Compositions for trna delivery as nanoparticles and methods of use thereof

Abstract

Compositions are provided that can be used to deliver a tRNA or tRNA derivative to a cell.SOLUTION: The disclosure provides nanoparticle compositions comprising a tRNA and an amino lipid delivery compound. The amino lipid delivery compound can be a dendrimer, dendron, or dendritic lipid, a polymer such as a polyamide or polyester, or a lipid having one or more hydrophobic moieties. In some embodiments, these compositions can be administered to a patient to treat a genetic disease or disorder, such as cystic fibrosis, Duchenne muscular dystrophy, or cancer.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 337,096, filed May 16, 2016, which is incorporated herein by reference in its entirety.

[0002] 1. Field The present disclosure relates generally to the fields of genetic diseases and disorders and pharmaceutical formulations, and more particularly to methods for delivering tRNA as nanoparticle compositions. [Background technology]

[0003] 2. Description of Related Art Protein synthesis in vivo is directed by the genetic code, which contains 61 three-base pair codons that code for different amino acids and three three-base pair codons that terminate protein synthesis. If a nucleic acid sequence encoding a protein is mutated to contain a stop codon in place of the codon for the adjacent amino acid, the resulting protein is premature and usually nonfunctional. Such mutations, called nonsense mutations, give rise to a number of different genetic diseases, including many cases of cystic fibrosis.

[0004] One potential treatment option would be to treat these nonsense mutations with tRNA, which allows the production of complete protein.Unfortunately, attempts to develop tRNA and tRNA compositions that can be administered to patients have only limited success.Therefore, new compositions and methods for delivering tRNA to patients are clinically important. Summary of the Invention

[0005] overview In some aspects, the present disclosure provides compositions that can be used to deliver tRNA or tRNA derivatives to cells. In some embodiments, the compositions (A) tRNA and; (B) Nanoparticle-forming aminolipid delivery compounds and In some embodiments, the aminolipid delivery compound is a dendrimer that includes a group that is positively charged at physiological pH and a lipophilic group, such as a dendrimer of the formula: Core - (repeating unit) n -Terminal group (I) wherein the core is linked to the repeat unit by removing one or more hydrogen atoms from the core and replacing them with the repeat unit; The core has the formula: TIFF2026034537000001.tif11128 formula, X1 is amino or alkylamino (C≦12) , dialkylamino (C≦12) , heterocycloalkyl (C≦12) , heteroaryl (C≦12) , or a substituted form thereof; R1 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; a is 1, 2, 3, 4, 5, or 6; or The core has the formula: TIFF2026034537000002.tif12128 formula, X2 is N(R5) y and; R5 is hydrogen, alkyl (C≦18) , or substituted alkyl (C≦18) and; y is 0, 1, or 2, provided that the sum of y and z is 3; R2 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; b is 1, 2, 3, 4, 5, or 6; z is 1, 2, or 3, provided that the sum of z and y is 3; or The core has the formula: TIFF2026034537000003.tif11128 formula, X3 is -NR6-, where R6 is hydrogen, alkyl (C≦8) , or substituted alkyl (C≦8) , -O-, or alkylaminodiyl (C≦8) , alkoxydiyl (C≦8) , Arendjiil (C≦8) , heteroarenediyl (C≦8) , heterocycloalkanediyl (C≦8) or a substituted form of any of these groups; R3 and R4 are each independently amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or substituted forms of either of these groups, or a group of the formula -(CH2CH2N) e (R c )R d is the basis of; where: e is 1, 2, or 3; R c and R d are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; c and d are each independently 1, 2, 3, 4, 5, or 6; or The core is an alkylamine (C≦18) , dialkylamine (C≦36) , heterocycloalkane (C≦12) or a substituted form of any of these groups; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: TIFF2026034537000004.tif17128 formula, A1 and A2 each independently represent -O-, -S-, or -NR a -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6)and; Y3 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: TIFF2026034537000005.tif11128In formula, X3 and X4 are alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R9 is alkyl (C≦8) or substituted alkyl (C≦8) and; The linker group has the formula: TIFF2026034537000006.tif16128 formula, Y1 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: TIFF2026034537000007.tif12128In formula, Y4 is alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either group; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino (C≦12), dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) where: R 11 is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6.

