PEGylated lipids and their use for drug delivery

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

each of R 1 and R 2 , independently, is a C 10 to C 30 aliphatic group; wherein the aliphatic group is optionally substituted by one or more groups each independently selected from R a ; and wherein the aliphatic group is optionally interrupted by cycloalkylene, —O—, —S—, —C(O)—, —OC(O)—, —C(O)O—, —N(R c )—, —C(O)N(R c )—, or —N(R c )C(O)—;

X is —(CR a R b ) i , —O—, —S—, —C(O)—, —N(R c )—, —OC(O)—, —C(O)O—, —OC(O)O—, —C(O)N(R c )—, —N(R c )C(O)—, —OC(O)N(R c )—, —N(R c )C(O)O—, —N(R c )C(O)N(R c )—, —SC(O)N(R c )—, or —N(R c )C(O)S—;

Y is —(CR a R b ) i , —O—, —S—, —C(O)—, —N(R c )—, —OC(O)—, —C(O)O—, —OC(O)O—, —C(O)N(R c )—, —N(R c )C(O)—, —OC(O)N(R c )—, —N(R c )C(O)O—, —N(R c )C(O)N(R c )—, —SC(O)N(R c )—, or —N(R c )C(O)S—;

L is -L 1 -Z 1 -(L 2 -Z 2 ) c -L 3 -;

L 1 is a bond, —(CR 5 R 5′ ) i —, or —(CR 5 R 5′ ) i —(C(R a )═C(R b )) k —(C≡C) k —(CR a R b ) j —;

Z 1 is —O—, —S—, —N(R c )—, —OC(O)—, —C(O)O—, —OC(O)O—, —OC(O)N(R c )—, —N(R c )C(O)O—, —N(R c )C(O)—, —C(O)N(R c )—, —N═C(R a )—, —C(R a )═N—, —O—N═C(R a )—, or —O—N(R c )—;

L 2 is —(CR a R b ) p — or —(CR a R b ) j —(C(R a )═C(R b )) k —(C≡C) k —(CR a R b ) j ;

Z 2 is —O—, —S—, —N(R c )—, —OC(O)—, —C(O)O—, —OC(O)O—, —OC(O)N(R c )—, —N(R c )C(O)O—, —N(R c )C(O)—, —C(O)N(R c )—, —N═C(R a )—, —C(R a )═N—, —O—N═C(R a )—, or —O—N(R c )—;

L 3 is —(CR a R b ) i —;

each A, independently, is -L 4 -, —NH-(L 4 ) q —(CR a R b ) r —C(O)—, or —C(O)—(CR a R b ) r -(L 4 ) q -NH—; wherein each q, independently, is 0, 1, 2, 3, or 4; and each r, independently, is 0, 1, 2, 3, or 4;

each L 4 , independently, is —(CR a R b ) s O— or —O(CR a R b ) s —; wherein each s, independently, is 0, 1, 2, 3, or 4;

R 3 is —H, —R c , or —OR c ;

each of R 4 and R 4′ , independently, is —H, halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, or cycloalkoxy;

each R 5 and each R 5′ , independently, is —H, halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, or cycloalkyl;

or R 4 and one R 5 , taken together, form a 5- to 8-membered cycloalkyl or heterocyclic ring;

each R a , independently, is —H, halo, cyano, hydroxy, nitro, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, heteroaryl, or heterocyclyl;

each R b , independently, is —H, halo, cyano, hydroxy, nitro, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, heteroaryl, or heterocyclyl;

each R c is —H, alkyl, acyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl;

a is 0 or 1;

b ranges from 25 to 100;

c is 0 or 1;

each occurrence of i, independently, is 1, 2, 3, 4, 5, or 6; each occurrence of j, independently, is 0, 1, 2, or 3;

each occurrence of k, independently, is 0, 1, 2, or 3; and

p is 1 to 10;

with the proviso that

(i) X and Y are not simultaneously —CH 2 —; and

(ii) when a is 1 and L 1 is —CH 2 —, then

(a) X and Y are not simultaneously —O—; and

(b) X and Y are not simultaneously —C(O)O—.

2. The compound of claim 1 , wherein X is —(CH 2 ) i —.

3. The compound of claim 1 , wherein X is —CH 2 — and Y is —O—, —S—, —OC(O)—, —C(O)O—, —OC(O)N(R c )—, —N(R c )C(O)O—, —SC(O)N(R c )—, or —N(R c )C(O)S—.

4. The compound of claim 1 , wherein X is not —CH 2 —; and Y is —(CR a R b ) i —, —C(O)—, —N(R c )—, —C(O)N(R c )—, —N(R c )C(O)—, —OC(O)N(R c )—, —N(R c )C(O)O—, —N(R c )C(O)N(R c )—, —SC(O)N(R c )—, or —N(R c )C(O)S—.

5. The compound of claim 4 , wherein Z 1 is —C(O)O— or —C(O)N(R c )—.

6. The compound of claim 1 , wherein X is —N(R c )—, —C(O)N(R c )—, —N(R c )C(O)—, —OC(O)N(R c )—, —N(R c )C(O)O—, —N(R c )C(O)N(R c )—, —SC(O)N(R c )—, or —N(R c )C(O)S—.

