BRANCHED TAIL LIPID COMPOUNDS AND COMPOSITIONS FOR INTRACELLULAR DELIVERY OF THERAPEUTIC AGENTS
The disclosure features novel lipids and compositions involving the same. Lipid nanoparticles (e.g., empty LNPs or loaded LNPs) include a novel lipid as well as additional lipids such as phospholipids, structural lipids, and PEG lipids. Lipid nanoparticles (e.g., empty LNPs or loaded LNPs) 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 lipid of Formula (I-1):
or its N-oxide, or a salt or isomer thereof,
wherein R′ a is:
and R′ b is:
wherein
denotes a point of attachment;
R aβ , R aγ , and R aδ are each independently selected from the group consisting of H, C 1-12 alkyl, and C 2-12 alkenyl, wherein at least one of R aβ , R aγ , and R aδ is selected from the group consisting of C 1-12 alkyl and C 2-12 alkenyl;
R bβ , R bγ , and R bδ are each independently selected from the group consisting of H, C 1-12 alkyl, and C 2-12 alkenyl, wherein at least one of R bβ , R bγ , and R bδ is selected from the group consisting of C 1-12 alkyl and C 2-12 alkenyl;
R 2 and R 3 are each independently selected from the group consisting of C 1-14 alkyl and C 2-14 alkenyl;
R 4 is selected from —(CH 2 ) n NRTQ, —(CH 2 ) n NRS(O) 2 TQ, —(CH 2 ) n NRC(O)H and —(CH 2 ) n NRC(O)TQ wherein n is selected from 1, 2, 3, 4, and 5;
T is a bond or a C 1-3 alkyl linker, C 2-3 alkenyl linker, or C 2-3 alkynyl linker;
Q is selected from 3-14 membered heterocycle containing 1-5 heteroatoms selected from N, O, and S, C 3-10 carbocycle, C 1-6 alkyl, C 1-6 alkoxy, and C 2-6 alkenyl, wherein the alkyl, alkoxy, alkenyl, heterocycle, and carbocycle are each optionally substituted with one or more R Q ;
each R Q independently is selected from the group consisting of oxo, hydroxyl, cyano, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 1-6 alkanolyl, C 3-10 carbocycle, —C(O)C 1-6 alkyl, and —NRC(O)C 1-6 alkyl;
each R is independently selected from H, C 1-6 alkyl, and C 2-6 alkenyl;
each R′ is independently selected from C 1-12 alkyl and C 2-12 alkenyl;
m is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9; and
l is selected from 1, 2, 3, 4, 5, 6, 7, 8, and 9.
2 . A lipid of Formula (I):
or its N-oxide, or a salt or isomer thereof,
wherein R′ a is:
and R′ b is:
wherein
denotes a point of attachment;
R aγ and R bγ are each independently C 1-12 alkyl or C 1-12 alkenyl;
R 2 and R 3 are each independently selected from the group consisting of C 1-14 alkyl and C 2-14 alkenyl;
R 4 is selected from —(CH 2 ) n NRTQ, —(CH 2 ) n NRS(O) 2 TQ, —(CH 2 ) n NRC(O)H and —(CH 2 ) n NRC(O)TQ wherein n is selected from 1, 2, 3, 4, and 5;
T is a bond or a C 1-3 alkyl linker, C 2-3 alkenyl linker, or C 2-3 alkynyl linker;
Q is selected from 3-14 membered heterocycle containing 1-5 heteroatoms selected from N, O, and S, C 3-10 carbocycle, C 1-6 alkyl, C 1-6 alkoxy, and C 2-6 alkenyl, wherein the alkyl, alkoxy, alkenyl, heterocycle, and carbocycle are each optionally substituted with one or more R Q ;
each R Q independently is selected from the group consisting of oxo, hydroxyl, cyano, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 1-6 alkanolyl, C 3-10 carbocycle, —C(O)C 1-6 alkyl, and —NRC(O)C 1-6 alkyl;
each R is independently selected from H, C 1-6 alkyl, and C 2-6 alkenyl;
each R′ is independently selected from C 1-12 alkyl and C 2-12 alkenyl;
m is selected from 3, 4, 5, 6, and 7; and
l is selected from 3, 4, 5, 6, and 7.
3 . The lipid of any one of the preceding claims , wherein m and 1 are each independently selected from 4, 5, and 6.
