METHODS AND COMPOSITIONS FOR DELIVERY OF ACTIVE AGENTS

1 . A cationic lipid having the formula:

or a pharmaceutically acceptable salt thereof, wherein

R 1 is a C 10 to C 30 group having the formula -L 1a -(CR 1a R 1b ) α -[L 1b -(CR 1a R 1b ) β ] γ -L 1c -R 1c , wherein:

L 1a is a bond, —CR 1a R 1b —, —O—, —CO—, —NR 1d —, —S—, or a combination thereof;

each R 1a and each R 1b , independently, is H; halo; hydroxy; cyano; C 1 -C 6 alkyl optionally substituted by halo, hydroxy, or alkoxy; C 3 -C 8 cycloalkyl optionally substituted by halo, hydroxy, or alkoxy; —OR 1c ; —NR 1c R 1d ; aryl; heteroaryl; or heterocyclyl;

each L 1b , independently, is a bond, —(CR 1a R 1b ) 1-2 —, —O—, —CO—, —NR 1d —, —S—,

or a combination thereof;

or has the formula

wherein j, k, and l are each independently 0, 1, 2, or 3, provided that the sum of j, k and l is at least 1 and no greater than 8; and R 1f and R 1g are each independently R 1b , or adjacent R 1f and R 1g , taken together, are optionally a bond;

or has the formula

wherein j and k are each independently 0, 1, 2, 3, or 4 provided that the sum of j and k is at least 1; and R 1f and R 1g are each independently R 1b , or adjacent R 1f and R 1g , taken together, are optionally a bond;

or has the formula:

wherein — Ar— is a 6 to 14 membered arylene group optionally substituted by zero to six R 1a groups;

or has the formula:

wherein -Het- is a 3 to 14 membered heterocyclylene or heteroarylene group optionally substituted by zero to six R 1a groups;

L 1c is —(CR 1a R 1b ) 1-2 —, —O—, —CO—, —NR 1d —, —S—,

or a combination thereof;

each R 1c is independently H; halo; hydroxy; cyano; C 1 -C 6 alkyl optionally substituted by halo, hydroxy, or alkoxy; C 3 -C 8 cycloalkyl optionally substituted by halo, hydroxy, or alkoxy; aryl; heteroaryl; or heterocyclyl; or R 1c has the formula:

each R 1d is independently H; halo; hydroxy; cyano; C 1 -C 6 alkyl optionally substituted by halo, hydroxy, or alkoxy; C 3 -C 8 cycloalkyl optionally substituted by halo, hydroxy, or alkoxy; aryl; heteroaryl; or heterocyclyl;

α is 0-6;

each β, independently, is 0-6;

γ is 0-6;

R 2 is a C 10 to C 30 group having the formula -L 2a -(CR 2a R 2b ) δ -[L 2b -(CR 2a R 2b ) ε ] ζ -L 2c -R 2c , wherein:

L 2a is a bond, —CR 2a R 2b —, —O—, —CO—, —NR 2d —, —S—, or a combination thereof;

each R 2a and each R 2b , independently, is H; halo; hydroxy; cyano; C 1 -C 6 alkyl optionally substituted by halo, hydroxy, or alkoxy; C 3 -C 8 cycloalkyl optionally substituted by halo, hydroxy, or alkoxy; —OR 1c ; —NR 1c R 1d ; aryl; heteroaryl; or heterocyclyl;

each L 2b , independently, is a bond, —(CR 1a R 1b ) 1-2 —, —O—, —CO—, —NR 1d —, —S—,

or a combination thereof; or has the formula

wherein j, k, and l are each independently 0, 1, 2, or 3, provided that the sum of j, k and l is at least 1 and no greater than 8; and R 2f and R 2g are each independently R 2b , or adjacent R 2f and R 2g , taken together, are optionally a bond;

or has the formula

wherein j and k are each independently 0, 1, 2, 3, or 4 provided that the sum of j and k is at least 1; and R 2f and R 2g are each independently R 2b , or adjacent R 2f and R 2g , taken together, are optionally a bond;

or has the formula:

wherein —Ar— is a 6 to 14 membered arylene group optionally substituted by zero to six R 2a groups

or has the formula:

wherein -Het- is a 3 to 14 membered heterocyclylene or heteroarylene group optionally substituted by zero to six R 2a groups;

