles of lipids in the lipid particle.   
     
     
         25 . The method of  claim 24 , wherein the PEG-modified lipid is 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG). 
     
     
         26 . The method of  claim 24 , wherein the PEG-modified lipid comprises a PEG molecule having an average molecular weight of 2,000 Da. 
     
     
         27 . The method of  claim 26 , wherein the PEG-modified lipid is 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG) comprising the PEG molecule having an average molecular weight of 2,000 Da. 
     
     
         28 . The method of  claim 24 , wherein the lipid particle comprises 45-65 mol % of the cationic lipid, 5-10 mol % distearoylphosphatidylcholine (DSPC), 25-40 mol % cholesterol, and 0.5-5 mol % of the PEG-modified lipid. 
     
     
         29 . The method of  claim 24 , wherein the lipid particle comprises about 50 mol % of the cationic lipid, about 10 mol % of distearoylphosphatidylcholine (DSPC), about 38.5 mol % cholesterol, and about 1.5 mol % of the PEG-modified lipid, wherein the mol % is based on total lipid content of the lipid particle. 
     
     
         30 . The method of  claim 24 , wherein the nucleic acid comprises an RNA.