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 nanoparticle comprising
(a) a small interfering RNA (siRNA),
(b) a cationic lipid, and
(c) a neutral lipid,
wherein the cationic lipid is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
2. The lipid nanoparticle of claim 1 , further comprising a PEG-modified lipid.
3. The lipid nanoparticle of claim 1 , further comprising a sterol.
4. The lipid nanoparticle of claim 1 , comprising the cationic lipid, the neutral lipid, a PEG-modified lipid, and a sterol.
5. The lipid nanoparticle of claim 4 , comprising about 25 mol % to about 75 mol % of the cationic lipid, wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
6. The lipid nanoparticle of claim 5 , comprising about 35 mol % to about 65 mol % of the cationic lipid.
7. The lipid nanoparticle of claim 5 , comprising about 45 mol % to about 65 mol % of the cationic lipid.
8. The lipid nanoparticle of claim 4 , comprising no more than about 15 mol % of the neutral lipid, wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
9. The lipid nanoparticle of claim 8 , comprising about 3 mol % to about 12 mol % of the neutral lipid.
10. The lipid nanoparticle of claim 4 , wherein the neutral lipid is dipalmitoylphosphatidylcholine (DPPC) or distearylphosphatidylcholine (DSPC).
11. The lipid nanoparticle of claim 4 , comprising about 5 mol % to about 50 mol % of the sterol, wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
12. The lipid nanoparticle of claim 11 , comprising about 15 mol % to about 45 mol % of the sterol.
13. The lipid nanoparticle of claim 4 , wherein the sterol is cholesterol.
14. The lipid nanoparticle of claim 4 , comprising about 0.1 mol % to about 20 mol % of the PEG-modified lipid, wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
15. The lipid nanoparticle of claim 14 , comprising about 0.5 mol % to about 10 mol % of the PEG-modified lipid.
16. The lipid nanoparticle of claim 4 , wherein the PEG-modified lipid is PEG-DMG or PEG-c-DMA.
17. The lipid nanoparticle of claim 4 , wherein the PEG-modified lipid comprises a PEG molecule having an average PEG molecular weight of 2000 Da.
18. The lipid nanoparticle of claim 4 , wherein the PEG-modified lipid is 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG) comprising a PEG molecule having an average molecular weight of 2,000 Da.
19. The lipid nanoparticle of claim 4 , comprising
about 25 mol % to about 75 mol % of the cationic lipid,
about 0.5 mol % to about 15 mol % of the neutral lipid,
about 5 mol % to about 50 mol % of the sterol, and
about 0.5 mol % to about 20 mol % of the PEG-modified lipid;
wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
20. The lipid nanoparticle of claim 4 , comprising
about 35 mol % to about 65 mol % of the cationic lipid,
about 3 mol % to about 12 mol % of the neutral lipid,
about 15 mol % to about 45 mol % of the sterol, and
about 0.5 mol % to about 10 mol % of the PEG-modified lipid;
wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
21. The lipid nanoparticle of claim 4 , comprising
about 45 mol % to about 65 mol % of the cationic lipid,
about 5 mol % to about 10 mol % of the neutral lipid,
about 25 mol % to about 40 mol % of the sterol, and
about 0.5 mol % to about 5 mol % of the PEG-modified lipid;
wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
22. The lipid nanoparticle of claim 4 , comprising
about 50 mol % of the cationic lipid,
about 10 mol % distearoylphosphatidylcholine (DSPC),
about 38.5 mol % cholesterol, and
about 1.5 mol % of the PEG-modified lipid,
wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
23. A pharmaceutical composition comprising a lipid nanoparticle according to claim 4 and a pharmaceutically acceptable diluent.
24. The pharmaceutical composition of claim 23 , wherein the pharmaceutically acceptable diluent comprises phosphate buffered saline or physiological saline.
25. A method of modulating the expression of a target gene in a cell, comprising providing to the cell a lipid nanoparticle of claim 4 .
26. The method of claim 25 , wherein the cell is in a human.
27. A lipid nanoparticle comprising
(a) a small interfering RNA (siRNA),
(b) about 35 mol % to about 65 mol % of a cationic lipid,
(c) about 3 mol % to about 12 mol % distearoylphosphatidylcholine (DSPC),
(d) about 0.5 mol % to about 10 mol % 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG), and
(e) about 15 mol % to about 45 mol % cholesterol;
wherein
the mol % is based on 100% total moles of lipids in the lipid nanoparticle; and
the cationic lipid is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
28. A pharmaceutical composition comprising a lipid nanoparticle according to claim 27 and a pharmaceutically acceptable diluent.
29. A method of modulating the expression of a target gene in a cell, comprising providing to the cell a lipid nanoparticle of claim 27 .
30. A compound having the formula:
or a pharmaceutically acceptable salt thereof.