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 structure (I) 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, alkylhetrocycle, 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; E is O, S, N(Q), C(O), N(Q)C(O), C(O)N(Q), (Q)N(CO)O, O(CO)N(Q), S(O), NS(O)2N(Q), S(O)2, N(Q)S(O)2, SS, O═N, aryl, heteroaryl, cyclic or heterocycle; and, Q is H, alkyl, ω-aminoalkyl, ω-(substituted)aminoalky, ω-phosphoalkyl or ω-thiophosphoalkyl.
1. A lipid of formula XXXVIII:
or a salt or isomer, wherein
E is (O)(CO)N(Q);
Q is H;
R 1 and R 2 are each independently for each occurrence C 10 -C 30 alkyl;
R x is H;
R 3 is optionally substituted C 1 -C 10 alkyl, ω-aminoalkyl, or ω-(substituted)aminoalkyl; and
n is 1.
2. A lipid particle comprising a lipid of claim 1 .
3. The lipid particle of claim 2 , wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.
4. The lipid particle of claim 3 , wherein the lipid particle consists essentially of
a. the lipid of claim 1 ;
b. a neutral lipid selected from DSPC, DPPC, POPC, DOPE and SM;
c. sterol; and
d. PEG-DMG,
in a molar ratio of about 20-60% lipid of claim 2 :5-25% neutral lipid:25-55% sterol:0.5-15% PEG-DMG.
5. The lipid particle of claim 2 , further comprising a therapeutic agent.
6. The lipid particle of claim 5 , wherein the therapeutic agent is a nucleic acid.
7. The lipid particle of claim 6 , wherein the nucleic acid is a plasmid.
8. The lipid particle of claim 6 , wherein the nucleic acid is an immunostimulatory oligonucleotide.
9. The lipid particle of claim 6 , wherein the nucleic acid is selected from an siRNA, an antisense oligonucleotide, a microRNA, an antagomir, an aptamer, and a ribozyme.
10. The lipid particle of claim 9 , wherein the nucleic acid is an siRNA.
11. A pharmaceutical composition comprising a lipid particle of claim 6 and a pharmaceutically acceptable excipient, carrier, or diluent.
12. The lipid particle of claim 5 , wherein the molar ratio is 52% lipid of claim 2 :5% neutral lipid:30% sterol:13% PEG-DMG.
13. A pharmaceutical composition comprising a lipid particle of claim 10 , and a pharmaceutically acceptable excipient, carrier, or diluent.
14. The lipid of claim 1 , wherein R 3 is optionally substituted C 1 -C 10 alkyl.
15. The lipid of claim 1 , wherein R 3 is ω-aminoalkyl or ω-(substituted)aminoalkyl.