LIPIDS FOR DELIVERY OF THERAPEUTIC AGENTS
The current disclosure relates to lipid-based compositions and methods useful in administering therapeutic agents such as, for example, nucleic acids (e.g., siRNA, ASO, tRNA, miRNA, mRNA, DNA, and the like), proteins, peptides, and other macromolecules, which do not have the ability to easily cross a cell membrane. In particular, certain embodiments of the disclosure relate to reversible zwitterionic lipids having a tertiary amine with an increased pKa and extended linker domains (e.g., ≥C3), that may be incorporated into lipid-based compositions (e.g., lipid nanoparticles) to increase efficiency of delivery and release of a therapeutic agent(s) to a subject. The present disclosure provides compositions comprising such reversible zwitterionic lipids, optionally in association with a therapeutic agent (e.g., a therapeutic mRNA and/or nucleic acid controller system), as well as methods of synthesizing the ionizable lipid particle compositions provided herein.
1 . A pharmaceutical composition comprising a reversible zwitterionic lipid of Formula I having the following structure:
or a salt or isomer thereof, wherein
R 1 and R 2 are either the same or different and are independently C 7 -C 22 alkyl, C 7 -C 22 alkenyl, or C 7 -C 22 alkynyl, optionally R 1 , R 2 , or R 1 and R 2 are an optionally substituted heterocycle or R 1 and R 2 may join to form an optionally substituted heterocycle;
R 3 is optionally substituted C 3 -C 22 alkyl, C 3 -C 22 alkenyl, or C 3 -C 22 alkynyl; and
n is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22.
2 . The pharmaceutical composition of claim 1 , or salt or isomer thereof, wherein R 1 and R 2 are the same.
3 . The pharmaceutical composition of claim 1 , or salt or isomer thereof, wherein R 1 or R 2 are independently selected from the group consisting of C 7 -C 18 alkyl, C 7 -C 18 alkenyl, and C 7 -C 18 alkynyl, and R 3 is optionally substituted C 7 -C 18 alkyl, C 7 -C 18 alkenyl, or C 7 -C 18 alkynyl, optionally wherein R 1 and R 2 are independently selected from the group of C 7 -C 18 alkyl, C 7 -C 18 alkenyl, or C 7 -C 18 alkynyl and R 3 is optionally substituted C 7 -C 18 alkyl, C 7 -C 18 alkenyl, or C 7 -C 18 alkynyl.
4 . The pharmaceutical composition of claim 3 , or salt or isomer thereof, wherein n is 3 or 4.
5 . The pharmaceutical composition of claim 1 , or salt or isomer thereof, wherein R 1 or R 2 are independently selected from the group consisting of C 7 -C 12 alkyl, C 7 -C 12 alkenyl, and C 7 -C 12 alkynyl, and R 3 is optionally substituted C 7 -C 12 alkyl, C 7 -C 12 alkenyl, or C 7 -C 12 alkynyl, and n is 3, 4, 5, 6, 7, or 8, optionally wherein R 1 and R 2 are independently selected from the group consisting of C 7 -C 12 alkyl, C 7 -C 12 alkenyl, and C 7 -C 12 alkynyl and R 3 is optionally substituted C 7 -C 12 alkyl, C 7 -C 12 alkenyl, or C 7 -C 12 alkynyl and n is 3, 4, 5, 6, 7, or 8.
6 . The pharmaceutical composition of claim 5 , or salt or isomer thereof, wherein n is 3 or 4.
7 . The pharmaceutical composition of claim 1 , or salt or isomer thereof, wherein R 1 is selected from the group consisting of C 7 -C 10 alkyl, C 7 -C 10 alkenyl, and C 7 -C 10 alkynyl, R 2 is the same as R 1 , and R 3 is optionally substituted C 7 -C 12 alkyl, C 7 -C 12 alkenyl, or C 7 -C 12 alkynyl and n is 3, 4, 5, 6, or 7.
8 . The pharmaceutical composition of claim 7 , or salt or isomer thereof, wherein n is 3 or 4.
