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 formula (I) provides lipids having the following structure XXXIII wherein: R 1 and R 2 are each independently for each occurrence optionally substituted C 10 -C 30 alkyl, optionally substituted C 10 -C 30 alkenyl, optionally substituted C 10 -C 30 alkynyl, optionally substituted C 10 -C 30 acyl, or -linker-ligand; R 3 is H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, alky lhetro cycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, ω-aminoalkyls, ω-(substituted)aminoalkyls, ω-phosphoalkyls, ω-thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; and E is C(O)O or OC(O).
1. A lipid having the structure
or a salt or isomer thereof, wherein:
R 1 and R 2 are each independently for each occurrence optionally substituted C 10 -C 20 alkenyl or optionally substituted C 10 -C 20 alkynyl;
R 3 is ω-aminoalkyl or ω-(substituted)aminoalkyl; and
E is C(O)O;
provided that when R 3 is 2-(dimethylamino)ethyl, R 1 and R 2 are not each linoleyl.
2. The lipid of claim 1 wherein R 3 is ω-aminoalkyl.
3. The lipid of claim 1 wherein R 3 is ω-(substituted)aminoalkyl.
4. The lipid of claim 1 wherein R 3 is 2-(dimethylamino)ethyl, 3-(diisopropylamino)propyl, or 3-(N-ethyl-n-isopropylamino)-1-methylpropyl.
5. The lipid of claim 1 wherein R 3 is alkylaminoalkyl, dialkylaminoalkyl, or alkylheterocycle.
6. The lipid of claim 1 wherein R 1 and R 2 are each optionally substituted C 10 -C 20 alkenyl.
7. The lipid of claim 1 wherein R 1 and R 2 are each linoleyl.
8. A lipid particle comprising a lipid of claim 1 .
9. The lipid particle of claim 8 , wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.
10. The lipid particle of claim 9 wherein the lipid capable of reducing aggregation is a PEG-lipid.
11. The lipid particle of claim 8 , further comprising a therapeutic agent.
12. The lipid particle of claim 11 , wherein the therapeutic agent is a nucleic acid.
13. The lipid particle of claim 12 , wherein the nucleic acid is selected from the group consisting of an siRNA and an antisense oligonucleotide.
14. The lipid particle of claim 13 , wherein the nucleic acid is an siRNA.
15. A pharmaceutical composition comprising a lipid particle of claim 11 and a pharmaceutically acceptable excipient, carrier, or diluent.
16. A method of modulating the expression of a target gene in a cell, comprising providing to a cell the lipid particle of claim 11 .
17. The method of claim 16 , wherein the therapeutic agent is selected from a siRNA and an antisense oligonucleotide.
18. A method of treating a disease or disorder characterized by overexpression of a polypeptide in a subject, comprising providing to the subject the pharmaceutical composition of claim 15 , wherein the therapeutic agent is selected from an siRNA and an antisense oligonucleotide, and wherein the siRNA, or antisense oligonucleotide, comprises a polynucleotide that specifically binds to a polynucleotide that encodes the polypeptide, or a complement thereof.
19. The lipid particle of claim 8 comprising a lipid of claim 1 , a neutral lipid, cholesterol, and a PEG lipid, wherein the lipid of claim 1 , the neutral lipid, the cholesterol, and the PEG lipid are present in molar ratios of 20-70%:5-45%:20-55%:0.5-15%, respectively.