BIODEGRADABLE LIPIDS FOR THE DELIVERY OF ACTIVE AGENTS
The present invention relates to a cationic lipid having one or more biodegradable groups located in a lipidic moiety (e.g., a hydrophobic chain) of the cationic lipid. These cationic lipids may be incorporated into a lipid particle for delivering an active agent, such as a nucleic acid. The invention also relates to lipid particles comprising a neutral lipid, a lipid capable of reducing aggregation, a cationic lipid of the present invention, and optionally, a sterol. The lipid particle may further include a therapeutic agent such as a nucleic acid.
1 - 19 . (canceled)
20 . A lipid nanoparticle comprising
(a) a nucleic acid;
(b) a cationic lipid, and
(c) a neutral lipid,
wherein the cationic lipid is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
21 . The lipid nanoparticle of claim 20 , further comprising a PEG-modified lipid.
22 . The lipid nanoparticle of claim 20 , further comprising a sterol.
23 . The lipid nanoparticle of claim 20 , comprising the cationic lipid, the neutral lipid, a PEG-modified lipid, and a sterol.
24 . The lipid nanoparticle of claim 23 , comprising about 25 mol % to about 75 mol % of the cationic lipid, wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
25 . The lipid nanoparticle of claim 24 , comprising about 35 mol % to about 65 mol % of the cationic lipid.
26 . The lipid nanoparticle of claim 24 , comprising about 45 mol % to about 65 mol % of the cationic lipid.
27 . The lipid nanoparticle of claim 23 , comprising no more than about 15 mol % of the neutral lipid, wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
28 . The lipid nanoparticle of claim 27 , comprising about 3 mol % to about 12 mol % of the neutral lipid.
29 . The lipid nanoparticle of claim 23 , wherein the neutral lipid is dipalmitoylphosphatidylcholine (DPPC) or distearylphosphatidylcholine (DSPC).
30 . The lipid nanoparticle of claim 23 , comprising about 5 mol % to about 50 mol % of the sterol, wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
31 . The lipid nanoparticle of claim 30 , comprising about 15 mol % to about 45 mol % of the sterol.
32 . The lipid nanoparticle of claim 23 , wherein the sterol is cholesterol.
33 . The lipid nanoparticle of claim 23 , comprising about 0.1 mol % to about 20 mol % of the PEG-modified lipid, wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
34 . The lipid nanoparticle of claim 33 , comprising about 0.5 mol % to about 10 mol % of the PEG-modified lipid.
35 . The lipid nanoparticle of claim 23 , wherein the PEG-modified lipid is PEG-DMG or PEG-c-DMA.
36 . The lipid nanoparticle of claim 23 , wherein the PEG-modified lipid comprises a PEG molecule having an average PEG molecular weight of 2000 Da.
37 . The lipid nanoparticle of claim 23 , wherein the PEG-modified lipid is 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG) comprising a PEG molecule having an average molecular weight of 2,000 Da.
38 . The lipid nanoparticle of claim 23 , comprising
about 25 mol % to about 75 mol % of the cationic lipid,
about 0.5 mol % to about 15 mol % of the neutral lipid,
about 5 mol % to about 50 mol % of the sterol, and
about 0.5 mol % to about 20 mol % of the PEG-modified lipid;
wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
39 . The lipid nanoparticle of claim 23 , comprising
about 35 mol % to about 65 mol % of the cationic lipid,
about 3 mol % to about 12 mol % of the neutral lipid,
about 15 mol % to about 45 mol % of the sterol, and
about 0.5 mol % to about 10 mol % of the PEG-modified lipid;
wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
40 . The lipid nanoparticle of claim 23 , comprising
about 45 mol % to about 65 mol % of the cationic lipid,
about 5 mol % to about 10 mol % of the neutral lipid,
about 25 mol % to about 40 mol % of the sterol, and
about 0.5 mol % to about 5 mol % of the PEG-modified lipid;
wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
41 . The lipid nanoparticle of claim 23 , comprising
about 50 mol % of the cationic lipid,
about 10 mol % distearoylphosphatidylcholine (DSPC),
about 38.5 mol % cholesterol, and
about 1.5 mol % of the PEG-modified lipid,
wherein the mol % is based on 100% total moles of lipids in the lipid nanoparticle.
42 . The lipid nanoparticle of claim 23 , wherein the nucleic acid is an RNA.
43 . The lipid nanoparticle of claim 42 , wherein the nucleic acid is a single stranded RNA.
44 . The lipid nanoparticle of claim 42 , wherein the nucleic acid is a double stranded RNA.
45 . The lipid nanoparticle of claim 23 , wherein the nucleic acid is a single stranded DNA.
46 . The lipid nanoparticle of claim 23 , wherein the nucleic acid is a double stranded DNA.
47 . The lipid nanoparticle of claim 23 , wherein the nucleic acid is a DNA-RNA hybrid.
48 . A pharmaceutical composition comprising a lipid nanoparticle according to claim 23 and a pharmaceutically acceptable diluent.
49 . The pharmaceutical composition of claim 48 , wherein the pharmaceutically acceptable diluent comprises phosphate buffered saline or physiological saline.
50 . A method of modulating the expression of a target gene in a cell, comprising providing to the cell a lipid nanoparticle of claim 23 .
51 . The method of claim 50 , wherein the cell is in a human.
52 . The method of claim 50 , wherein the nucleic acid is an RNA.
53 . The method of claim 52 , wherein the nucleic acid is a single stranded RNA.
54 . The method of claim 52 , wherein the nucleic acid is a double stranded RNA.
55 . The method of claim 50 , wherein the nucleic acid is a single stranded DNA.
56 . The method of claim 50 , wherein the nucleic acid is a double stranded DNA.
57 . The method of claim 50 , wherein the nucleic acid is a DNA-RNA hybrid.
58 . A lipid nanoparticle comprising
(a) a nucleic acid,
(b) about 35 mol % to about 65 mol % of a cationic lipid,
(c) about 3 mol % to about 12 mol % distearoylphosphatidylcholine (DSPC),
(d) about 0.5 mol % to about 10 mol % 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG), and
(e) about 15 mol % to about 45 mol % cholesterol;
wherein
the mol % is based on 100% total moles of lipids in the lipid nanoparticle; and
the cationic lipid is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
59 . The lipid nanoparticle of claim 58 , wherein the nucleic acid is an RNA.
60 . The lipid nanoparticle of claim 59 , wherein the nucleic acid is a single stranded RNA.
61 . The lipid nanoparticle of claim 59 , wherein the nucleic acid is a double stranded RNA.
62 . The lipid nanoparticle of claim 58 , wherein the nucleic acid is a single stranded DNA.
63 . The lipid nanoparticle of claim 58 , wherein the nucleic acid is a double stranded DNA.
64 . The lipid nanoparticle of claim 58 , wherein the nucleic acid is a DNA-RNA hybrid.
65 . A pharmaceutical composition comprising a lipid nanoparticle according to claim 58 and a pharmaceutically acceptable diluent.
66 . A method of delivering an active agent to a cell, comprising providing to the cell a lipid nanoparticle of claim 58 .
67 . The method of claim 66 , wherein the nucleic acid is an RNA.
68 . The method of claim 67 , wherein the nucleic acid is a single stranded RNA.
69 . The method of claim 67 , wherein the nucleic acid is a double stranded RNA.
70 . The method of claim 66 , wherein the nucleic acid is a single stranded DNA.
71 . The method of claim 66 , wherein the nucleic acid is a double stranded DNA.
72 . The method of claim 66 , wherein the nucleic acid is a DNA-RNA hybrid.