Amino alcohol cationic lipids for oligonucleotide delivery
View Patent ↗The instant invention provides for novel cationic lipids that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with oligonucleotides. It is an object of the instant invention to provide a cationic lipid scaffold that is more efficacious than traditional cationic lipids. The present invention employs amino alcohols to enhance the efficiency of in vivo delivery of siRNA.
1. A cationic lipid of Formula A:
wherein:
R 1 and R 2 are independently selected from methyl, ethyl and propyl, wherein said methyl, ethyl and propyl is optionally substituted with one to three substituents selected from R′;
R 3 is selected from H, methyl, ethyl and propyl;
R′ is independently selected from halogen, R″, OR″, SR″, CN, CO 2 R″ and CON(R″) 2 ;
R″ is independently selected from H and (C 1 -C 6 )alkyl, wherein said alkyl is optionally substituted with halogen and OH;
L 1 is selected from C 4 -C 22 alkyl and C 4 -C 22 alkenyl, said alkyl and alkenyl are optionally substituted with R′; and
L 2 is selected from C 4 -C 22 alkyl and C 4 -C 22 alkenyl, said alkyl and alkenyl are optionally substituted with R′;
or any pharmaceutically acceptable salt or stereoisomer thereof.
2. A cationic lipid of Formula A according to claim 1 , wherein:
L 1 is C 4 -C 22 alkenyl.
3. A lipid nanoparticle comprising a cationic lipid according to claim 1 .
4. The lipid nanoparticle of claim 3 , wherein the nanoparticle comprises oligonucleotides.
5. The lipid nanoparticle of claim 4 wherein the oligonucleotides are siRNA or miRNA.
6. The lipid nanoparticle of claim 5 wherein the oligonucleotides are siRNA.
7. The lipid nanoparticle of claim 4 , wherein the lipid nanoparticle comprises cholesterol and PEG-DMG.
8. The lipid nanoparticle of claim 7 , wherein the lipid nanoparticle further comprises DSPC.