Lipids and compositions for the delivery of therapeutics
View Patent ↗The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structures: (Formula (I) or (XXXV)).
1. A lipid of formula I
or a salt or isomer thereof, wherein
R 1 and R 2 are each independently for each occurrence optionally substituted C 10 -C 20 alkyl, optionally substituted C 10 -C 20 alkenyl, or optionally substituted C 10 -C 20 alkynyl;
R 3 is independently for each occurrence H, optionally substituted C 1 -C 10 alkyl, optionally substituted alkylheterocycle, optionally substituted heterocyclealkyl, optionally substituted amino, optionally substituted alkylamino, optionally substituted di(alkyl)amino, optionally substituted aminoalkyl, optionally substituted alkylaminoalkyl, or optionally substituted di(alkyl)aminoalkyl;
X and Y are each independently —O— or alkylene;
A 1 and A 2 are each independently —O— or —CH 2 —;
Z is N, or C(R 3 ); and
m and n are each independently 0 to 5, where m and n taken together result in a 5, 6, or 7 member ring.
2. A lipid selected from
and salts thereof.
3. A lipid particle comprising a lipid of claim 2 .
4. The lipid particle of claim 3 , wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.
5. The lipid particle of claim 3 , wherein the particle further comprising a therapeutic nucleic acid.
6. The lipid particle of claim 5 , wherein the nucleic acid is an siRNA.
7. A pharmaceutical composition comprising a lipid particle of claim 5 and a pharmaceutically acceptable excipient, carrier, or diluent.
8. A method of modulating the expression of a target gene in a cell, comprising providing to a cell the lipid particle of claim 6 .
9. The lipid of claim 1 , wherein R 1 and R 2 are each independently for each occurrence optionally substituted C 10 -C 20 alkyl.
10. The lipid of claim 1 , wherein R 1 and R 2 are each independently for each occurrence optionally substituted C 10 -C 20 alkenyl.
11. The lipid of claim 1 , wherein R 1 and R 2 are each independently for each occurrence optionally substituted C 10 -C 20 alkynyl.
12. The lipid of claim 1 , wherein X and Y are each independently —O—.
13. The lipid of claim 1 , wherein X and Y are each independently alkylene.
14. The lipid of claim 1 , wherein A 1 , and A 2 are each independently —O—.
15. The lipid of claim 1 , wherein A 1 , and A 2 are each independently —CH 2 —.
16. The lipid of claim 1 , wherein Z is N.
17. The lipid of claim 1 , wherein Z is C(R 3 ).