Cationic lipids for lipid nanoparticle delivery of therapeutics to hepatic stellate cells
Certain embodiments of the invention provide lipids useful for preparing lipid nanoparticles for delivering therapeutic agents to, e.g., hepatic stellate cells.
1 . A compound of formula (I):
wherein:
R 1 is a C 7 -C 30 hydrocarbyl;
R 2 is a C 2 -C 30 hydrocarbyl;
R 3 is C 1 -C 4 alkyl or —O—C 2 -C 30 hydrocarbyl;
R 4 is a C 2 -C 30 hydrocarbyl;
R 5 is a C 2 -C 30 hydrocarbyl;
R 6 is C 1 -C 4 alkyl or —O—C 2 -C 30 hydrocarbyl; and
X is
2 . The compound of claim 1 , wherein R 1 is (C 7 -C 20 )alkyl, (C 7 -C 20 )alkenyl, or (C 7 -C 20 )alkynyl.
3 . The compound of claim 1 , wherein R 1 is (C 7 -C 15 )alkenyl, having only one double bond.
4 . The compound of claim 1 , wherein R 2 is (C 2 -C 20 )alkyl, (C 2 -C 20 )alkenyl, or (C 2 -C 20 )alkynyl.
5 . The compound of claim 1 , wherein R 2 is a (C 7 -C 15 )alkenyl, having only one double bond.
6 . The compound of claim 1 , wherein R 3 is methyl.
7 . The compound of claim 1 , wherein R 4 is (C 2 -C 20 )alkyl, (C 2 -C 20 )alkenyl, or (C 2 -C 20 )alkynyl.
8 . The compound of claim 1 , wherein R 4 is (C 7 -C 15 )alkenyl, having only one double bond.
9 . The compound of claim 1 , wherein R 5 is (C 2 -C 20 )alkyl, (C 2 -C 20 )alkenyl, or (C 2 -C 20 )alkynyl.
10 . The compound of claim 1 , wherein R 5 is a (C 7 -C 15 )alkenyl, having only one double bond.
11 . The compound of claim 1 , wherein R 6 is methyl.
12 . A compound selected from the group consisting of:
or a salt thereof.
13 . A lipid particle comprising the compound of claim 1 .
14 . The lipid particle of claim 13 , wherein the lipid particle further comprises a therapeutic agent.
15 . The lipid particle of claim 14 , wherein the therapeutic agent is a nucleic acid therapeutic agent.
16 . The lipid particle of claim 14 , wherein the therapeutic agent is an interfering RNA agent.
17 . The lipid particle of claim 16 , wherein the therapeutic agent is siRNA.
18 . The lipid particle of claim 14 , wherein the therapeutic agent is mRNA.
19 . A lipid particle comprising the compound of claim 12 .
20 . A composition comprising the compound of claim 1 .
21 . A composition comprising the compound of claim 12 .
22 . A pharmaceutical composition comprising the lipid particle of claim 13 , and a pharmaceutically acceptable carrier.
23 . A pharmaceutical composition comprising the lipid particle of claim 19 , and a pharmaceutically acceptable carrier.
24 . A method for the in vivo delivery of a therapeutic agent, the method comprising: administering to a mammalian subject the lipid particle of claim 14 .
25 . A method for treating a disease or disorder in a mammalian subject in need thereof, the method comprising:
administering to the mammalian subject a therapeutically effective amount of the lipid particle of claim 14 .
26 . The method of claim 25 , wherein the disease or disorder is liver fibrosis.
27 . The method of claim 25 , wherein the disease or disorder is liver fibrosis associated non-alcoholic steatohepatitis (NASH) or alcoholic steatohepatitis (ASH).
28 . A method of delivering a therapeutic agent to a hepatic stellate cell (HSC), in vivo or in vitro, comprising contacting the HSC with the lipid particle of claim 14 .
29 . A method for the in vivo delivery of a therapeutic agent, the method comprising: administering to a mammalian subject the lipid particle of claim 19 , wherein the lipid particle further comprises the therapeutic agent.
30 . A method for treating a disease or disorder in a mammalian subject in need thereof, the method comprising:
administering to the mammalian subject a therapeutically effective amount of the lipid particle of claim 19 , wherein the lipid particle further comprises a therapeutic agent.