[0006] The aminolipid delivery compound can be a dendrimer of the following formula or a pharmaceutically acceptable salt thereof: The core has the formula: TIFF2026034537000008.tif10128 formula, X1 is amino or alkylamino (C≦12) , dialkylamino (C≦12) , heterocycloalkyl (C≦12) , heteroaryl (C≦12) , or a substituted form thereof; R1 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; a is 1, 2, 3, 4, 5, or 6; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: TIFF2026034537000009.tif17128In formula, A1 and A2 each independently represent -O- or -NR a -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl(C≦6) and; Y3 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: TIFF2026034537000010.tif11128 formula, X3 and X4 are alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R9 is alkyl (C≦8) or substituted alkyl (C≦8) and; The linker group has the formula: TIFF2026034537000011.tif16128 formula, Y1 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: TIFF2026034537000012.tif12128 formula, Y4 is alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either group; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino(C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) where: R 11 is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6.

[0007] In some embodiments, the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof: Core - (repeating unit) n -Terminal group (I) wherein the core is linked to the repeat unit by removing one or more hydrogen atoms from the core and replacing them with the repeat unit; The core has the formula: TIFF2026034537000013.tif12128 formula, X2 is N(R5) y and; R5 is hydrogen or alkyl (C≦8) , or substituted alkyl (C≦18) and; y is 0, 1, or 2, provided that the sum of y and z is 3; R2 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; b is 1, 2, 3, 4, 5, or 6; z is 1, 2, or 3, provided that the sum of z and y is 3; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: TIFF2026034537000014.tif17128In formula, A1 and A2 each independently represent -O- or -NR a -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; Y3 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: TIFF2026034537000015.tif11128 formula, X3 and X4 are alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R9 is alkyl (C≦8) or substituted alkyl (C≦8) and; The linker group has the formula: TIFF2026034537000016.tif16128 formula, Y1 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: TIFF2026034537000017.tif12128 formula, Y4 is alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either group; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) and The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6.

[0008] In some embodiments, the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof: Core - (repeating unit) n -Terminal group (I) wherein the core is linked to the repeat unit by removing one or more hydrogen atoms from the core and replacing them with the repeat unit; The core has the formula: TIFF2026034537000018.tif11128In formula, X3 is -NR6-, where R6 is hydrogen, alkyl (C≦8), or substituted alkyl (C≦8) , -O-, or alkylaminodiyl (C≦8) , alkoxydiyl (C≦8) , Arendjiil (C≦8) , heteroarenediyl (C≦8) , heterocycloalkanediyl (C≦8) or a substituted form of any of these groups; R3 and R4 are each independently amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or substituted forms of either of these groups, or a group of the formula -(CH2CH2N) e (R c )R d is the basis of; where: e is 1, 2, or 3; R c and R d are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; c and d are each independently 1, 2, 3, 4, 5, or 6; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: TIFF2026034537000019.tif17128 formula, A1 and A2 each independently represent -O- or -NR a -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; Y3 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: TIFF2026034537000020.tif11128 formula, X3 and X4 are alkanediyl (C≦12) , Alkendiyl (C≦12), Arendjiil (C≦12) or a substituted form of any of these groups; Y5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R9 is alkyl (C≦8) or substituted alkyl (C≦8) and; The linker group has the formula: TIFF2026034537000021.tif16128 formula, Y1 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: TIFF2026034537000022.tif12128 formula, Y4 is alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either group; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) where: R 11 is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6.

[0009] Y4 is alkanediyl (C≦18) or alkanediyl (C≦18) Alkanediyl in which one or more hydrogen atoms are replaced by -OH, -F, -Cl, -Br, -I, -SH, -OCH3, -OCH2CH3, -SCH3, or -OC(O)CH3 (C≦18) may be.

