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 pegylated lipid having 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;
provided that R 10 and R 11 are not both n-octadecyl when z is 42.
2. The pegylated lipid of claim 1 , wherein R 10 and R 11 are each independently straight, saturated alkyl chains containing from 12 to 16 carbon atoms.
3. The pegylated lipid of claim 1 , wherein z is about 45.
4. The pegylated lipid of claim 1 , having one of the following structures:
wherein n has a mean value ranging from 40 to 50.
5. A composition comprising the pegylated lipid of claim 1 and a cationic lipid.
6. The composition of claim 5 , wherein the cationic lipid has a structure of Formula I:
or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
L 1 and L 2 are each independently —O(C═O)—, —(C═O)O— or a carbon-carbon double bond;
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, independently either (a) H or C 1 -C 12 alkyl, or (b) R 2a is H or C 1 -C 12 alkyl, and R 2b together with the carbon atom to which it is bound is taken together with an adjacent R 2b and the carbon atom to which it is bound to form a carbon-carbon double bond,
R 3a and R 3b are, at each occurrence, independently either (a) H or C 1 -C 12 alkyl, or (b) R 3a is H or C 1 -C 12 alkyl, and R 3b together with the carbon atom to which it is bound is taken together with an adjacent R 3b and the carbon atom to which it is bound to form a carbon-carbon double bond;
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 1 to 24; and
e is 1 or 2.
7. The composition of claim 6 , wherein one of L 1 or L 2 is —O(C═O)—.
8. The composition of claim 6 , wherein one of L 1 or L 2 is —(C═O)O—.
9. The composition of claim 6 , wherein the cationic lipid has one of the following structures (Ia), (Ib) or (Ic):
10. The composition of claim 9 , wherein a, b, c and d are each independently an integer from 2 to 12.
11. The composition of claim 9 , wherein a, b, c and d are each independently an integer from 5 to 9.
12. The composition of claim 9 , wherein at least one of R 1a , R 2a , R 3a and R 4a is H.
13. The composition of claim 9 , wherein at least one of R 1a , R 2a , R 3a and R 4a is C 1 -C 8 alkyl.
14. The composition of claim 13 , wherein C 1 -C 8 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.
15. The composition of claim 9 , wherein each of R 5 and R 6 is methyl.
16. The composition of claim 9 , wherein e is 2.
17. The composition of claim 9 , wherein each of R 8 and R 9 is methyl.
18. The composition of claim 5 , wherein the cationic lipid has one of the following structures:
19. The composition of claim 5 , further comprising a nucleic acid.
20. The composition of claim 19 , wherein the nucleic acid is selected from antisense and messenger RNA.
21. The composition of claim 5 , further comprising one or more excipient selected from neutral lipids and steroids.
22. The composition of claim 21 , wherein the composition comprises one or more neutral lipids selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM.
23. The composition of claim 22 , wherein the neutral lipid is DSPC.
24. The composition of claim 21 , wherein the steroid is cholesterol.
25. The pegylated lipid of claim 1 , wherein R 10 and R 11 are each independently a straight or branched, saturated or unsaturated alkyl chain containing 12 carbon atoms.
26. The pegylated lipid of claim 1 , wherein R 10 and R 11 are each independently a straight or branched, saturated or unsaturated alkyl chain containing 14 carbon atoms.
27. The pegylated lipid of claim 1 , wherein R 10 and R 11 are each independently a straight or branched, saturated or unsaturated alkyl chain containing 16 carbon atoms.