Biodegradable lipids for the delivery of active agents
The present invention relates to a cationic lipid having one or more biodegradable groups located in a lipidic moiety (e.g., a hydrophobic chain) of the cationic lipid. These cationic lipids may be incorporated into a lipid particle for delivering an active agent, such as a nucleic acid. The invention also relates to lipid particles comprising a neutral lipid, a lipid capable of reducing aggregation, a cationic lipid of the present invention, and optionally, a sterol. The lipid particle may further include a therapeutic agent such as a nucleic acid.
1. A cationic lipid comprising a primary group and two biodegradable hydrophobic tails, wherein (a) the primary group includes a head group and a central moiety to which both the biodegradable hydrophobic tails and the head group are directly bonded, wherein the primary group has a protonatable group having a pK a of from about 4 to about 11, (b) the cationic lipid has an in vivo half life (t 1/2 ) of less than about 3 hours in the liver, (c) the cationic lipid has a logP value of at least 10.1, and (d) each biodegradable hydrophobic tail has the formula -(hydrophobic chain)-(biodegradable group)-(hydrophobic chain),
wherein in at least one biodegradable hydrophobic tail,
(i) 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;
(ii) the biodegradable group is separated from a terminus of the hydrophobic tail by from 6 to 12 carbon atoms;
(iii) the 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 the biodegradable group, and R 13 is a branched C 10 -C 20 alkyl; and
(iv) the total carbon atom content of the tail —R 12 -M 1 -R 13 is 21 to 26.
2. The cationic lipid of claim 1 , 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 group, and a central heteroaryl group.
3. The cationic lipid of claim 1 , wherein the biodegradable group is —OC(O)—.
4. The cationic lipid of claim 1 , wherein the biodegradable group is —C(O)O—.
5. The cationic lipid of claim 1 , wherein the chain length of —R 12 -M 1 -R 13 is at most 21 atoms from the first carbon atom after the primary group to a terminus of the tail.
6. The cationic lipid of claim 1 , 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 polyethylene glycol (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) 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.
7. The cationic lipid of claim 1 , wherein in both biodegradable hydrophobic tails,
(i) 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;
(ii) the biodegradable group is separated from a terminus of the hydrophobic tail by from 6 to 12 carbon atoms;
(iii) the 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 the biodegradable group, and R 13 is a branched C 10 -C 20 alkyl; and
(iv) the total carbon atom content of the tail —R 12 -M 1 -R 13 is 21 to 26.
8. The cationic lipid of claim 1 , wherein the cationic lipid has a logP value of at least about 10.2.
9. The cationic lipid of claim 1 , wherein the cationic lipid has a t lipid −t chol value of at least about 1.75.
10. The cationic lipid of claim 1 , wherein the cationic lipid has a pKa value of from about 4 to about 7.
11. The cationic lipid of claim 10 , wherein the cationic lipid has a pKa value of from about 6 to about 6.5.
12. The cationic lipid of claim 1 , wherein the cationic lipid has a logP value of at least about 10.1 and/or a t lipid −t chol value of at least about 1.4.
13. 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 log P value of at least 10.1;
(ii) a pKa of from about 4 to about 7;
(iii) for at least one hydrophobic tail, the biodegradable group is separated from a terminus of the hydrophobic tail by from 6 to 12 carbon atoms;
(iv) for at least one hydrophobic tail, the total number of carbon atoms in the hydrophobic tail is from 21 to 26;
(v) 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;
(vi) for at least one hydrophobic tail, the total number of carbon atoms between the linker group and a terminus of the hydrophobic tail is from about 15 to about 20;
(vii) for at least one hydrophobic tail, the terminal hydrophobic chain in the hydrophobic tail is a branched alkyl or branched alkenyl group; and
(viii) 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.
14. The cationic lipid of claim 1 , wherein the branched alkyl group has only one carbon atom which is bound to three other carbon atoms.
15. The cationic lipid of claim 1 , wherein the at least one biodegradable hydrophobic tail has the formula
where R 13 is a branched alkyl group having from 13 to 17 carbon atoms, and the total carbon length of the tail from the first carbon to a terminus of the tail is at most 20.
16. A method of delivering a nucleic acid molecule comprising administering to a subject a lipid particle comprising:
(i) a nucleic acid molecule,
(ii) a cationic lipid according to claim 1 , and
(iii) a PEG lipid.
17. The method of claim 16 , wherein the pKa of the cationic lipid is 6.0 to 7.0.
18. A cationic lipid comprising a primary group and two biodegradable hydrophobic tails, wherein
the primary group comprises (i) a head group that optionally comprises a primary, secondary, or tertiary amine, and (ii) a central moiety to which the head group and the two biodegradable hydrophobic tails are directly bonded;
the central moiety is a central carbon or nitrogen atom;
each biodegradable hydrophobic tail independently has the formula -(hydrophobic chain)-(biodegradable group)-(hydrophobic chain), wherein the biodegradable group is —OC(O)— or —C(O)O—;
for at least one biodegradable hydrophobic tail, the terminal hydrophobic chain in the biodegradable hydrophobic tail is a branched alkyl, where the branching occurs at the α-position relative to the biodegradable group and the 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 the biodegradable group, R 13 is a branched C 10 -C 20 alkyl, and the total carbon atom content of the tail —R 12 -M 1 -R 13 is 21 to 26;
in at least one hydrophobic tail, the biodegradable group is separated from a terminus of the hydrophobic tail by from 6 to 12 carbon atoms; and
the lipid has a pKa in the range of about 4 to about 11 and a logP of at least 10.1.
19. The cationic lipid of claim 18 , wherein the biodegradable group is —OC(O)—.
20. The cationic lipid of claim 18 , wherein the biodegradable group is —C(O)O—.
21. The cationic lipid of claim 18 , wherein both biodegradable hydrophobic tails have the formula —R 12 -M 1 -R 13 .
22. The cationic lipid of claim 18 , wherein the chain length of —R 12 -M 1 -R 13 is at most 21 atoms from the first atom after the central moiety to a terminus of the tail.
23. The cationic lipid of claim 18 , wherein the lipid has a pKa of from about 5 to about 7 when incorporated into a lipid particle.
24. The cationic lipid of claim 18 , wherein, in at least one hydrophobic tail, the number of carbon atoms between the central moiety and the biodegradable group in the hydrophobic tail ranges from 5 to 10.
25. The cationic lipid of claim 18 , wherein, in at least one hydrophobic tail, the total number of carbon atoms between the central moiety and a terminus of the hydrophobic tail ranges from 15 to 20.
26. The cationic lipid of claim 18 , wherein in at least one hydrophobic tail, the biodegradable group is separated from a terminus of the hydrophobic tail by from 8 to 12 carbon atoms.
27. The cationic lipid of claim 26 , wherein in at least one hydrophobic tail, the biodegradable group is separated from a terminus of the hydrophobic tail by 8 carbon atoms.
28. The cationic lipid of claim 18 , wherein in both biodegradable hydrophobic tails,
(i) 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;
(ii) the biodegradable group is separated from a terminus of the hydrophobic tail by from 6 to 12 carbon atoms;
(iii) the 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 the biodegradable group, and R 13 is a branched C 10 -C 20 alkyl; and
(iv) the total carbon atom content of the tail —R 12 -M 1 -R 13 is 21 to 26.