[0010] In other embodiments, the aminolipid delivery compound is an amino lipid comprising an anionic carboxylic acid group, a sulfonic acid group, or a phosphate group, a quaternary amino group, an amino group that is positively charged at physiological pH, and a lipophilic group. In some embodiments, the aminolipid delivery compound is further defined as the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000023.tif13128 formula, X1 is -S(O)2O - , -OP(O)OR e O - , -(CHR f ) z C(O)O - , or -NR g R h R i + where: R e , R g , R h , and R i are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R f is hydrogen, amino, hydroxy, or alkyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl(C≦12) , acyl (C≦12) , alkoxy (C≦12) , acyloxy (C≦12) , amide (C≦12) , alkoxy (C≦12) , alkoxy (C≦12) or a substituted form of any of the last ten groups; z is 1, 2, 3, or 4; Y1 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) , heteroarenediyl (C≦12) , heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) -Alkanediyl (C≦8) , -alkanediyl (C≦8) -heteroarenediyl (C≦12) , -alkanediyl (C≦8) -heteroarenediyl (C≦12) -Alkanediyl (C≦8) or a substituted form of any of these groups; Z1 is -N + R3R4- or -OP(O)O - O-; A is -NR a -, -S-, or -O-; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) or R a together with R3 or R4 to form an alkanediyl (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; R1 is a group of the formula: TIFF2026034537000024.tif16128In formula, R5, R6, and R2 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z2A'R7; where Z2 is alkanediyl (C≦6) , substituted alkanediyl (C≦6) or a group of the formula: TIFF2026034537000025.tif10128 formula, Z5 and Z6 are each independently alkanediyl (C≦6) or substituted alkanediyl (C≦6) and; X2 and X3 each independently represent -O-, -S-, or -NR m - and where: R m is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; a is 0, 1, 2, 3, 4, 5, or 6; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24)or R5, R6, and R2 are each independently -Z3A''R8; Z3 is alkanediyl (C≦6) , substituted alkanediyl (C≦6) or a group of the formula: TIFF2026034537000026.tif10128 formula, Z7 and Z8 are each independently alkanediyl (C≦6) or substituted alkanediyl (C≦6) and; X4 and X5 each independently represent -O-, -S-, or -NR n - and where: R n is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; b is 0, 1, 2, 3, 4, 5, or 6; A'' is -CHR k -, -S-, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; R1 is a group of the formula: TIFF2026034537000027.tif11128 formula, Y2 is Arrange (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) , alkoxydiyl (C≦12)or a substituted form of any of these groups; R9, R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z4A'''R 12 where: Z4 is alkanediyl (C≦6) , substituted alkanediyl (C≦6) or a group of the formula: TIFF2026034537000028.tif10128In formula, Z9 and Z 10 are each independently an alkanediyl (C≦6) or substituted alkanediyl (C≦6) and; X6 and X7 each independently represent -O-, -S-, or -NR o - and where: R o is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; c is 0, 1, 2, 3, 4, 5, or 6; A''' is -CHR k -, -S-, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; x and y are 0, 1, 2, 3, or 4; R3 and R4 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6)Alternatively, R3 or R4 is R a Together with (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6; However, when X1 is positively charged, Z1 is negatively charged, and when X1 is negatively charged, Z1 is positively charged.

[0011] In other embodiments, the aminolipid delivery compound is an aminolipid comprising an anionic sulfonic acid group and a quaternary amino group, a lipophilic group, and an amino group that is protonated at physiological pH. In some embodiments, the aminolipid delivery compound is a compound of the following formula, or a pharmaceutically acceptable salt thereof: TIFF2026034537000029.tif16128 formula, Y1 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) , heteroarenediyl (C≦12) , heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) -Alkanediyl (C≦8) , -alkanediyl (C≦8) -heteroarenediyl (C≦12) , -alkanediyl (C≦8) -heteroarenediyl (C≦12) -Alkanediyl (C≦8) or a substituted form of any of these groups; A is -NR a -, -S-, or -O-; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6)or R a together with R3 or R4 to form an alkanediyl (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; R1 is a group of the formula: TIFF2026034537000030.tif16128In formula, R5, R6, and R2 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z2A'R7; where Z2 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and R2 are each independently -Z3A''R8; Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; R1 is a group of the formula: TIFF2026034537000031.tif11128 formula, Y2 is Arrange (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) , alkoxydiyl (C≦12) or a substituted form of any of these groups; R9, R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z4A'''R 12 is selected from; where Z4 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A''' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; x and y are 1, 2, 3, or 4; R3 and R4 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) Alternatively, R3 or R4 is R a Together with (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6; Alternatively, a compound of the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000032.tif16128 formula, A is -O- or -NR2-, where R2 is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R1 is a group of the formula: TIFF2026034537000033.tif16128 formula, R5, R6, and X1 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently -(CH2) s CH(OH)R7, -(CH2) s C(O)OR7, -(CH2) s C(O)(NR a )R7; where: s is 1, 2, 3, or 4; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and X1 each independently represent -(CH2) t CH(OH)R8, -(CH2) t C(O)OR8, -(CH2) t C(O)(NR b )R8; where: t is 1, 2, 3, or 4; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or q is 1, 2, or 3; r is 1, 2, 3, or 4; R1 is a group of the formula: TIFF2026034537000034.tif11128 formula, Y is Arenejiil (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) or a substituted form of any of these groups; R9, R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl(C≦8) , -(CH2) u CH(OH)R 12 , -(CH2) u C(O)OR 12 , -(CH2) u C(O)(NR c )R 12 is selected from; where u is 1, 2, 3, or 4; R c is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; R3 and R4 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) and; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6.

