NOVEL LIPIDS AND COMPOSITIONS FOR THE DELIVERY OF THERAPEUTICS
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:
1 . A cationic lipid having the formula:
or a pharmaceutically acceptable salt thereof, 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 independently for each occurrence H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, alkylheterocycle, 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;
X and Y are each independently O, S, alkyl or N(Q);
Q is H, alkyl, ω-amninoalkyl, ω-(substituted)amninoalkyl, ω-phosphoalkyl or ω-thiophosphoalkyl;
A 2 is O, S, CH 2 , CHF or CF 2 ;
Z′ is O, S, N(Q) or alkyl; and
j is 0-10.
2 . (canceled)
3 . (canceled)
4 . (canceled)
5 . (canceled)
6 . (canceled)
7 . (canceled)
8 . (canceled)
9 . The cationic lipid of claim 1 , wherein X and Y are O.
10 . (canceled)
11 . The cationic lipid of claim 1 , wherein A 2 is —CH 2 —.
12 . (canceled)
13 . (canceled)
14 . The cationic lipid of claim 1 , wherein Z′ is N(Q).
15 . (canceled)
16 . (canceled)
17 . The cationic lipid of claim 1 , wherein Z′ is alkyl.
18 . The cationic lipid of claim 1 , wherein R 3 is alkylamine.
19 . (canceled)
20 . (canceled)
21 . The cationic lipid of claim 1 , wherein Q is alkyl.
22 . (canceled)
23 . (canceled)
24 . (canceled)
25 . A cationic lipid of the formula
or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 are independently optionally substituted C 10 -C 30 alkyl or optionally substituted C 10 -C 30 alkenyl; and
X and Y are independently hydrogen or C 1 -C 4 alkyl, or X and Y together with the nitrogen atom to which they are directly bound form a mono- or bi-cyclic heterocycle.
26 . (canceled)
27 . (canceled)
28 . (canceled)
29 . (canceled)
30 . (canceled)
31 . (canceled)
32 . (canceled)
33 . (canceled)
34 . (canceled)
35 . (canceled)
36 . (canceled)
37 . (canceled)
38 . (canceled)
39 . (canceled)
40 . The cationic lipid of claim 25 , wherein the compound is
or a pharmaceutically acceptable salt thereof, wherein X and Y are hydrogen or C 1 -C 4 alkyl.
41 . (canceled)
42 . (canceled)
43 . A lipid particle comprising a compound of claim 1 .
44 . (canceled)
45 . A lipid particle comprising a compound of claim 25 .
46 . The lipid particle of claim 43 , wherein the particle further comprises a therapeutic agent.
47 . The lipid particle of claim 45 , wherein the particle further comprises a therapeutic agent.
48 . (canceled)
49 . The lipid particle of claim 46 , wherein the therapeutic agent is a nucleic acid.
50 . The lipid particle of claim 47 , wherein the therapeutic agent is a nucleic acid.
51 . (canceled)
52 . The lipid particle of claim 49 , wherein the nucleic acid is siRNA or mRNA.
53 . The lipid particle of claim 50 , wherein the nucleic acid is siRNA or mRNA.
54 . (canceled)
55 . A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject the lipid particle of claim 46 .
56 . A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject the lipid particle of claim 47 .