BIODEGRADABLE LIPIDS FOR THE DELIVERY OF ACTIVE AGENTS

1 . A cationic lipid comprising a primary group and two biodegradable hydrophobic tails, wherein (a) the primary group comprises a protonatable group having a pK a of from about 4 to about 13, (b) the cationic lipid has an in vivo half life (t 1/2 ) of less than about 3 hours, and (c) at least one of the hydrophobic tails has the formula -(hydrophobic chain)-(biodegradable group)-(hydrophobic chain) where the terminal hydrophobic chain in the hydrophobic tail is a branched alkyl group. where the branching occurs at the α-position relative to the biodegradable group.

2 . The cationic lipid of claim 1 , wherein the primary group includes (i) a head group, and (ii) a central moiety to which both the biodegradable hydrophobic tails are directly bonded.

3 . The cationic lipid of claim 2 , wherein the central moiety is selected from the group consisting of a central carbon atom, a central nitrogen atom, a central carbocyclic group, a central aryl group, a central heterocyclic and a central heteroaryl group.

4 . The cationic lipid of claim 1 , wherein at least one biodegradable hydrophobic tail has the formula —R 12 -M 1 -R 13 , where R 12 is a C 4 -C 14 alkylene or C 4 -C 14 alkenylene, M 1 is a biodegradable group, and R 13 is a branched alkyl or branched alkenyl.

5 . The cationic lipid of claim 4 , wherein R n is a branched C 10 -C 20 alkyl or C 10 -C 20 alkenyl.

6 . The cationic lipid of claim 4 , wherein the chain length of —R 12 -M 1 -R 13 has at least 20 carbon atoms.

7 . The cationic lipid of claim 4 , wherein

each biodegradable group is independently selected from the group consisting of —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —OC(S)—, —C(S)O—, —S—S—, —C(R 5 )═N—, —N═C(R 5 )—, —C(R 5 )═N—O—, —O—N═C(R 5 )—, —C(O)(NR 5 )—, —N(R 5 )C(O)—, —C(S)(NR 5 )—, —N(R 5 )C(O)—, —N(R 5 )C(O)N(R 5 )—, —OC(O)O—, —OSi(R 5 ) 2 O—, —C(O)(CR 3 R 4 )C(O)O—, —OC(O)(CR 3 R 4 )C(O)—, or

each occurrence of R 3 and R 4 is, independently, H, halogen, OH, alkyl, alkoxy, —NH 2 , R 10 , alkylamino, or dialkylamino;

each occurrence of R 5 is, independently, H or alkyl;

each occurrence of R 10 is, independently, selected from PEG and polymers based on poly(oxazoline), poly(ethylene oxide), poly(vinyl alcohol), poly(glycerol), poly(N-vinylpyrrolidone), poly[N-(2-hydroxypropyl)methacrylamide] and poly(amino acid)s, wherein (i) the PEG or polymer is linear or branched, (ii) the PEG or polymer is polymerized by n subunits, (iii) n is a number-averaged degree of polymerization between 10 and 200 units and (iv) wherein the compound of formula has at most two R 10 groups; and

R 11 is a C 2 -C 8 alkyl or C 2 -C 8 alkenyl.

8 . The cationic lipid of claim 4 , wherein the biodegradable group is —OC(O)— or —C(O)O—.

9 . The cationic lipid of claim 1 , wherein the cationic lipid has a log P value of at least about 10.2.

10 . The cationic lipid of claim 1 , wherein the cationic lipid has a t lipid -t chol value of at least about 1.75.

11 . The cationic lipid of claim 1 , wherein the cationic lipid has a pKa value of from about 4 to about 7.

12 . The cationic lipid of claim 11 , wherein the cationic lipid has a pKa value of from about 6 to about 6.5.

13 . The cationic lipid of claim 1 , wherein the cationic lipid has a log P value of at least about 10.1 and/or a t lipid -t chol value of at least about 1.4.

14 . A cationic lipid comprising (i) a head group, (ii) two hydrophobic tails, each of the formula -(hydrophobic chain)-(biodegradable group)-(hydrophobic chain), and (iii) a linker group bound to the head group and the hydrophobic tails, wherein the cationic lipid has:

(i) a pKa of from about 4 to about 7;

(ii) in at least one hydrophobic tail, a biodegradable group is separated from the terminus of the hydrophobic tail by from about 6 to about 12 carbon atoms;

(iii) for at least one hydrophobic tail, the total number of carbon atoms in the hydrophobic tail is from about 17 to about 26;

(iv) for at least one hydrophobic tail, the number of carbon atoms between the linker group and the biodegradable group in the hydrophobic tail ranges from about 5 to about 10;

(v) for at least one hydrophobic tail, the total number of carbon atoms between the linker group and the terminus of the hydrophobic tail is from about 15 to about 20;

(vi) for at least one hydrophobic tail, the terminal hydrophobic chain in the hydrophobic tail is a branched alkyl or branched alkenyl group; and

(vii) when formulated as a lipid nanoparticle, the cationic lipid has an in vivo half life (t 1/2 ) in the liver of less than about 3 hours.

15 . The cationic lipid of claim 14 , wherein the cationic lipid has one or more of the following properties:

(viii) when formulated as a lipid nanoparticle, the cationic lipid is eliminated from the liver in mice with a greater than 10-fold reduction in lipid levels relative to C max within the first 24 hours post-dose;

(ix) when formulated as a lipid nanoparticle, the cationic lipid is eliminated from the spleen in mice with an equal or greater than 10-fold reduction in lipid levels relative to C max within the first 168 hours post-dose; and

(x) when formulated as a lipid nanoparticle, the cationic lipid is eliminated from plasma with a terminal plasma half-life (t 1/2β ) in rodents and non-human primates of 48 hours or shorter.

16 . A cationic lipid comprising (i) a head group, (ii) two hydrophobic tails, each of the formula -(hydrophobic chain)-(biodegradable group)-(hydrophobic chain), and (iii) a linker group bound to the head group and the hydrophobic tails, wherein (a) the cationic lipid has a log P of at least 10.1 and a pKa from 4 to 7, (b) the biodegradable group is separated from the terminus of the hydrophobic tail by 6 to 12 carbon atoms, (c) for both hydrophobic tails, the terminal hydrophobic chain in the hydrophobic tail is a branched alkyl group where the branching occurs at the α-position.

17 . A method of delivering a nucleic acid molecule comprising administering a nucleic lipid particle comprising:

(i) the nucleic acid molecule,

(ii) a cationic lipid having at least one hydrophobic tail of the formula -(hydrophobic chain)-(biodegradable group)-(hydrophobic chain) where the terminal hydrophobic chain in the hydrophobic tail is a branched alkyl where the branching occurs at the α position on the hydrophobic chain relative to the biodegradable group, and

(iii) a PEG lipid,

wherein the cationic lipid (a) remains intact until delivery of the nucleic acid molecule after which cleavage of the hydrophobic tail occurs in vivo, and (b) has a pKa of 6 to 7 and an in vivo half life (t 1/2 ) of less than about 3 hours.

18 . The method of claim 17 , wherein the pKa of the cationic lipid is 6.0 to 6.5.

19 . The method of claim 17 , wherein the biodegradable group is —OC(O)— or —C(O)O—.