US2019099493A1PendingUtilityA1
Targeting Lipids
Est. expiryDec 4, 2027(~1.3 yrs left)· nominal 20-yr term from priority
A61P 37/02A61P 3/06A61P 3/10A61P 25/00A61P 35/00A61K 47/16A61K 47/22A61K 47/543A61K 31/713A61K 48/00A61K 47/549A61K 31/7052A61K 31/70A61K 31/7088A61K 47/60A61K 47/28Y02P20/55C07H 21/02A61K 31/7004Y02A50/467Y02A50/385Y02A50/411A61K 47/56A61K 47/554Y02A50/30
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Claims
Abstract
The present invention provides targeting lipids of structure where L 100 is a lipid, lipophile, alkyl, alkenyl or alkynyl, L 101 is a ligand or —CH 2 CH 2 (OCH 2 CH 2 ) p O(CH 2 ) q CH 2 -ligand, p is 1-1000, and q is 1-20. In addition, the invention provides compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel lipids and nucleic acid-lipid particles that provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo.
Claims
exact text as granted — not AI-modified1 . A targeting lipid having a structure shown in formula (CI):
wherein:
L 100 is independently for each occurrence lipid, lipophile, alkyl, alkenyl or alkynyl, each of which is optionally substituted with one or more substituents;
L 101 is independently for each occurrence a ligand or —CH 2 CH 2 (OCH 2 CH 2 ) p O(CH 2 ) q CH 2 -ligand;
p is 1-1000; and
q is 1-20.
2 . A targeting lipid having a structure shown in formula (CIII)
L 110 is L 112 ,
R 100 is independently for each occurrence absent, CO, NH, O, S, S—S, —C(CH 3 ) 2 —S—S—, —CH(CH 3 )—S—S—, C(O), OC(O), C(O)O, NHC(O), C(O)NH, NHCH 2 , CH 2 , CH 2 NH, CH 2 O, CH═N—O, heteroaryl, heterocycle,
A is O, NH, NCH3, S, CH2, S—S, —C(CH 3 ) 2 —S—S—, —CH(CH 3 )—S—S—, —O—N═C—, —C(O)—N(H)—N═C—, —C═N—O—, —C═N—N(H)—C(O)—, —C(O)N(Me)-N═C—, —C═N—N(Me)-C(O)—, —O—C(O)—O—, —O—C(O)—NH—, —NH—C(O)—O—, —NH—C(O)—NH—, —N(Me)-C(O)—N(Me)-, —N(H)—C(O)—N(Me)-, —N(Me)-C(O)—N(H)—, —C(O)—O—, —C(O)—N(H)—, —C(O)—N(Me)-, —O—C(O)—, —NH—C(O)—, —N(Me)-C(O)—, —C═N—, —N═C—,
heterocycle or heteroaryl;
L 111 is L 113 , L 114 ,
L 112 is independently for each occurrence lipid, lipophile, alkyl, alkenyl or alkynyl, each of which is optionally substituted with one or more substituents;
L 113 is independently for each occurrence —CH 2 CH 2 (OCH 2 CH 2 ) p O(CH 2 ) q CH 2 -L 114 ;
L 114 is independently for each occurrence a ligand, —C(O)-ligand, —O—C(O)-ligand, —N(H)-ligand, —O—C(O)—N(H)-ligand, —O—C(O)—O-ligand, —NH—C(O)—N(H)-ligand, —NH—C(O)—O-ligand, —S—S-ligand, —O—N═C-ligand, —NH—N═C-ligand, —C═N—O-ligand, —C═N—N(H)-ligand, heterocycle-ligand, heteroaryl-ligand,
p is 1-1000; and
q is 1-20.
3 . A targeting lipid having a structure shown in formula (I)
wherein:
L A is a ligand chosen from a carbohydrate, glucose, mannose, galactose, N-acetyl-galactosamine, fucose, glucosamine, lactose, maltose, folate, peptide, or has the structure shown in formula II-V:
q, q 2A , q 2B , q 3A , q 3B , q 4A , q 4B , q 5A , q 5B and q 5C represent independently for each occurrence 0-20;
p, P 2A , P 2B , P 3A , P 3B , P 4A , P 4B , P 5A , P 5B , P 5C , T, T 2A , T 2B , T 3A , T 3B , T 4A , T 4B , T 5A , T 5B and T 5C are each independently for each occurrence absent, NR′, O, S, C(O), OC(O), C(O)O, NHC(O), C(O)NH, NHCH 2 , CH 2 , CH 2 NH or CH 2 O, NHCH(R a )C(O), —C(O)—CH(R a )—NH—, CO, CH═N—O, CH 2 S, urea, heterocycle, heteroaryl, H
Q, Q 2A , Q 2B , Q 3A , Q 3B , Q 4A , Q 4B , Q 5A , Q 5B and Q 5C are independently for each occurrence absent, —(CH 2 ) n —, —C(R′)(R″)(CH 2 ) n —, —(CH 2 ) m C(R′)(R″)—, —(CH 2 CH 2 O) p CH 2 CH 2 —, or —(CH 2 CH 2 O) p CH 2 CH 2 NH—;
L B is selected from a group consisting of lipophile, steroid, terpene, vitamin, ceramide, or has the structure of formula (VI):
R, R 2 , R 2A , R 2B , R 3A , R 3B , R 4A , R 4B , R 5A , R 5B , R 5C , R 6 , R 6A and R 6B are each independently for each occurrence absent, CO, NH, NR′, O, S, C(O), OC(O), C(O)O, NHC(O), C(O)NH, NHCH 2 , CH 2 , CH 2 NH or CH 2 O, NHCH(R a )C(O), —C(O)—CH(R a )—NH—, CO, CH═N—O,
L 2A , L 2B , L 3A , L 3B , L 4A , L 4B , L 5A , L 5B and L 5C are each independently for each occurrence a carbohydrate, a carbohydrate analog, glucose, mannose, galactose, N-acetyl-galactosamine, fucose, glucosamine, lactose, maltose, folate or a peptide;
R′ and R″ are each independently H, CH 3 , OH, SH, NH 2 , NR 10 R 20 , alkyl, alkenyl or alkynyl;
R a is H or amino acid side chain;
R 10 and R 20 are each independently alkyl, alkenyl or alkynyl;
L 6A and L 6B are each independently alkyl, alkenyl or alkynyl, each of which is optionally substituted with one or more substituents;
m represent independently for each occurrence 0-50;
n represent independently for each occurrence 1-20; and
p represent independently for each occurrence 0-50.