[0012] The aminolipid delivery compound can be a compound of the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000035.tif17128 formula, R1 is a group of the formula: TIFF2026034537000036.tif16128 formula, R5, R6, and R2 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8), or -Z2A'R7; where Z2 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and R2 are each independently -Z3A''R8; Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; R a , R3, and R4 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl(C≦6) and; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6; Alternatively, it may be a compound of the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000037.tif17128 formula, R1 is a group of the formula: TIFF2026034537000038.tif16128 formula, R5, R6, and X1 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently -(CH2) s CH(OH)R7, -(CH2) s C(O)OR7, -(CH2) s C(O)(NR a )R7; where: s is 1, 2, 3, or 4; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and X1 each independently represent -(CH2) t CH(OH)R8, -(CH2) t C(O)OR8, -(CH2) t C(O)(NR b )R8; where: t is 1, 2, 3, or 4; R bis hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or q is 1, 2, or 3; r is 1, 2, 3, or 4; R2, R3, and R4 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) and; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6.

[0013] In one embodiment, the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000039.tif17128 formula, R1 is a group of the formula: TIFF2026034537000040.tif11128 formula, Y is Arenejiil (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) or a substituted form of any of these groups; R9, R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , -(CH2) u CH(OH)R 12 , -(CH2) u C(O)OR 12 , -(CH2) u C(O)(NR c )R 12 is selected from; where u is 1, 2, 3, or 4; R c is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; R2, R3, and R4 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) and; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6.

[0014] In other embodiments, the aminolipid delivery compound comprises a sulfonamide group, a quaternary ammonium group, an amino group that is protonated at physiological pH, and a lipophilic group. In some embodiments, the aminolipid delivery compound is a compound of the following formula, or a pharmaceutically acceptable salt thereof: TIFF2026034537000041.tif16128 formula, R1 is a group of the formula: TIFF2026034537000042.tif12128 formula, R7 and R8 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000043.tif11128 formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦24) , acyloxy (C≦24) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4; R2, R3, R4, R5, and R6 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) and; m and n are each independently 1, 2, 3, 4, or 5.

[0015] The aminolipid delivery compound can be a compound of the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000044.tif16128 formula, R1, R2, and R3 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000045.tif12128 formula, R7 and R8 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000046.tif11128 formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦24) , acyloxy (C≦24) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4; R4, R5, and R6 are each independently hydrogen, alkyl, (C≦6) , or substituted alkyl (C≦6) and; m and n are each independently 1, 2, 3, 4, or 5.

[0016] In other embodiments, the amino lipid comprises a polyester group, a thioether group, and an amine group that is protonated at physiological pH. In some embodiments, the amino lipid comprises a polyester group of the following formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000047.tif18128 formula, X1 is alkyl (C≦18) or substituted alkyl(C≦18) and; X2 is hydrogen, alkyl (C≦18) , or substituted alkyl (C≦18) and; R1 is -AZ; where: A is alkanediyl (C≦18) or substituted alkanediyl (C≦18) and; Z is -NR3R4; where: R3 and R4 are each independently hydrogen, alkyl, or (C≦18) , substituted alkyl (C≦18) or R3 and R4 together are selected from alkanediyl; (C≦18) or substituted alkanediyl (C≦18) and; R2 is alkyl (C≦24) , alkenyl (C≦24) , substituted alkyl (C≦24) , or substituted alkenyl (C≦24) and; x and y are each independently 0, 1, 2, 3, 4, or 5; m and n each independently represent an integer of 0 to 250, provided that at least one of m and n exceeds 1; The repeat units defined by m and n are randomly distributed throughout the polymer.

