Cyclic cationic lipids and methods of use

Patent metadata

Field	Value
Publication number	US-10077232-B2
Application number	US-201113696999-A
Country	US
Kind code	B2
Filing date	May 12, 2011
Priority date	May 12, 2010
Publication date	Sep 18, 2018
Grant date	Sep 18, 2018

Abstract

The present invention provides compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel cationic lipids and nucleic acid-lipid particles that provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo. The compositions of the present invention are highly potent, thereby allowing effective knock-down of a specific target protein at relatively low doses. In addition, the compositions and methods of the present invention are less toxic and provide a greater therapeutic index compared to compositions and methods previously known in the art.

First claim

What is claimed is:

1. A cationic lipid of Formula III having the following structure:

or salts thereof, wherein:
R 1 and R 2 are either the same or different and are independently hydrogen (H) or an optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, or R 1 and R 2 may join to form an optionally substituted heterocyclic ring;
R 3 is either absent or is hydrogen (H) or a C 1 -C 6 alkyl to provide a quaternary amine;
R 4 and R 5 are either the same or different and are independently an optionally substituted C 10 -C 24 alkyl, C 10 -C 24 alkenyl, C 10 -C 24 alkynyl, or C 10 -C 24 acyl, wherein at least one of R 4 and R 5 comprises at least one optionally substituted cyclic alkyl group;
X is O, S, N(R 6 ), C(O), C(O)O, OC(O), C(O)N(R 6 ), N(R 6 )C(O), OC(O)N(R 6 ), C(O)O, C(O)S, C(S)O, S(O), S(O)(O), C(S), or an optionally substituted heterocyclic ring, wherein R 6 is hydrogen (H) or an optionally substituted C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl; and
Y is either absent or is an optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl.

2. The cationic lipid of claim 1 , wherein R 1 and R 2 are independently selected from the group consisting of a methyl group and an ethyl group.

3. The cationic lipid of claim 1 , wherein X is C(O)O or O.

4. The cationic lipid of claim 1 , wherein Y is (CH 2 ) n and n is 0, 1, 2, 3, 4, 5, or 6.

5. The cationic lipid of claim 4 , wherein n is 2, 3, or 4.

6. The cationic lipid of claim 1 , wherein the at least one optionally substituted cyclic alkyl group comprises an optionally substituted saturated cyclic alkyl group, an optionally substituted unsaturated cyclic alkyl group, or a combination thereof.

7. The cationic lipid of claim 6 , wherein the optionally substituted saturated cyclic alkyl group comprises an optionally substituted C 3-8 cycloalkyl group.

8. The cationic lipid of claim 6 , wherein the optionally substituted saturated cyclic alkyl group comprises a cyclopropyl group.

9. The cationic lipid of claim 6 , wherein the optionally substituted unsaturated cyclic alkyl group comprises an optionally substituted C 3-8 cycloalkenyl group.

10. The cationic lipid of claim 1 , wherein R 4 and R 5 both independently comprise at least one, two, or three optionally substituted cyclic alkyl groups.

11. The cationic lipid of claim 1 , wherein R 4 and R 5 are both C 12 -C 20 alkyl groups having at least one, two, or three optionally substituted cyclic alkyl groups.

12. The cationic lipid of claim 1 , wherein R 4 and R 5 are both C 18 alkyl groups having at least one, two, or three optionally substituted cyclic alkyl groups.

13. The cationic lipid of claim 10 , wherein the at least one, two, or three optionally substituted cyclic alkyl groups comprise cyclopropyl groups.

14. The cationic lipid of claim 1 , wherein R 4 and R 5 both comprise the same number of optionally substituted cyclic alkyl groups.

15. The cationic lipid of claim 1 , wherein R 4 and R 5 both comprise the same type(s) of optionally substituted cyclic alkyl groups.

16. A cationic lipid having a structure selected from the group consisting of:

17. A lipid particle comprising a cationic lipid of claim 1 .

18. The lipid particle of claim 17 , wherein the particle further comprises a non-cationic lipid.

19. The lipid particle of claim 18 , wherein the non-cationic lipid is selected from the group consisting of a phospholipid, cholesterol, or a mixture of a phospholipid and cholesterol.

20. The lipid particle of claim 17 , wherein the particle further comprises a conjugated lipid that inhibits aggregation of particles.

21. The lipid particle of claim 20 , wherein the conjugated lipid that inhibits aggregation of particles comprises a polyethyleneglycol (PEG)-lipid conjugate.

22. The lipid particle of claim 21 , wherein the PEG-lipid conjugate comprises a PEG-diacylglycerol (PEG-DAG) conjugate, a PEG-dialkyloxypropyl (PEG-DAA) conjugate, or a mixture thereof.

23. The lipid particle of claim 17 , wherein the particle further comprises a therapeutic agent.

24. The lipid particle of claim 23 , wherein the therapeutic agent is a nucleic acid.

25. The lipid particle of claim 24 , wherein the nucleic acid is an interfering RNA.

26. The lipid particle of claim 25 , wherein the interfering RNA is an siRNA.

27. A pharmaceutical composition comprising a lipid particle of claim 17 and a pharmaceutically acceptable carrier.

28. A method for introducing a therapeutic agent into a mammalian cell, the method comprising:
contacting the cell with a lipid particle of claim 23 .

29. A method for the in vivo delivery of a therapeutic agent, the method comprising:
administering to a mammal a lipid particle of claim 23 .

30. The cationic lipid of claim 3 , wherein X is C(O)O.

Assignees

• Heyes James
• Wood Mark
• Martin Alan
• Arbutus Biopharma Corp

Inventors

• Heyes James
• Wood Mark
• Martin Alan

Classifications

• C07C229/12

  to carbon atoms of acyclic carbon skeletons · CPC title

• C07C2601/02

  with a three-membered ring · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C07C217/28 Primary

  having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines · CPC title

• A61K31/7105

  Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links · CPC title