4 . A targeting lipid of claim 3 , wherein L A is
5 . A targeting lipid of claim 3 , wherein L A is
q 5A , q 5B and q 5C represent independently for each occurrence 0-20;
P 5A , P 5B , P 5C , T 5A , T 5B and T 5C are each independently for each occurrence absent, CO, NH, NR′, O, S, C(O), OC(O), C(O)O, NHC(O), C(O)NH, NHCH 2 , CH 2 , CH 2 NH or CH 2 O, NHCH(R a )C(O), —C(O)—CH(R a )—NH—, CO, CH═N—O,
Q 5A , Q 5B and Q 5C are independently for each occurrence absent, —(CH 2 ) n —, —C(R′)(R″)(CH 2 ) n —, —(CH 2 ) m C(R′)(R″)—, —(CH 2 CH 2 O) p CH 2 CH 2 —, or —(CH 2 CH 2 O) p CH 2 CH 2 NH—;
R 5A , R 5B and R 5C are each independently for each occurrence absent, CO, NH, NR′, O, S, C(O), OC(O), C(O)O, NHC(O), C(O)NH, NHCH 2 , CH 2 , CH 2 NH or CH 2 O, NHCH(R a )C(O), —C(O)—CH(R a )—NH—, CO, CH═N—O,
L 5A , L 5B and L 5C are each independently for each occurrence a carbohydrate, glucose, mannose, galactose, N-acetyl-galactosamine, fucose, glucosamine, lactose, maltose, folate or a peptide;
R′ is independently H, CH 3 , OH, SH, NH 2 , NH(Alkyl) or N(diAlkyl);
R a is H or amino acid side chain;
n represent independently for each occurrence 0-20; and
m represent independently for each occurrence 0-50.
6 . A targeting lipid of claim 5 , wherein L A is
7 . A targeting lipid of claim 3 , wherein L B is
8 . A targeting lipid of claim 3 , wherein L B is
wherein R 6 , R 6A and R 6B are each independently for each occurrence absent, CO, NH, NR′, O, S, C(O), OC(O), C(O)O, NHC(O), C(O)NH, NHCH 2 , CH 2 , CH 2 NH or CH 2 O, NHCH(R a )C(O), —C(O)—CH(R a )—NH—, CO, CH═N—O,
R′ is independently for each occurrence H, CH 3 , OH, SH, NH 2 , NH(Alkyl=Me, Et, Pr, isoPr, Bu, Bn) or N(diAlkyl=Me 2 , Et 2 , Bn 2 );
R a is H or amino acid side chain;
L 6A and L 6B are each independently alkyl, alkenyl or alkynyl, each of which is optionally substituted with one or more substituents.
9 . A targeting lipid of claim 8 , wherein R 6 is chosen from O, S or NH.
10 . A targeting lipid of claim 8 , wherein R 6A and R 6B are chosen from O, S or NH.
11 . A targeting lipid of claim 8 , wherein R, R 6A and R 6B are O.
12 . A targeting lipid of claim 8 , wherein L 6A and L 6B are alkyl.
13 . A targeting lipid of claim 8 , wherein L B is
14 . A targeting lipid of claim 8 , wherein L B is
15 . A targeting lipid of claim 8 , wherein L B is
16 . A pharmaceutical formulation comprising (i) a targeting lipid of claim 3 ; (ii) a cationic lipid; (iii) a neutral lipid selected from DSPC, POPC, DOPE, and SM; (iv) cholesterol; and (v) PEG-DMG, or PEG-DMA, wherein the components are in a molar ratio of about 0.5-50% targeting lipid:20-60% cationic lipid:5-25% neutral lipid:25-55% Chol:0.5-15% PEG-DMG or PEG-DMA.
17 . The pharmaceutical formulation of claim 16 , further comprising a therapeutic agent.
18 . The pharmaceutical formulation of claim 17 , wherein said therapeutic agent is an oligonucleotide.
19 . The pharmaceutical formulation of claim 18 , wherein said oligonucleotide is single stranded.
20 . The pharmaceutical formulation of claim 18 , wherein said oligonucleotide agent is double stranded.
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