9 . The pharmaceutical composition of claim 1 , or salt or isomer thereof, wherein R 1 and R 2 are independently C 8 -C 12 alkyl, R 3 is optionally substituted C 8 -C 12 alkyl, and n is 3 or 4.
10 . The pharmaceutical composition of claim 1 , or salt or isomer thereof, wherein R 1 is C 8 -C 12 alkyl, R 2 is the same as R 1 , R 3 is optionally substituted C 8 -C 12 alkyl, and n is 3 or 4.
11 . The pharmaceutical composition of claim 1 , or salt or isomer thereof, wherein R 1 , R 2 , and R 3 are independently an alkyl selected from the group consisting of heptane, octane, nonane, decane, undecane, and dodecane.
12 . The pharmaceutical composition of claim 1 , or salt or isomer thereof, wherein one or more of R 1 , R 2 , and R 3 are independently an alkenyl selected from the group consisting of hept-1-ene, hept-2-ene, hept-3-ene, oct-1-ene, oct-2-ene, oct-3-ene, oct-4-ene, non-1-ene, non-2-ene, non-3-ene, non-4-ene, non-5-ene, dec-1-ene, dec-2-ene, dec-3-ene, dec-4-ene, dec-5-ene, dec-6-ene, undec-1-ene, undec-2-ene, undec-3-ene, undec-4-ene, undec-5-ene, undec-6-ene, undec-7-ene, dodec-1-ene, dodec-2-ene, dodec-3-ene, dodec-4-ene, dodec-5-ene, dodec-6-ene, dodec-8-ene, and an alkenyl group comprising two or more double bonds.
13 . The pharmaceutical composition of claim 1 , or salt or isomer thereof, wherein one or more of R 1 , R 2 , and R 3 are independently an alkynyl selected from the group consisting of hept-1-yne, hept-2-yne, hept-3-yne, oct-1-yne, oct-2-yne, oct-3-yne, oct-4-yne, non-1-yne, non-2-yne, non-3-yne, non-4-yne, non-5-yne, dec-1-yne, dec-2-yne, dec-3-yne, dec-4-yne, dec-5-yne, dec-6-yne, undec-1-yne, undec-2-yne, undec-3-yne, undec-4-yne, undec-5-yne, undec-6-yne, undec-7-yne, dodec-1-yne, dodec-2-yne, dodec-3-yne, dodec-4-yne, dodec-5-yne, dodec-6-yne, dodec-8-yne, and an alkynyl group comprising two or more triple bonds.
14 . A pharmaceutical composition comprising a reversible zwitterionic lipid selected from among:
and salts and isomers thereof.
15 . A composition selected from among the following:
A pharmaceutical composition comprising a reversible zwitterionic lipid selected from among:
and salts and isomers thereof;
A pharmaceutical composition comprising a reversible zwitterionic lipid selected from among:
and salts and isomers thereof;
A pharmaceutical composition comprising a reversible zwitterionic lipid selected from among:
and salts and isomers thereof;
A pharmaceutical composition comprising a reversible zwitterionic lipid selected from among:
and salts and isomers thereof;
A pharmaceutical composition comprising a reversible zwitterionic lipid selected from among:
and salts and isomers thereof;
A pharmaceutical composition comprising a reversible zwitterionic lipid selected from among:
and salts and isomers thereof;
A pharmaceutical composition comprising a reversible zwitterionic lipid selected from among:
and salts and isomers thereof;
A reversible zwitterionic lipid selected from among:
and salts and isomers thereof.
16 - 22 . (canceled)
23 . A lipid particle comprising a reversible zwitterionic lipid of claim 15 .
24 . The lipid particle of claim 23 , further comprising a therapeutic agent.
25 . The lipid particle of claim 24 , wherein the therapeutic agent is a nucleic acid.
26 . A pharmaceutical composition comprising a lipid particle of claim 23 and a pharmaceutically acceptable excipient, carrier, or diluent.