[0017] In some embodiments, A is -CH2CH2-. Z can be -NR3R4; where R3 and R4 are each independently alkyl. (C≦18) or substituted alkyl (C≦18) In some embodiments, R3 is alkyl (C≦18) , for example, methyl, ethyl, propyl, or butyl. Similarly, R4 is alkyl (C≦18) In other embodiments, Z is -NR3R4; where R3 and R4 together represent an alkanediyl group. (C≦18) or substituted alkanediyl (C≦18) ,for example TIFF2026034537000048.tif4135. In some embodiments, X1 is alkyl (C≦18) or substituted alkyl (C≦18) X1 is alkyl (C≦6) or substituted alkyl (C≦6) For example, X1 is methyl. In some embodiments, X2 is hydrogen. In some embodiments, R2 is alkyl. (C≦24) butyl, hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl.

[0018] In one embodiment, x is 1. In one embodiment, y is 1. In some embodiments, m is an integer from 1 to 100. Furthermore, m can be an integer from 1 to 50. In one embodiment, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, n is an integer from 1 to 100. Furthermore, n can be an integer from 1 to 50. In one embodiment, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, the polymer comprises a molar ratio of repeating units m to repeating units n of about 10:1 to about 1:10. The molar ratio of repeating units m to repeating units n can be from about 5:1 to about 1:5, for example, 3:1, 1:1, or 1:3.

[0019] In some embodiments, the polymer has an average molecular weight of about 1,000 to about 100,000, for example, about 2,000 to about 10,000, as measured by gel permeation chromatography.

[0020] In some embodiments, the compound is further defined as the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000049.tif36128 formula, R1, R2, and R3 are each independently hydrogen, alkyl, or (C≦8) , or substituted alkyl (C≦8) and; R4 is hydrogen, halo, hydroxy, alkyl (C≦8) , or substituted alkyl (C≦8) and; R5 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either of these groups; R6 is Y1-R7; where: Y1 is alkanediyl (C≦8) , substituted alkanediyl (C≦8) , -(CH2) r C(O)- or -(CH2) r C(O)NR a (CH2) s - and; where: r and s are each independently 1, 2, or 3; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R7 is amino or heteroaryl (C≦12) , heterocycloalkyl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , arylalkylamino (C≦12) or a substituted form of any of these groups; a, b, m, d, e, and n are each independently 1, 2, 3, or 4; c and f are each independently 1 to 10; x and y are each independently an integer of 0 to 250, provided that at least one of x and y exceeds 1.

[0021] In some embodiments, a is 1 or 2. In one example, a can be 1. In some embodiments, b is 1 or 2. In one example, b can be 1. In some embodiments, m is 1 or 2. In one example, m can be 1. In some embodiments, d is 1 or 2. In one example, d can be 1. In some embodiments, e is 1 or 2. In one example, e can be 1. In some embodiments, n is 1 or 2. In one example, n can be 1. In some embodiments, c is 5 to 9, for example, 6 or 8. In some embodiments, f is 5 to 9, for example, 6 or 8.

[0022] In some embodiments, R1 is hydrogen. R2 is alkyl. (C≦8) In some embodiments, R3 can be alkyl, for example, ethyl. (C≦8) In some embodiments, R4 is hydroxy. In other embodiments, R4 is halo. In some embodiments, R5 is alkyl. (C≦24) or substituted alkyl (C≦24) R5 is alkyl (C≦24) , for example, hexyl, decyl, or dodecyl.

[0023] In some embodiments, R6 is Y1-R7; where: Y1 is alkanediyl (C≦8) or substituted alkanediyl (C≦8) and; R7 is amino or heteroaryl (C≦12) , heterocycloalkyl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , arylalkylamino (C≦12) or a substituted version of any of these groups.

[0024] Y1 can be -CH2CH2-. In some embodiments, R7 is amino. In other embodiments, R7 is alkylamino. (C≦12) , dialkylamino (C≦12) , arylalkylamino (C≦12)or a substituted version of any of these groups. R7 can be -NH2, -NHCH2CH2CH2CH3, -N(CH3)2, or -N(CH2CH3)2.

[0025] In other embodiments, R6 is Y1-R7; where: Y1 is -(CH2) r C(O)- or -(CH2) r C(O)NR a (CH2) s - and; where: r and s are each independently 1, 2, 3, or 4; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R7 is amino or heteroaryl (C≦12) , heterocycloalkyl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , arylalkylamino (C≦12) or a substituted version of any of these groups.