L 2c is —(CR 2a R 2b ) 1-2 —, —O—, —CO—, —NR 1d , —S—,

or a combination thereof;

R 2c is H; halo; hydroxy; cyano; C 1 -C 6 alkyl optionally substituted by halo, hydroxy, or alkoxy; C 3 -C 8 cycloalkyl optionally substituted by halo, hydroxy, or alkoxy; aryl; heteroaryl; or heterocyclyl; or R 2c has the formula:

R 2d is H; halo; hydroxy; cyano; C 1 -C 6 alkyl optionally substituted by halo, hydroxy, or alkoxy; C 3 -C 8 cycloalkyl optionally substituted by halo, hydroxy, or alkoxy; aryl; heteroaryl; or heterocyclyl;

δ is 0-6;

each ε, independently, is 0-6;

ζ is 0-6;

Hd 1 is —X—(CR 3 R 4 ) n —N(R 5 )(R 6 )(R 7 ) and Hd 2 is H, halo, hydroxy, alkyl, or alkoxy;

or Hd 1 and Hd 2 , taken together, have the formula:

wherein:

X and Y are each independently —O—, —S—, —NR 8 —, —S—S—, —OC(O)—, —C(O)O—, —NR 8 C(O)—, —C(O)NR 8 —, —NR 8 C(O)O—, —OC(O)NR 8 —, —NR 8 C(O)NR 8 —, —NR 8 C(S)O—, —OC(S)NR 8 —, —NR 8 C(S)NR 8 —, or —CR 3 R 4 —;

each R 3 and each R 4 , independently, is H; halo; hydroxy; cyano; C 1 -C 6 alkyl optionally substituted by halo, hydroxy, or alkoxy; C 3 -C 8 cycloalkyl optionally substituted by halo, hydroxy, or alkoxy; aryl; heteroaryl; or heterocyclyl;

R 5 and R 6 are each independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl,

wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted by H; halo; hydroxy; cyano; oxo, nitro; C 1 -C 6 alkyl optionally substituted by halo, hydroxy, or alkoxy; C 3 -C 8 cycloalkyl optionally substituted by halo, hydroxy, or alkoxy; aryl; heteroaryl; or heterocyclyl;

or R 5 and R 6 are taken together with the N atom to which they are both attached to form a 3-8 membered heteroaryl or heterocyclyl;

wherein each of heteroaryl and heterocyclyl is optionally substituted by H; halo; hydroxy; cyano; oxo, nitro; C 1 -C 6 alkyl optionally substituted by halo, hydroxy, or alkoxy; C 3 -C 8 cycloalkyl optionally substituted by halo, hydroxy, or alkoxy; aryl; heteroaryl; or heterocyclyl;

R 7 is absent, H, alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl,

wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted by H; halo; hydroxy; cyano; oxo, nitro; C 1 -C 6 alkyl optionally substituted by halo, hydroxy, or alkoxy; C 3 -C 8 cycloalkyl optionally substituted by halo, hydroxy, or alkoxy; aryl; heteroaryl; or heterocyclyl;

R 8 is H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl,

wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted by H; halo; hydroxy; cyano; oxo, nitro; C 1 -C 6 alkyl optionally substituted by halo, hydroxy, or alkoxy; C 3 -C 8 cycloalkyl optionally substituted by halo, hydroxy, or alkoxy; aryl; heteroaryl; or heterocyclyl;

m is 0 to 6; and

n is 0 to 5.

2 . The cationic lipid of claim 1 , wherein R 1 is a C 12 to C 20 group having the formula -L 1a -(CR 1a R 1b ) α -[L 1b -(CR 1a R 1b ) β ] γ -L 1c -R 1c , wherein

at least one L 1b has the formula or has the formula

wherein j, k, and l are each independently 0, 1, 2, or 3, provided that the sum of j, k and l is at least 1 and no greater than 8; and R 1f and R 1g are each independently R 1b , or adjacent R 1f and R 1g , taken together, are optionally a bond.