7. The compound of claim 1 , wherein Y is —N(R c )—, —C(O)N(R c )—, —N(R c )C(O)—, —OC(O)N(R c )—, —N(R c )C(O)O—, —N(R c )C(O)N(R c )—, —SC(O)N(R c )—, or —N(R c )C(O)S—.

8. The compound of claim 1 , wherein each A is L 4 and each L 4 , independently, is —OCH 2 CH 2 —, —OCH 2 CH 2 CH 2 —, or —OCH 2 CH(CH 3 )—.

9. The compound of claim 1 , wherein R 3 is alkoxy.

10. The compound of claim 1 , wherein the molecular weight of the compound is between 500 g/mol and 5,000 g/mol.

11. The compound of claim 1 , wherein each of R 1 and R 2 , independently, is a C 12 to C 20 alkyl or a C 12 to C 20 alkenyl group.

12. The compound of claim 1 , wherein the variables q and s are each independently 1, 2, 3, or 4.

13. The compound of claim 1 , wherein:

each of R 1 and R 2 , independently, is a C 12 to C 20 alkyl or a C 12 to C 20 alkenyl group;

X is —CH 2 —, —O—, —OC(O)—, —C(O)O—, —C(O)NH—, —NHC(O)—, —OC(O)NH—, —NHC(O)O—, or —NHC(O)NH—;

Y is —O—, —S—, —OC(O)—, —NHC(O)—, —OC(O)NH—, —NHC(O)O—, —NHC(O)NH—, or —SC(O)NH—;

a is 1;

L 1 is a bond or —(CH 2 ) i —,

c is 0;

L 3 is —(CH 2 ) i —;

each A, independently, is -L 4 -;

each L 4 , independently, is —OCH 2 CH 2 — or —OCH 2 CH(CH 3 )—; and

R 3 is —OR c wherein R c is —H or alkyl.

14. A compound selected from:

and pharmaceutically acceptable salts thereof,

wherein

n ranges from 25 to 100; and

m is 1, 2, 3, 4, 5, or 6.

15. A lipid particle comprising a compound of claim 1 .

16. The lipid particle of claim 15 , further comprising a cationic lipid.

17. The lipid particle of claim 16 , further comprising a neutral lipid and a sterol.

18. The lipid particle of claim 17 , wherein the neutral lipid is selected from DSPC, DPPC, POPC, DOPE, or SM.

19. The lipid particle of claim 18 , wherein the cationic lipid is present in a molar ratio of about 20% and about 60%; the neutral lipid is present in a molar ratio of about 5% to about 25%; the sterol is present in a molar ratio of about 25% to about 55%; and the compound according to claim 1 is present in a molar ratio of about 0.5% to about 15%.

20. The lipid particle of claim 15 , further comprising an active agent, wherein the active agent is a nucleic acid selected from the group consisting of a plasmid, an immunostimulatory oligonucleotide, an siRNA, an antisense oligonucleotide, a microRNA, an antagomir, an aptamer, and a ribozyme.

21. A pharmaceutical composition comprising a lipid particle of claim 20 and a pharmaceutically acceptable carrier.

22. A method of modulating the expression of a target gene in a cell, comprising providing to the cell a lipid particle of claim 20 such that the expression of the target gene is modulated by the lipid particle.

23. A method of inducing an immune response in a subject, comprising providing to the subject the pharmaceutical composition of claim 21 , wherein the active agent is an immunostimulatory oligonucleotide and wherein the immune response is induced by the active agent in the pharmaceutical composition.

24. The method of claim 22 , wherein the target gene is selected from the group consisting of Factor VII, Eg5, PCSK9, TPX2, apoB, SAA, TTR, RSV, PDGF beta gene, Erb-B gene, Src gene, CRK gene, GRB2 gene, RAS gene, MEKK gene, JNK gene, RAF gene, Erk1/2 gene, PCNA(p21) gene, MYB gene, JUN gene, FOS gene, BCL-2 gene, Cyclin D gene, VEGF gene, EGFR gene, Cyclin A gene, Cyclin E gene, WNT-1 gene, beta-catenin gene, c-MET gene, PKC gene, NFKB gene, STAT3 gene, survivin gene, Her2/Neu gene, SORT1 gene, XBP1 gene, topoisomerase I gene, topoisomerase II alpha gene, p73 gene, p21(WAF1/CIP1) gene, p27(KIP1) gene, PPM1D gene, RAS gene, caveolin I gene, MIB I gene, MTAI gene, M68 gene, tumor suppressor genes, and p53 tumor suppressor gene.

25. The method of claim 24 , wherein the target gene contains one or more mutations.

26. The compound of claim 1 , wherein b ranges from 30 to 60.

27. The compound of claim 1 , wherein b ranges from 40 to 50.

28. The compound of claim 14 , wherein n ranges from 30 to 60.

29. The compound of claim 14 , wherein n ranges from 40 to 50.