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 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , R 9 , L 1 , L 2 , a, b, c, d and e 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 a structure of Formula I:
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
L 1 and L 2 are each independently —O(C═O)— or —(C═O)O—;
R 1a and R 1b are, at each occurrence, independently either (a) H or C 1 -C 12 alkyl, or (b) R 1a is H or C 1 -C 12 alkyl, and R 1b together with the carbon atom to which it is bound is taken together with an adjacent R 1b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 2a and R 2b are, at each occurrence, H;
R 3a and R 3b are, at each occurrence, H;
R 4a and R 4b are, at each occurrence, independently either (a) H or C 1 -C 12 alkyl, or (b) R 4a is H or C 1 -C 12 alkyl, and R 4b together with the carbon atom to which it is bound is taken together with an adjacent R 4b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 5 and R 6 are each independently methyl or cycloalkyl;
R 7 is, at each occurrence, independently H or C 1 -C 12 alkyl;
R 8 and R 9 are each independently unsubstituted C 1 -C 12 alkyl; or R 8 and R 9 , together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring comprising one nitrogen atom;
a and d are each independently an integer from 0 to 24;
b and c are each independently an integer from 4 to 12; and
e is 1 or 2,
provided that:
R 1a and R 1b are not isopropyl when a is 6 or n-butyl when a is 8.
2. The compound of claim 1 , wherein one of L 1 or L 2 is —O(C═O)—.
3. The compound of claim 1 , wherein one of L 1 or L 2 is —(C═O)O—.
4. The compound of claim 1 , wherein the compound has one of the following structures (Ib) or (Ic):
5. The compound of claim 1 , wherein a and d are each independently an integer from 2 to 12.
6. The compound of claim 1 , wherein a, b, c and d are each independently an integer from 5 to 9.
7. The compound of claim 1 , wherein at least one of R 1a and R 4a is H.
8. The compound of claim 1 , wherein R 1a and R 4a are H at each occurrence.
9. The compound of claim 1 , wherein at least one of R 1a and R 4a is C 1 -C 8 alkyl.
10. The compound of claim 9 , wherein C 1 -C 8 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.
11. The compound of claim 1 , wherein at least one of R 1b and R 4b is H.
12. The compound of claim 1 , wherein R 1b and R 4b are H at each occurrence.
13. The compound of claim 1 , wherein R 1b together with the carbon atom to which it is bound is taken together with an adjacent R 1b and the carbon atom to which it is bound to form a carbon-carbon double bond.
14. The compound of claim 1 , wherein R 4b together with the carbon atom to which it is bound is taken together with an adjacent R 4b and the carbon atom to which it is bound to form a carbon-carbon double bond.
15. The compound of claim 1 , wherein one of R 5 or R 6 is methyl.
16. The compound of claim 1 , wherein each of R 5 and R 6 is methyl.
17. The compound of claim 1 , wherein one of R 5 or R 6 is cycloalkyl.
18. The compound of claim 1 , wherein each of R 5 and R 6 is cycloalkyl.
19. The compound of claim 18 , wherein the cycloalkyl is unsubstituted.
20. The compound of claim 17 , wherein the cycloalkyl is substituted.
21. The compound of claim 17 , wherein the cycloalkyl is substituted with C 1 -C 6 alkyl.
22. The compound of claim 21 , wherein C 1 -C 6 alkyl is tert-butyl.
23. The compound of claim 17 , wherein cycloalkyl is cyclohexyl.
24. The compound of claim 1 , wherein at least one R 7 is H.
25. The compound of claim 24 , wherein each R 7 is H.
26. The compound of claims 1 , wherein at least one R 7 is C 1 -C 6 alkyl.
27. The compound of claim 1 , wherein e is 2.
28. The compound of claim 1 , wherein at least one of R 8 or R 9 is methyl.
29. The compound of claim 1 , wherein each of R 8 and R 9 is methyl.
30. A compound having one of the following structures:
31. A composition comprising the compound of claim 1 and a nucleic acid.
32. A method for administering a nucleic acid to a patient in need thereof, the method comprising preparing or providing the composition of claim 31 , and administering the composition to the patient.
33. The composition of claim 31 , further comprising one or more excipient selected from the group consisting of neutral lipids, steroids and polymer conjugated lipids.
34. The composition of claim 33 , wherein the composition comprises one or more neutral lipids selected from the group consisting of DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM.
35. The composition of claim 34 , wherein the neutral lipid is DSPC.
36. The composition of claim 33 , having a molar ratio of the compound to the neutral lipid of from about 2:1 to about 8:1.
37. The composition of claim 33 , wherein the steroid is cholesterol.
38. The composition of claim 37 , having a molar ratio of the compound to cholesterol of from about 2:1 to 1:1.
39. The composition of claim 33 , wherein the polymer conjugated lipid is a pegylated lipid.
40. The composition of claim 39 , having a molar ratio of the compound to the pegylated lipid of from about 100:1 to about 25:1.
41. The composition of claim 39 , wherein the pegylated lipid is PEG-DMG.
42. The composition of claim 39 , wherein the pegylated lipid has the following structure (II):
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
R 10 and R 11 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
z has a mean value ranging from 30 to 60.
43. The composition of claim 42 , wherein R 10 and R 11 are each independently straight, saturated alkyl chains containing from 12 to 16 carbon atoms.
44. The composition of claim 42 , wherein the average z is about 45.
45. The composition of claim 42 , wherein the pegylated lipid has one of the following structures:
wherein n has a mean value ranging from 40 to 50.
46. The composition of claim 31 , wherein the nucleic acid comprises an antisense nucleic acid.
47. The composition of claim 31 , wherein the nucleic acid comprises messenger RNA.