3 . The cationic lipid of claim 2 , wherein at least one L 1b has the formula:

4 . The cationic lipid of claim 1 , wherein R 2c has the formula:

and L 2c is —NHC(O)—.

5 . (canceled)

6 . The cationic lipid of claim 1 , wherein -L 1a -(CR 1a R 1b ) α — is —(CH 2 ) 8 —.

7 . The cationic lipid of claim 6 , wherein at least one -[L 1b -(CR 1a R 1b ) β ]— is

8 . The cationic lipid of claim 7 , wherein -[L 1b -(CR 1a R 1b ) β ] γ — is

9 . The cationic lipid of claim 7 , wherein L 1c -R 1c is —(CH 2 ) 3 —CH 3 or —CH 3 .

10 . The cationic lipid of claim 1 , wherein R 1 and R 2 are free of carbon-carbon double-bonds.

11 . (canceled)

12 . The cationic lipid of claim 1 , wherein Hd 1 has the formula —X—(CR 3 R 4 ) n —N(R 5 )(R 6 )(R 7 ), Hd 2 is H, X is O, and R 7 is absent, and R 5 and R 6 are each independently alkyl optionally substituted by halo; hydroxy; cyano; oxo; nitro; C 3 -C 8 cycloalkyl optionally substituted by halo, hydroxy, or alkoxy; aryl; heteroaryl; or heterocyclyl.

13 - 14 . (canceled)

15 . The cationic lipid of claim 1 , wherein Hd 1 and Hd 2 , taken together, have the formula:

X and Y are each independently O, and m is 0, 1, or 2, n is 1, 2, 3, 4, or 5, R 7 is absent; and R 5 and R 6 are each independently alkyl optionally substituted by halo; hydroxy; cyano; oxo, nitro; C 3 -C 8 cycloalkyl optionally substituted by halo, hydroxy, or alkoxy; aryl; heteroaryl; or heterocyclyl.

16 - 20 . (canceled)

21 . A lipid particle comprising a neutral lipid, a lipid capable of reducing aggregation, and a cationic lipid of claim 1 .

22 . The lipid particle of claim 21 , wherein the neutral lipid is selected from DSPC, DPPC, POPC, DOPE, and SM; the lipid capable of reducing aggregation is a PEG lipid; and the lipid particle further comprises a sterol, 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 PEG lipid is PEG-DMA, PEG-DMG, or a combination thereof, and is present in a molar ratio of about 0.5% to about 15%.

23 . (canceled)

24 . The lipid particle of claim 21 , 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.

25 . (canceled)

26 . A pharmaceutical composition comprising a lipid particle of claim 24 and a pharmaceutically acceptable carrier.

27 . A method of modulating the expression of a target gene in a cell, comprising providing to the cell a lipid particle of claim 24 .

28 . (canceled)

29 . A method of treating a disease or disorder characterized by the overexpression of a polypeptide in a subject, comprising providing to the subject the pharmaceutical composition of claim 26 wherein the active agent is a nucleic acid selected from the group consisting of an siRNA, a microRNA, and an antisense oligonucleotide, and wherein the siRNA, microRNA, or antisense oligonucleotide includes a polynucleotide that specifically binds to a polynucleotide that encodes the polypeptide, or a complement thereof.

30 . A method of treating a disease or disorder characterized by underexpression of a polypeptide in a subject, comprising providing to the subject the pharmaceutical composition of claim 26 , wherein the active agent is a plasmid that encodes the polypeptide or a functional variant or fragment thereof.

31 . A method of inducing an immune response in a subject, comprising providing to the subject the pharmaceutical composition of claim 26 , wherein the active agent is an immunostimulatory oligonucleotide.

32 - 33 . (canceled)

34 . The cationic lipid of claim 1 having the formula

or a pharmaceutically acceptable salt thereof.