Biodegradable lipids for the delivery of active agents
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.
1. A cationic lipid comprising a head group, hydrophobic tails, and a central moiety to which the head group and the hydrophobic tails are directly bonded, wherein
(a) the central moiety is a nitrogen atom;
(b) the hydrophobic tails consist of two hydrophobic tails, wherein 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 —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 each hydrophobic tail is 21 to 26 carbon atoms;
(d) in each hydrophobic tail, 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.
2. The cationic lipid of claim 1 , wherein, in each hydrophobic tail, 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 hydrophobic tail.
3. The cationic lipid of claim 2 , 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 atoms.
4. The cationic lipid of claim 3 , wherein the lipid has a pKa of from about 5 to about 7 when incorporated into a lipid particle.
5. The cationic lipid of claim 1 , wherein:
(b) in each hydrophobic tail, R 12 is a C 5 -C 10 alkylene or C 5 -C 10 alkenylene, and R 13 is a branched C 10 -C 20 alkyl where the branching occurs at the α-position relative to M 1 ;
(d) in each hydrophobic tail, M 1 is separated from a terminus of the hydrophobic tail by from 8 to 12 carbon atoms;
(f) the chain length of each hydrophobic tail is at most 21 atoms from the first atom after the central moiety to a terminus of the hydrophobic tail; and
(g) in each hydrophobic tail, the total number of carbon atoms between the central moiety and a terminus of the hydrophobic tail ranges from 15 to 20.
6. 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, hydrophobic tails, and a central moiety to which the head group and the hydrophobic tails are directly bonded, wherein
(a) the central moiety is a nitrogen atom;
(b) the hydrophobic tails consist of two hydrophobic tails, wherein 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 —OC(O)—, and R 13 is a C 10 -C 20 alkyl, where
M 1 is separated from a terminus of the hydrophobic tail by from 6 to 12 carbon atoms; and
(c) R 13 is branched at the α-position relative to M 1 , where the total carbon atom content of the at least one hydrophobic tail is 21 to 26 carbon atoms; and
(d) the lipid has at least one protonatable group.
7. The method of claim 6 , wherein the nucleic acid comprises RNA.
8. The method of claim 7 , 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.
9. The method of claim 8 , 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 at least one hydrophobic tail ranges from 15 to 20; and
(iii) M 1 is separated from a terminus of the at least one hydrophobic tail by from 8 to 12 carbon atoms.
10. The method of claim 9 , 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 atoms.
11. The method of claim 10 , 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.
12. The method of claim 11 , 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.
13. The method of claim 12 , wherein the PEG-modified lipid comprises a PEG molecule having an average molecular weight of 2,000 Da.