4 . The lipid of any one of the preceding claims , wherein R aγ is C 2-6 alkyl.
5 . The lipid of any one of the preceding claims , wherein R bγ is C 2-6 alkyl.
6 . The lipid of any one of the preceding claims , wherein each R′ independently is C 1-6 alkyl.
7 . The lipid of any one of the preceding claims , wherein R 2 and R 3 are each independently C 5-10 alkyl.
8 . The lipid of any one of the preceding claims , wherein the lipid is of Formula (I-A1), (I-A2), (I-A3), or (I-A4):
9 . The lipid of any one of the preceding claims , wherein n is 2, 3, or 4.
10 . The lipid of any one of the preceding claims , wherein R is H.
11 . The lipid of any one of the preceding claims , wherein T is a bond.
12 . The lipid of any one of the preceding claims , wherein Q is selected from 5 or 6 membered heterocycle containing 1-3 heteroatoms selected from N, O, and S, C 3-8 carbocycle, C 1-6 alkyl, and C 1-6 alkoxy.
13 . The lipid of any one of the preceding claims , wherein T is a C 1-3 alkyl linker and Q is 5 or 6 membered heterocycle containing 1-3 heteroatoms selected from N, O, and S.
14 . The lipid of any one of the preceding claims , wherein Q is substituted with one or two R Q .
15 . The lipid of any one of the preceding claims , wherein each R Q independently is selected from oxo, amino, C 1-6 alkylamino, C 1-6 alkyl, C 1-6 alkoxy, and C 3-10 carbocycle.
16 . The lipid of any one of the preceding claims , wherein R 4 is selected from:
17 . A lipid selected from:
Cpd
Structure
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and
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18 . An empty lipid nanoparticle (empty LNP) comprising the lipid of any one of the preceding claims , a phospholipid, a structural lipid, and a PEG lipid.
19 . The empty LNP of any one of the preceding claims , comprising about 40 mol % to about 60 mol % said lipid, about 0 mol % to about 20 mol % phospholipid, about 30 mol % to about 50 mol % structural lipid, and about 0 mol % to about 5 mol % PEG lipid.
20 . The empty LNP of any one of the preceding claims , 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-phosphoethanolamine (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), sphingomyelin, and mixtures thereof.
21 . The empty LNP of any one of the preceding claims , wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, and mixtures thereof.
22 . The empty LNP of any one of the preceding claims , 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.
23 . The empty LNP of any one of the preceding claims , wherein the PEG lipid is selected from PEG-III and PEG-II:
wherein s PL1 is an integer between 1 and 100,
wherein r PEG is an integer between 1 and 100, and mixtures thereof.
24 . The empty LNP of any one of the preceding claims , wherein the PEG lipid is selected from PEG 2k -DMG and PEG-1:
and mixtures thereof.
25 . A loaded lipid nanoparticle (loaded LNP), which comprises the empty LNP of any one of the preceding claims and one or more therapeutic and/or prophylactic agents.
26 . The loaded LNP of any one of the preceding claims , wherein the one or more therapeutic and/or prophylactic agents is a nucleic acid.
27 . The loaded LNP of any one of the preceding claims , wherein the nucleic acid is an RNA, and wherein the RNA is selected from the group consisting of a short interfering RNA (siRNA), an asymmetrical interfering RNA (aiRNA), a RNA interference (RNAi) molecule, a microRNA (miRNA), an antagomir, an antisense RNA, a ribozyme, a Dicer-substrate RNA (dsRNA), a small hairpin RNA (shRNA), a messenger RNA (mRNA), and mixtures thereof.
28 . The loaded LNP of any one of the preceding claims , wherein the RNA is an mRNA.
29 . A pharmaceutical composition comprising the loaded LNP of any one of the preceding claims and a pharmaceutically acceptable carrier.
30 . A method of delivering a therapeutic and/or prophylactic agent to a cell within a subject, the method comprising administering to the subject the loaded LNP of any one of the preceding claims .
31 . A method of specifically delivering a therapeutic and/or prophylactic agent to an organ of a subject, the method comprising administering to the subject the loaded LNP of any one of the preceding claims .
32 . A method of producing a polypeptide of interest in a cell within a subject, the method comprising administering to the subject the loaded LNP of any one of the preceding claims .
33 . A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject the loaded LNP of any one of the preceding claims .