Lipids and lipid nanoparticle formulations for delivery of nucleic acids
Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1 , R 2 , R 3 , L 1 , L 2 , G 1 , G 2 and G 3 are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, compositions comprising the compounds and methods for their use and preparation are also provided.
1. A compound having the following structure (IF):
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
G 1 and G 2 are each independently unsubstituted C 4 -C 12 alkylene or C 4 -C 12 alkenylene;
G 3 is C 3 -C 6 alkylene;
R 1 and R 2 are each independently branched C 6 -C 24 alkyl;
R 3 is H, OR 5 , CN, —C(═O)OR 4 , —OC(═O)R 4 or —NR 5 C(═O)R 4 ;
R 4 is C 1 -C 12 alkyl; and
R 5 is H or C 1 -C 6 alkyl.
2. The compound of claim 1 , having the following structures (IH):
wherein:
R 6 is H, OH or C 1 -C 24 alkyl;
y and z are each independently integers ranging from 4 to 12;
and n is an integer ranging from 3 to 6.
3. The compound of claim 2 , wherein n is 3.
4. The compound of claim 2 , wherein n is.
5. The compound of claim 2 , wherein y and z are each independently an integer ranging from 4 to 9.
6. The compound of claim 1 , wherein R 1 and R 2 each, independently have the following structure:
wherein:
R 7a and R 7b are, at each occurrence, independently H or C 1 -C 12 alkyl; and
a is an integer from 2 to 12,
wherein R 7a , R 7b and a are each selected such that R 1 and R 2 are each independently a branched alkyl comprising from 6 to 20 carbon atoms.
7. The compound of claim 6 , wherein a is an integer from 8 to 12.
8. The compound of claim 6 , wherein at least one occurrence of R 7a is H.
9. The compound of claim 6 , wherein R 7a is H at each occurrence.
10. The compound of claim 6 , wherein at least one occurrence of R 7b is C 1 -C 8 alkyl.
11. The compound of claim 10 , wherein C 1 -C 8 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.
12. The compound of claim 1 , wherein R 1 or R 2 , or both, has one of the following structures:
13. The compound of claim 1 , wherein R 3 is OH.
14. The compound of claim 1 , wherein R 3 is CN.
15. The compound of claim 1 , wherein R 3 is —C(═O)OR 4 , —OC(═O)R 4 or —NHC(═O)R 4 .
16. The compound of claim 15 , wherein R 4 is methyl or ethyl.
17. The compound of claim 1 , having one of the following structures:
18. A composition comprising the compound of claim 1 and a therapeutic agent comprising a nucleic acid.
19. The composition of claim 18 , further comprising one or more excipient selected from neutral lipids, steroids and polymer conjugated lipids.
20. The composition of claim 19 , wherein the composition comprises one or more neutral lipids selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM.
21. The composition of claim 20 , wherein the neutral lipid is DSPC.
22. The composition of claim 18 , wherein the molar ratio of the compound to the neutral lipid ranges from about 2:1 to about 8:1.
23. The composition of claim 19 , wherein the steroid is cholesterol.
24. The composition of claim 23 , wherein the molar ratio of the compound to cholesterol ranges from 5:1 to 1:1.
25. The composition of claim 19 , wherein the polymer conjugated lipid is a pegylated lipid.
26. The composition of claim 25 , wherein the molar ratio of the compound to the pegylated lipid ranges from about 100:1 to about 20:1.
27. The composition of claim 25 , wherein the pegylated lipid is PEG-DAG, PEG-PE, PEG-S-DAG, PEG-cer or a PEG dialkyoxypropylcarbamate.
28. The composition of claim 25 , wherein the pegylated lipid has the following structure (II):
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
R 8 and R 9 are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and
w has a mean value ranging from 30 to 60.
29. The composition of claim 28 , wherein R 8 and R 9 are each independently straight, saturated alkyl chains containing from 12 to 16 carbon atoms.
30. The composition of claim 28 , wherein the average w is about 49.
31. The composition of claim 18 , wherein the nucleic acid is selected from antisense and messenger RNA.
32. A method for administering a therapeutic agent comprising a nucleic acid to a patient in need thereof, the method comprising administering the composition of claim 18 to the patient.
33. A lipid nanoparticle comprising the compound of claim 1 and a therapeutic agent comprising a nucleic acid.
34. The lipid nanoparticle of claim 33 , wherein the therapeutic agent is selected from antisense and messenger RNA.