[0026] In some embodiments, r is 2 or 3. In one example, r can be 3. In some embodiments, s is 2 or 3. In one example, s can be 3. In some embodiments, R a is hydrogen. In some embodiments, R7 is heteroaryl (C≦12) or substituted heteroaryl (C≦12) In other embodiments, R7 is heterocycloalkyl, for example, pyridinyl or imidazolyl. (C≦12) or substituted heterocycloalkyl (C≦12) In other embodiments, R7 is a dialkylamino group, such as morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, 4-N-methylpiperazinyl, 4-N-(2-hydroxyethyl)piperazinyl, or 4-N-(2-dimethylaminoethyl)piperazinyl. (C≦12) or substituted dialkylamino (C≦12)In other embodiments, R7 is arylalkylamino, for example, dimethylamino, diethylamino, dibutylamino, di(2-hydroxyethyl)amino. (C≦12) or substituted arylalkylamino (C≦12) , for example (N-methyl,N-phenyl)amino.

[0027] In other embodiments, the dendrimer has the following formula or a pharmaceutically acceptable salt thereof: Core - (repeating unit) n -Terminal group (I) wherein the core is linked to the repeat unit by removing one or more hydrogen atoms from the core and replacing them with the repeat unit; The core is an alkylamine (C≦18) , dialkylamine (C≦36) , heterocycloalkane (C≦12) or a substituted form of any of these groups; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: TIFF2026034537000050.tif17128In formula, A1 and A2 each independently represent -O- or -NR a -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; Y3 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: TIFF2026034537000051.tif11128In formula, X3 and X4 are alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl(C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R9 is alkyl (C≦8) or substituted alkyl (C≦8) and; The linker group has the formula: TIFF2026034537000052.tif16128 formula, Y1 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: TIFF2026034537000053.tif12128 formula, Y4 is alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either of these groups; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) where: R 11 is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6.

[0028] In some embodiments, the terminal group is further defined by the formula: TIFF2026034537000054.tif12128 formula, Y4 is alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either of these groups; R 10 is hydrogen.

[0029] In other embodiments, the terminal group is further defined by the formula: TIFF2026034537000055.tif12128 formula, Y4 is alkanediyl (C≦18) and; R 10 is hydrogen.

[0030] In some embodiments, Y4 is alkanediyl (C4~18) In another embodiment, the terminal group is further defined by the formula: TIFF2026034537000056.tif12128 formula, Y4 is alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either of these groups; R 10 is alkylamino (C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) is.

[0031] In other embodiments, the terminal group is further defined by the formula: TIFF2026034537000057.tif12128 formula, Y4 is alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either of these groups; R10 is hydroxy.

[0032] In some embodiments, the core is further defined by the formula: TIFF2026034537000058.tif11128 formula, X1 is alkylamino (C≦12) , dialkylamino (C≦12) , heterocycloalkyl (C≦12) , heteroaryl (C≦12) or a substituted form thereof; R1 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; a is 1, 2, 3, 4, 5, or 6.

[0033] In some embodiments, X1 is alkylamino (C≦12) or substituted alkylamino (C≦12) In another embodiment, X is dialkylamino. (C≦12) or substituted dialkylamino (C≦12) In other embodiments, X is heterocycloalkyl. (C≦12) or substituted heterocycloalkyl (C≦12) In other embodiments, X is heteroaryl, for example, 4-piperidinyl, N-piperidinyl, N-morpholinyl, N-pyrrolidinyl, 2-pyrrolidinyl, N-piperazinyl, or N-4-methylpiperazinyl. (C≦12) or substituted heteroaryl (C≦12) , for example 2-pyridinyl or N-imidazolyl.

[0034] R1 can be hydroxyl or amino. In other embodiments, R1 is alkylamino. (C≦12) or substituted alkylamino (C≦12) In some embodiments, R is alkylamino (C≦12), for example, methylamino or ethylamino. In some embodiments, a is 1, 2, 3, or 4. Specifically, a can be 2 or 3. In some embodiments, a is 2. In other embodiments, a is 3. In some embodiments, the core is further defined as a compound of the formula: TIFF2026034537000059.tif82142.

