Compounds and compositions for intracellular delivery of therapeutic agents
The disclosure features novel lipids and compositions involving the same. Nanoparticle compositions include a novel lipid as well as additional lipids such as phospholipids, structural lipids, and PEG lipids. Nanoparticle compositions further including therapeutic and/or prophylactics such as RNA are useful in the delivery of therapeutic and/or prophylactics to mammalian cells or organs to, for example, regulate polypeptide, protein, or gene expression.
1. A compound of Formula (I):
or salts or isomers thereof, wherein:
R 1 is —R″M′R′ or C 5-20 alkenyl;
R 2 and R 3 are each independently selected from C 1-14 alkyl and C 2-14 alkenyl;
R 4 is —(CH 2 ) n Q, wherein Q is OH and n is selected from 3, 4, and 5;
M and M′ are each independently —C(O)O— or —OC(O)—;
R 5 , R 6 , and R 7 are each H;
R′ is a linear C 1-12 alkyl, or C 1-12 alkyl substituted with C 6-9 alkyl;
R″ is C 3-14 alkyl;
m is selected from 5, 6, 7, 8, 9, 10, 11, 12, and 13.
2. The compound of claim 1 , wherein n is 3 or 4.
3. The compound of claim 1 , wherein R 2 and R 3 are each independently C 6-8 alkyl.
4. The compound of claim 3 , wherein R 2 and R 3 are the same.
5. The compound of claim 3 , wherein R 2 and R 3 are different.
6. The compound of claim 1 , wherein R′ is C 6-9 alkyl substituted with C 6-9 alkyl.
7. The compound of claim 1 , wherein R′ is a linear C 6-9 alkyl.
8. The compound of claim 1 , wherein the compound is selected from:
9. A compound of Formula (I):
or salts or isomers thereof, wherein:
R 1 is —R″M′R′ or C 5-20 alkenyl;
R 2 and R 3 are each independently selected from C 1-14 alkyl and C 2-14 alkenyl;
R 4 is —(CH 2 ) n Q, wherein Q is OH and n is selected from 1, 2, 3, 4, and 5;
M and M′ are each independently —C(O)O— or —OC(O)—;
R 5 , R 6 , and R 7 are each H;
R′ is a linear C 1-12 alkyl, or C 1-12 alkyl substituted with C 6-9 alkyl;
R″ is C 6-14 alkyl;
m is selected from 6, 7, 8, 9, 10, 11, 12, and 13.
10. The compound of claim 9 , wherein n is 2, 3, or 4.
11. The compound of claim 9 , wherein R″ is C 6-9 alkyl.
12. The compound of claim 9 , wherein m is selected from 6, 7, 8, and 9.
13. The compound of claim 9 , wherein R 2 and R 3 are each independently C 6-8 alkyl.
14. The compound of claim 13 , wherein R 2 and R 3 are the same.
15. The compound of claim 13 , wherein R 2 and R 3 are different.
16. The compound of claim 9 , wherein R′ is C 6-9 alkyl substituted with C 6-9 alkyl.
17. The compound of claim 9 , wherein R′ is a linear C 6-9 alkyl.
18. The compound of claim 9 , wherein the compound is selected from:
19. A compound of Formula (IA):
or a salt or isomer thereof, wherein
l is selected from 1, 2, 3, 4, and 5;
m is selected from 5, 6, 7, 8, and 9;
M 1 is a bond or M′;
R 4 is unsubstituted C 1-3 alkyl, or —(CH 2 ) n Q, in which Q is OH, —NHC(S)N(R) 2 , —NHC(O)N(R) 2 , —N(R)C(O)R, —N(R)S(O) 2 R, —N(R)R 8 , —NHC(═NR 9 )N(R) 2 , —NHC(═CHR 9 )N(R) 2 , —OC(O)N(R) 2 , —N(R)C(O)OR, —N(OR)C(O)R, —N(OR)S(O) 2 R, —N(OR)C(O)OR, —N(OR)C(O)N(R) 2 , —N(OR)C(S)N(R) 2 , —N(OR)C(═NR 9 )N(R) 2 , —N(OR)C(═CHR 9 )N(R) 2 , or heteroaryl, and each n is selected from 1, 2, 3, 4, or 5;
M and M′ are independently selected
from —C(O)O—, —OC(O)—, —C(O)N(R′)-, —P(O)(OR′)O-,
—S—S—, an aryl group, and a heteroaryl group; and
R 2 and R 3 are both C 1-14 alkyl, or C 2-14 alkenyl;
R 8 is selected from the group consisting of C 3-6 carbocycle and heterocycle;
R 9 is selected from the group consisting of H, CN, NO 2 , C 1-6 alkyl, —OR, —S(O) 2 R, —S(O) 2 N(R) 2 , C 2-6 alkenyl, C 3-6 carbocycle and heterocycle;
each R is independently selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H; and
R′ is a linear alkenyl.
20. A nanoparticle composition comprising a lipid component comprising a compound of claim 1 .
21. The nanoparticle composition of claim 20 , wherein the lipid component further comprises a phospholipid, wherein the phospholipid is selected from the group consisting of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine,1,2-dioleoyl-sn-glycero-3-phosphoethanola mine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), dipalmitoylphosphatidylglycerol (DPPG), palmitoyloleoylphosphatidylethanolamine (POPE), distearoyl-phosphatidyl-ethanolamine (DSPE), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), 1-stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), 1-stearoyl-2-oleoyl-phosphatidylcholine (SOPC), sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyloleoyl phosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine (LPE), and mixtures thereof.
22. The nanoparticle composition of claim 20 , wherein the lipid component further comprises a structural lipid, wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, alpha-tocopherol, and mixtures thereof.
23. The nanoparticle composition of claim 20 , wherein the lipid component further comprises a PEG lipid, wherein the PEG lipid is selected from the group consisting of a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, and mixtures thereof.
24. The nanoparticle composition of claim 20 , further comprising a therapeutic and/or prophylactic agent.
25. The nanoparticle composition of claim 24 , wherein the therapeutic and/or prophylactic agent is a nucleic acid.
26. A nanoparticle composition comprising a lipid component comprising a compound of claim 9 .
27. The nanoparticle composition of claim 26 , wherein the lipid component further comprises a phospholipid, wherein the phospholipid is selected from the group consisting of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine,1,2-dioleoyl-sn-glycero-3-phosphoethanola mine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), dipalmitoylphosphatidylglycerol (DPPG), palmitoyloleoylphosphatidylethanolamine (POPE), distearoyl-phosphatidyl-ethanolamine (DSPE), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), 1-stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), 1-stearoyl-2-oleoyl-phosphatidylcholine (SOPC), sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyloleoyl phosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine (LPE), and mixtures thereof.
28. The nanoparticle composition of claim 26 , wherein the lipid component further comprises a structural lipid, wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, alpha-tocopherol, and mixtures thereof.
29. The nanoparticle composition of claim 26 , wherein the lipid component further comprises a PEG lipid, wherein the PEG lipid is selected from the group consisting of a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, and mixtures thereof.
30. The nanoparticle composition of claim 26 , further comprising a therapeutic and/or prophylactic agent, wherein the therapeutic and/or prophylactic agent is a nucleic acid.