Methods and compositions for delivery of active agents
View Patent ↗A lipid particle can include a cationic lipid. Synthesis of the cationic lipid can include a ylide-based reaction, such as a Wittig reaction or sulfur ylide reaction. In some cases, the synthesis can also include a Michael addition or a related addition reaction.
1. A compound of formula IA:
or a salt thereof, wherein
X and Y are each, independently, alkyl or aryl;
L 1 and L 2 are each, independently, alkylene linking units, which may optionally contain one or more double bonds and further may optionally be interrupted by one or more heteroatoms and/or one or more cycloalkylene groups;
R 1 and R 2 are each, independently, C 10 -C 30 aliphatic group, each of which may optionally contain one or more double bonds, and may optionally be interrupted by one or more heteroatoms and/or one or more cycloalkylene groups;
Z is —C(O)O—, —OC(O)—, —C(O)N(R 3 )—, —N(R 3 )C(O)—, —O(CO)N(R 3 ), —N(R 3 )C(O)O—, —C(O)N(R 3 )C(O)O—, —OC(O)N(R 3 )C(O)— or —N(R 3 )C(O)N(R 3 )—;
each occurrence of R 3 is, independently, H, alkyl or aryl, and
--- represents a single bond or a double bond, where when --- represents a single bond, C* is further substituted by hydrogen or alkyl,
wherein L 2 is a linear alkylene unit and contains one or more double bonds and one or more cycloalkylene groups.
2. The compound of claim 1 , wherein R 1 and R 2 are each, independently, C 10 -C 30 alkyl or C 10 -C 30 alkenyl.
3. The compound of claim 2 , wherein one of R 1 and R 2 is a linear C 10 -C 30 alkyl or C 10 -C 30 alkenyl group and the other of R 1 and R 2 is a branched C 10 -C 30 alkyl or C 10 -C 30 alkenyl group.
4. The compound of claim 1 , wherein Z is —C(O)O—, —C(O)N(R 3 )—, —O(CO)N(R 3 ), —C(O)N(R 3 )C(O)O—, or —N(R 3 )C(O)N(R 3 )—.
5. The compound of claim 4 , wherein R 3 is H or alkyl.
6. The compound of claim 1 , wherein
X and Y are each, independently, C 1 -C 4 alkyl; and
each occurrence of R 3 is independently H or C 1 -C 4 alkyl.
7. A compound selected from:
and salts thereof.
8. The compound of claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt.
9. The compound of claim 1 , wherein the compound is in the form of a cationic lipid.
10. A lipid particle comprising a neutral lipid, a lipid capable of reducing aggregation, and a cationic lipid of claim 9 .
11. The lipid particle of claim 10 , wherein the neutral lipid is selected from DSPC, DPPC, POPC, DOPE, or SM; the lipid capable of reducing aggregation is a PEG lipid; and the lipid particle further comprises a sterol.
12. The lipid particle of claim 10 , wherein the cationic lipid is present in a mole percentage of about 20% and about 60%; the neutral lipid is present in a mole percentage of about 5% to about 25%; the sterol is present in a mole percentage of about 25% to about 55%; and the PEG lipid is PEG-DMA, PEG-DMG, or a combination thereof, and is present in a mole percentage of about 0.5% to about 15%.
13. The lipid particle of claim 10 , further comprising an active agent.
14. The lipid particle of claim 13 , wherein the active agent is a nucleic acid selected from a plasmid, an immunostimulatory oligonucleotide, an siRNA, an antisense oligonucleotide, a microRNA, an antagomir, an aptamer, and a ribozyme.
15. A pharmaceutical composition comprising a lipid particle of claim 13 and a pharmaceutically acceptable carrier.
16. A method of modulating the expression of a target gene in a cell, comprising providing to the cell a lipid particle of claim 13 .
17. The method of claim 16 , wherein the active agent is a nucleic acid selected from a plasmid, an immunostimulatory oligonucleotide, an siRNA, an ami sense oligonucleotide, a microRNA, an antagomir, an aptamer, and a ribozyme.
18. A method of inducing an immune response in a subject, comprising providing to the subject the pharmaceutical composition of claim 15 , wherein the active agent is an immunostimulatory oligonucleotide.
19. The method of claim 16 , 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, SGRT1 gene, XBP1 gene, topoisomerase I gene, topoisomerase II alpha gene, p73 gene, p21(WAF1/CIP1) gene, p27(KIP1) gene, PPM ID gene, RAS gene, caveolin I gene, MIB I gene, MTAI gene, M68 gene, tumor suppressor genes, and p53 tumor suppressor gene.
20. The method of claim 19 , wherein the target gene contains one or more mutations.