[0035] In other embodiments, the core is further defined by the formula: TIFF2026034537000060.tif12128 formula, X2 is N(R5) y and; R5 is hydrogen or alkyl (C≦8) , or substituted alkyl (C≦18) and; y is 0, 1, or 2, provided that the sum of y and z is 3; R2 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; b is 1, 2, 3, 4, 5, or 6; z is 1, 2, or 3, provided that the sum of z and y is 3.

[0036] In some embodiments, X2 is N. In other embodiments, X2 is NR5, where R5 is hydrogen or alkyl. (C≦8) In some embodiments, R5 is hydrogen. In other embodiments, R5 is methyl. In some embodiments, z is 3. In other embodiments, z is 2.

[0037] R2 can be hydroxyl or amino. In other embodiments, R2 is alkylamino. (C≦12) or substituted alkylamino (C≦12) R2 is alkylamino (C≦12) In other embodiments, R2 can be dialkylamino. (C≦12) or substituted dialkylamino (C≦12)R2 is dialkylamino (C≦12) , e.g., dimethylamino. In some embodiments, b is 1, 2, 3, or 4. For example, b can be 2 or 3. In some embodiments, b is 2. In other embodiments, b is 3. In other embodiments, the core is further defined as: TIFF2026034537000061.tif56150.

[0038] In other embodiments, the core is further defined as: TIFF2026034537000062.tif11128 formula, X3 is -NR6-, where R6 is hydrogen, alkyl (C≦8) , or substituted alkyl (C≦8) , -O-, or alkylaminodiyl (C≦8) , alkoxydiyl (C≦8) , Arendjiil (C≦8) , heteroarenediyl (C≦8) , heterocycloalkanediyl (C≦8) or a substituted form of any of these groups; R3 and R4 are each independently amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or substituted forms of either of these groups, or a group of the formula -(CH2CH2N) e (R c )R d is the basis of; where: e is 1, 2, or 3; R c and R d are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; c and d are each independently 1, 2, 3, 4, 5, or 6.

[0039] In some embodiments, X3 is -O-. In other embodiments, X3 is -NR6-, where R6 is hydrogen, alkyl, (C≦8) , or substituted alkyl(C≦8) In other embodiments, X3 is alkylaminodiyl, for example, -NH- or -NCH3-. (C≦8) or substituted alkylaminodiyl (C≦8) In other embodiments, X3 is alkoxydiyl, for example, -NHCH2CH2NH- or -NHCH2CH2NHCH2CH2NH-. (C≦8) or substituted alkoxydiyl (C≦8) In other embodiments, X3 is arenediyl, for example, -OCH2CH2O-. (C≦8) or substituted arenediyl (C≦8) In other embodiments, X3 is heterocycloalkanediyl, for example, benzenediyl. (C≦8) or substituted heterocycloalkanediyl (C≦8) , for example N,N'-piperazinediyl.

[0040] In some embodiments, R3 is amino. R3 can be hydroxy. R3 can be alkylamino. (C≦12) or substituted alkylamino (C≦12) In some embodiments, R3 is alkylamino. (C≦12) For example, methylamino. R3 is dialkylamino. (C≦12) or substituted dialkylamino (C≦12) In some embodiments, R3 is dialkylamino. (C≦12) For example, dimethylamino. R4 can be amino. R4 can be hydroxy. R4 can be alkylamino. (C≦12) or substituted alkylamino (C≦12) In some embodiments, R4 is alkylamino. (C≦12) For example, methylamino. R4 is dialkylamino. (C≦12) or substituted dialkylamino (C≦12) In some embodiments, R4 is dialkylamino. (C≦12) In some embodiments, R4 is -(CH2CH2N) e (R c )R d and; where: e is 1, 2, or 3; R c and R d are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) is.

[0041] In some embodiments, e is 1 or 2. In one example, e can be 1. In some embodiments, R c is hydrogen. In some embodiments, R d is hydrogen. In some embodiments, c is 1, 2, 3, or 4. In one example, c can be 2 or 3. In some embodiments, c is 2. In other embodiments, c is 3. In some embodiments, d is 1, 2, 3, or 4. In one example, d can be 2 or 3. In some embodiments, d is 2. In other embodiments, d is 3. In other embodiments, the core is further defined as: TIFF2026034537000063.tif89146.

