Lipid particles with asymmetric cationic lipids for RNA delivery

1. Lipid particles comprising a cationic lipid, wherein the cationic lipid comprises a compound of formula I

wherein

R 1 consists of a linear or branched alkyl consisting of 1 to 20 carbons, an alkenyl or alkynyl consisting of 2 to 12 carbons, or a cholesteryl;

R 2 consists of a linear or branched alkyl consisting of 1 to 20 carbons or an alkenyl consisting of 2 to 20 carbons;

L 1 consists of a linear alkylene consisting of 3 to 9 carbons or, when R 1 consists of a cholesteryl then L 1 consists of a linear alkylene or alkenylene consisting of 3 to 4 carbons;

X 1 consists of —O—(CO)— or —(CO)—O—;

X 2 consists of S or O;

L 2 consists of a bond or a linear alkylene of 1 to 6 carbons;

R 3 consists of a linear or branched alkylene with 1 to 6 carbons; and

R 4 and R 5 are the same or different, each consisting of a linear or branched alkyl of 1 to 6 carbons;

or a pharmaceutical preparation thereof.

2. The lipid particles of claim 1 , further comprising a nucleic acid.

3. The lipid particles of claim 2 , wherein the nucleic acid comprises a mRNA or a siRNA.

4. The lipid particles of claim 3 , wherein the mRNA or siRNA is encapsulated by the lipid particles.

5. The lipid particles of claim 4 , wherein 30-100% of the lipid particles have mRNA or siRNA encapsulated therein.

6. The lipid particles of claim 2 , comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more mRNA that express one or more polypeptides.

7. The lipid particles of claim 1 , further comprising a phospholipid.

8. The lipid particles of claim 7 wherein the phospholipid is phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyloleoyl phosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, distearoylphosphatidylcholine, or dilinoleoylphosphatidylcholine.

9. The lipid particles of claim 1 , further comprising a conjugated lipid.

10. The lipid particles of claim 9 , wherein the conjugated lipid is a polyethylene glycol (PEG) coupled to dialkyloxypropyls, PEG coupled to diacylglycerols, PEG coupled to cholesterol, PEG coupled to phosphatidylethanolamines, PEG conjugated to ceramides, cationic PEG lipids, polyoxazoline (POZ)-lipid conjugates, polyamide oligomers, and mixtures thereof.

11. The lipid particles of claim 10 , further comprising cholesterol, 5α-cholestanol, 5α-coprostanol, cholesteryl-(2′-hydroxy)-ethyl ether, cholesteryl-(4′-hydroxy)-butyl ether, 6-ketocholestanol, 5α-cholestane, cholestenone, 5α-cholestanone, 5α-cholestanone, cholesteryl decanoate, or mixtures thereof.

12. The lipid particles of claim 1 , further comprising a variety of lipids, wherein the cationic lipid comprises 30-70 mole % of lipids in the lipid particles.

13. The lipid particles of claim 1 , wherein the lipid particles have a mean diameter of 30 nm to 150 nm.

14. The lipid particles of claim 1 , wherein the cationic lipid comprises a compound of formula I wherein X 1 consists of —O—(CO)—.

15. The lipid particles of claim 1 , wherein the cationic lipid comprises a compound of formula I wherein X 2 consists of S.

16. The lipid particles of claim 1 , wherein the cationic lipid comprises a compound of formula I wherein R 3 consists of ethylene, n-propylene, or isopropylene.

17. The lipid particles of claim 1 , wherein the cationic lipid comprises a compound of formula I wherein R 4 and R 5 separately consist of methyl, ethyl, or isopropyl.

18. The lipid particles of claim 1 , wherein the cationic lipid comprises a compound of formula I wherein L 2 consists of a bond or a methylene.

19. The lipid particles of claim 1 , wherein the cationic lipid comprises a compound of formula I wherein R 1 and R 2 each consist of a branched alkyl; or each consists of 13-20 carbon atoms.

20. The lipid particles of claim 1 , wherein the cationic lipid is selected from the compounds of formula ATX-A-1 to ATX-A-22

or a pharmaceutically acceptable salt thereof.