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 lipid compound, 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:
the central moiety is a nitrogen atom;
each of the two hydrophobic tails independently consists of an aliphatic group interrupted by an ester group; and
at least one of the hydrophobic tails has the formula —R 12 -M 1 -R 13 , wherein:
R 12 is a C 4 -C 14 alkyl group,
M 1 is an ester group, and
R 13 is a C 10 -C 20 alkyl group that is branched at the α-position relative to M 1 ;
the chain length of formula —R 12 -M 1 -R 13 is from 17 to 24 atoms;
the total carbon atom content of the at least one hydrophobic tail is 21 to 26 carbon atoms; and
wherein the lipid compound contains a protonatable group such that the lipid compound is positively charged at a pH at or below pH 7.4.
2. The lipid compound of claim 1 , wherein both hydrophobic tails have the formula —R 12 -M 1 -R 13 , wherein M 1 is —OC(O)—.
3. The lipid compound of claim 2 , wherein the two hydrophobic tails are identical.
4. The lipid compound of claim 3 , wherein the head group consists of a saturated aliphatic group and a hydroxyl group.
5. The lipid compound of claim 1 , wherein the ester group in each hydrophobic tail is —C(O)O—.
6. The lipid compound of claim 5 , wherein the at least one hydrophobic tail has the formula:
where R 13 is branched at the α-position relative to the —C(O)O— group, and
where R 13 is a C 13 -C 17 alkyl and the maximum length of R 13 is 11 carbon atoms.
7. The lipid compound of claim 6 , wherein the hydrophobic tails have different chemical formulas.
8. The lipid compound of claim 7 , wherein the head group consists of a saturated aliphatic group and a hydroxyl group.
9. The lipid compound of claim 8 , wherein, in the at least one hydrophobic tail, R 13 is a C 17 alkyl.
10. A lipid compound, comprising a head group, two identical 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 nitrogen atom;
each hydrophobic tail has the formula —R 12 -M 1 -R 13 , wherein:
R 12 is a C 4 -C 14 alkyl group,
M 1 is —OC(O)—, and
R 13 is a C 10 -C 20 alkyl group that is branched at the α-position relative to M 1 ;
the chain length of formula —R 12 -M 1 -R 13 is from 17 to 24 atoms; and
the total carbon atom content of each hydrophobic tail is 21 to 26 carbon atoms.
11. The lipid compound of claim 10 , wherein R 12 is n-hexyl.
12. The lipid compound of claim 11 , wherein the head group consists of a saturated aliphatic group and a hydroxyl group.
13. A method for delivering a nucleic acid comprising administering to a subject a lipid particle comprising a nucleic acid, a lipid compound, a neutral lipid, a PEG-lipid, and a sterol, wherein:
the lipid compound 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 nitrogen atom;
each of the two hydrophobic tails independently consists of an aliphatic group interrupted by an ester group; and
at least one of the hydrophobic tails has the formula —R 12 -M 1 -R 13 , wherein:
R 12 is a C 4 -C 14 alkyl group,
M 1 is an ester group, and
R 13 is a C 10 -C 20 alkyl group that is branched at the α-position relative to M 1 ;
the chain length of formula —R 12 -M 1 -R 13 is from 17 to 24 atoms; and
the total carbon atom content of the at least one hydrophobic tail is 21 to 26 carbon atoms; and
wherein the lipid compound contains a protonatable group such that the lipid compound is positively charged at a pH at or below pH 7.4.
14. The method of claim 13 , wherein the nucleic acid comprises RNA.
15. The method of claim 14 , wherein the ester group in each hydrophobic tail is —C(O)O—.
16. The method of claim 15 , wherein the at least one hydrophobic tail has the formula:
where R 13 is branched at the α-position relative to the —C(O)O— group, and
where R 13 is a C 13 -C 17 alkyl and the maximum length of R 13 is 11 carbon atoms.
17. The method of claim 16 , wherein the hydrophobic tails have different chemical formulas.
18. The method of claim 17 , wherein the lipid particle is administered in a pharmaceutical composition, which further comprises a pharmaceutically acceptable diluent and sodium acetate.
19. The method of claim 18 , wherein the head group consists of a saturated aliphatic group and a hydroxyl group.
20. The method of claim 19 , wherein, in the at least one hydrophobic tail, R 13 is a C 17 alkyl.
21. The method of claim 14 , wherein both hydrophobic tails have the formula —R 12 -M 1 -R 13 , wherein M 1 is —OC(O)—.
22. The method of claim 21 , wherein the two hydrophobic tails are identical.
23. The method of claim 22 , wherein the lipid particle is administered in a pharmaceutical composition, which further comprises a pharmaceutically acceptable diluent, potassium chloride, and sodium chloride.
24. The method of claim 23 , wherein the head group consists of a saturated aliphatic group and a hydroxyl group.