Nanomaterials
The present disclosure describes compositions, preparations, nanoparticles (such as lipid nanoparticles), and/or nanomaterials and methods of their use.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
each of L 1 and L 1′ is independently a covalent bond, —C(O)—, or —OC(O)—;
each of L 2 and L 2′ is independently a covalent bond, an optionally substituted bivalent saturated or unsaturated, straight or branched C1-C12 hydrocarbon chain, or
each Cy A is independently an optionally substituted ring selected from phenylene or 3- to 7-membered saturated or partially unsaturated carbocyclene;
each m is independently 0, 1, or 2;
each of L 3 and L 3′ is independently a covalent bond, —O—, —C(O)O—, —OC(O)—, or —OC(O)O—;
each of R 1 and R 1′ is independently an optionally substituted group selected from saturated or unsaturated, straight or branched C 1 -C 20 hydrocarbon chain wherein 1-3 methylene units are optionally and independently replaced with —O— or —NR—, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, 1-adamantyl, 2-adamantyl, sterolyl, phenyl, or
each L 4 is independently a bivalent saturated or unsaturated, straight or branched C 1 -C 20 hydrocarbon chain;
each A 1 and A 2 is independently an optionally substituted C 1 -C 20 aliphatic or -L 5 -R 5 ,
or A 1 and A 2 , together with their intervening atoms, may form an optionally substituted ring:
wherein
x is selected from 1 or 2; and
# represents the point of attachment to L 4 ;
each L 5 is independently a bivalent saturated or unsaturated, straight or branched C 1 -C 20 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with —O— or —NR—;
each R 5 is independently an optionally substituted group selected from a 6- to 10-membered aryl ring or a 3- to 8-membered carbocyclic ring;
Y 1 is a covalent bond, —C(O)—, or —C(O)O—;
Y 2 is a bivalent saturated or unsaturated, straight or branched C 1 -C 6 hydrocarbon chain, wherein 1-2 methylene units are optionally and independently replaced with cyclopropylene, —O—, or —NR—;
Y 3 is an optionally substituted group selected from saturated or unsaturated, straight or branched C 1 -C 14 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with —O— or —NR—, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, 1-adamantyl, 2-adamantyl, or phenyl;
X 1 is a covalent bond, —O—, or —NR—;
X 2 is an optionally substituted bivalent saturated or unsaturated, straight or branched C 1 -C 12 hydrocarbon chain, wherein 1-3 methylene units are optionally and independently replaced with —O—, —NR—, or -Cy B -;
each Cy B is independently an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclene, phenylene, 3- to 7-membered heterocyclene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
X 3 is hydrogen or an optionally substituted ring selected from 3- to 7-membered saturated or partially unsaturated carbocyclyl, phenyl, 3- to 7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R is independently hydrogen or an optionally substituted C 1 -C 6 aliphatic group.
2. The compound of claim 1 , wherein R 1 is
3. The compound of claim 1 , wherein each of A 1 and A 2 is independently selected from:
4. The compound of claim 1 , wherein R 1′ is selected from:
5. The compound of claim 1 , wherein —X 2 —X 3 is selected from:
6. The compound of claim 1 , wherein the compound is of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein n1 is 1, 2, 3, or 4.
7. The compound of claim 1 , wherein the compound is of Formula (IIA):
or a pharmaceutically acceptable salt thereof, wherein n1 is 1, 2, 3, or 4; and n2 is 1, 2, 3, 4, 5, 6, or 7.
8. The compound of claim 1 , wherein the compound is of Formula (IIB):
or a pharmaceutically acceptable salt thereof, wherein n1 is 1, 2, 3, or 4; and n2 is 1, 2, 3, 4, 5, 6, or 7.
9. The compound of claim 1 , wherein the compound is of Formula (IIC):
or a pharmaceutically acceptable salt thereof, wherein n1 is 1, 2, 3, or 4; and n2 is 1, 2, 3, 4, 5, 6, or 7.
10. The compound of claim 1 , wherein the compound is of Formula (III):
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein the compound is of Formula (IIIA):
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , wherein the compound is of Formula (IV):
or a pharmaceutically acceptable salt thereof, wherein n1 is 1, 2, 3, or 4.
13. The compound of claim 1 , wherein the compound is of Formula (V):
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , wherein the compound is of Formula (VA):
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , wherein the compound is of Formula (VI):
or a pharmaceutically acceptable salt thereof, wherein n1 is 1, 2, 3, or 4.
16. The compound of claim 1 , wherein the compounds is of Formula (VIA):
or a pharmaceutically acceptable salt thereof, wherein n1 is 1, 2, 3, or 4.
17. The compound of claim 1 , wherein the compound is selected from
or a pharmaceutically acceptable salt thereof.
18. A lipid nanoparticle (LNP) preparation comprising an ionizable lipid according to claim 1 .
19. A pharmaceutical composition comprising a LNP preparation of claim 18 and a pharmaceutically acceptable excipient.
20. A method for administering a therapeutic and/or prophylactic agent to a subject in need thereof, the method comprising administering the LNP preparation of claim 18 to the subject.
21. A method for treating a disease or a disorder in a subject in need thereof, the method comprising administering the LNP preparation of claim 18 to the subject, wherein the therapeutic and/or prophylactic agent is effective to treat the disease.
22. A method of delivering a therapeutic and/or prophylactic agent to a mammalian cell derived from a subject, the method comprising contacting the cell of the subject having been administered the LNP preparation of claim 18 .
23. A method of producing a polypeptide of interest in a mammalian cell, the method comprising contacting the cell with the LNP preparation of claim 18 , wherein the therapeutic and/or prophylactic agent is or comprises an mRNA, and wherein the mRNA encodes the polypeptide of interest, whereby the mRNA is capable of being translated in the cell to produce the polypeptide of interest.
24. A method of inhibiting production of a polypeptide of interest in a mammalian cell, the method comprising contacting the cell with the LNP preparation of claim 18 , wherein the therapeutic and/or prophylactic agent is or comprises an RNA, whereby the RNA is capable of inhibiting production of the polypeptide of interest.
25. A method of specifically delivering a therapeutic and/or prophylactic agent to a mammalian organ, the method comprising contacting a mammalian organ with the LNP preparation of claim 18 , whereby the therapeutic and/or prophylactic agent is delivered to the organ.
26. A method of vaccinating by administering the LNP preparation of claim 18 .
27. A method of inducing an adaptive immune response in a subject, comprising administering to the subject an effective amount of a composition comprising at least one RNA; wherein the composition comprises a LNP preparation comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof.