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-aminoalkyl, ω-(substituted)aminoalkyl, 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 . The cationic lipid of claim 1 , wherein R 1 and R 2 are each independently unsubstituted C 10 -C 30 alkyl or unsubstituted C 10 -C 30 alkenyl.
3 . The cationic lipid of claim 1 , wherein R 1 and R 2 are each independently unsubstituted C 10 -C 30 alkenyl.
4 . The cationic lipid of claim 1 , wherein R 1 and R 2 are
5 . The cationic lipid of claim 1 , wherein R 1 and R 2 are each independently unsubstituted C 10 -C 30 alkyl.
6 . The cationic lipid of claim 1 , wherein R 1 and R 2 comprise the same number of unsaturation sites.
7 . The cationic lipid of claim 1 , wherein R 3 is a C 1 -C 10 alkyl.
8 . The cationic lipid of claim 1 , wherein R 3 is a heterocycle.
9 . The cationic lipid of claim 1 , wherein X and Y are O.
10 . The cationic lipid of claim 4 , wherein X and Y are O.
11 . The cationic lipid of claim 1 , wherein A 2 is —CH 2 —.
12 . The cationic lipid of claim 9 , wherein A 2 is —CH 2 —.
13 . The cationic lipid of claim 10 , wherein A 2 is —CH 2 —.
14 . The cationic lipid of claim 1 , wherein Z′ is N(Q).
15 . The cationic lipid of claim 9 , wherein Z′ is N(Q).
16 . The cationic lipid of claim 13 , wherein Z′ is N(Q).
17 . The cationic lipid of claim 1 , wherein Z′ is alkyl.
18 . The cationic lipid of claim 1 , wherein R 3 is alkylamine.
19 . The cationic lipid of claim 9 , wherein R 3 is alkylamine.
20 . The cationic lipid of claim 13 , wherein R 3 is alkylamine.
21 . The cationic lipid of claim 1 , wherein Q is alkyl.
22 . The cationic lipid of claim 14 , wherein Q is alkyl.
23 . The cationic lipid of claim 15 , wherein Q is alkyl.
24 . The cationic lipid of claim 16 , wherein Q is alkyl.
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 . The cationic lipid of claim 25 , wherein R 1 and R 2 are independently unsubstituted C 10 -C 30 alkyl or unsubstituted C 10 -C 30 alkenyl.
27 . The cationic lipid of claim 25 , wherein R 1 and R 2 are independently unsubstituted C 10 -C 30 alkyl.
28 . The cationic lipid of claim 25 , R 1 and R 2 are independently unsubstituted C 10 -C 30 alkenyl.
29 . The cationic lipid of claim 25 , wherein R 1 and R 2 are
30 . The cationic lipid of claim 25 , wherein X and Y are methyl.
31 . The cationic lipid of claim 26 , wherein X and Y are methyl.
32 . The cationic lipid of claim 27 , wherein X and Y are methyl.
33 . The cationic lipid of claim 28 , wherein X and Y are methyl.
34 . The cationic lipid of claim 29 , wherein X and Y are methyl.
35 . The cationic lipid of claim 25 , X and Y together are —(CH 2 ) n — where n is 4 to 6.
36 . The cationic lipid of claim 26 , X and Y together are —(CH 2 ) n — where n is 4 to 6.
37 . The cationic lipid of claim 27 , X and Y together are —(CH 2 ) n — where n is 4 to 6.
38 . The cationic lipid of claim 28 , X and Y together are —(CH 2 ) n — where n is 4 to 6.
39 . The cationic lipid of claim 29 , X and Y together are —(CH 2 ) n — where n is 4 to 6.
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 . The cationic lipid of claim 40 , wherein X and Y are methyl.
42 . The cationic lipid of claim 40 , wherein X and Y together are —(CH 2 ) n — where n is 4 to 6.
43 . A lipid particle comprising a compound of claim 9 .
44 . A lipid particle comprising a compound of claim 14 .
45 . A lipid particle comprising a compound of claim 25 .
46 . The lipid particle of claim 43 , wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.
47 . The lipid particle of claim 44 , wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.
48 . The lipid particle of claim 45 , wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.
49 . The lipid particle of claim 43 , further comprises a nucleic acid.
50 . The lipid particle of claim 44 , further comprises a nucleic acid.
51 . The lipid particle of claim 45 , further comprises a nucleic acid.
52 . The lipid particle of claim 49 , wherein the nucleic acid is an siRNA.
53 . The lipid particle of claim 50 , wherein the nucleic acid is an siRNA.
54 . The lipid particle of claim 51 , wherein the nucleic acid is an siRNA.