[0042] In other embodiments, the core is an alkylamine (C≦18) , dialkylamine (C≦36) , heterocycloalkane (C≦12) or a substituted version of any of these groups. In some embodiments, the core is an alkylamine (C≦18) or substituted alkylamines (C≦18) In other embodiments, the core is a dialkylamine, such as octylamine, decylamine, dodecylamine, tetradecylamine, hexadecylamine, and octadecylamine. (C≦36) or substituted dialkylamine (C≦36) In other embodiments, the core is a heterocycloalkane, such as N-methyl, N-dodecylamine, dioctylamine, or didecylamine. (C≦12) or substituted heterocycloalkane (C≦12) , for example 4-N-methylpiperazinyl.

[0043] In some embodiments, Y is alkanediyl (C≦8) or substituted alkanediyl (C≦8)Y1 is alkanediyl (C≦8) In some embodiments, Y3 can be alkanediyl, for example -CH2CH2-. (C≦8) or substituted alkanediyl (C≦8) Y3 is alkanediyl (C≦8) In other embodiments, Y3 is of the formula: TIFF2026034537000064.tif10128 formula, X3 and X4 are alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted version of any of these groups.

[0044] In some embodiments, X3 is alkanediyl (C≦12) or substituted alkanediyl (C≦12) In some embodiments, X4 is alkanediyl, for example -CH2CH2-. (C≦12) or substituted alkanediyl (C≦12) For example, -CH2CH2-. Y5 can be a covalent bond.

[0045] In other embodiments, Y3 is of the formula: TIFF2026034537000065.tif10128 formula, X3 and X4 are alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted version of any of these groups.

[0046] In some embodiments, X3 is alkanediyl (C≦12)or substituted alkanediyl (C≦12) For example, X3 is -CH2CH2-. In some embodiments, X4 is alkanediyl (C≦12) or substituted alkanediyl (C≦12) For example, -CH2CH2-. Y5 can be a covalent bond. In other embodiments, Y5 is -CH2- or -C(CH3)2-.

[0047] In some embodiments, A is -O-. In other embodiments, A is -NR a -R a can be hydrogen. In some embodiments, A2 is -O-. In other embodiments, A2 is -NR a -R a In some embodiments, R9 is alkyl. (C≦8) , e.g., methyl. In some embodiments, n is 0, 1, 2, 3, or 4. n can be 0, 1, 2, or 3. In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3.

[0048] In other embodiments, the compound is further defined as the following formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000066.tif16128 formula, R1 is a group of the formula: TIFF2026034537000067.tif15128 formula, R5, R6, and R2 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8), or -Z2A'R7; where Z2 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and R2 are each independently -Z3A''R8; Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6; Alternatively, it is further defined as a compound of the formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000068.tif16128 formula, R1 is a group of the formula: TIFF2026034537000069.tif16128 formula, R5, R6, and X1 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , -(CH2) s CH(OH)R7, -(CH2) s C(O)OR7, or -(CH2) s C(O)(NR a )R7; where: s is 1, 2, 3, or 4; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and X1 each independently represent -(CH2) t CH(OH)R8, -(CH2) t C(O)OR8, -(CH2) t C(O)(NR b )R8; where: t is 1, 2, 3, or 4; R b is hydrogen, alkyl (C≦6) , or substituted alkyl(C≦6) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or q is 1, 2, or 3; r is 1, 2, 3, or 4; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6.

[0049] In some embodiments, the compound is further defined as the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000070.tif14128In formula, R1 is a group of the formula: TIFF2026034537000071.tif16128 formula, R5, R6, and R2 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z2A'R7; where Z2 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R jis hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and R2 are each independently -Z3A''R8; Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; Alternatively, it is further defined as a compound of the formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000072.tif14128 formula, R1 is a group of the formula: TIFF2026034537000073.tif16128In formula, R5, R6, and X1 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12), -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , -(CH2) s CH(OH)R7, -(CH2) s C(O)OR7, or -(CH2) s C(O)(NR a )R7; where: s is 1, 2, 3, or 4; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and X1 each independently represent -(CH2) t CH(OH)R8, -(CH2) t C(O)OR8, -(CH2) t C(O)(NR b )R8; where: t is 1, 2, 3, or 4; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or q is 1, 2, or 3; r is 1, 2, 3, or 4.

[0050] In some embodiments, the compound is further defined as the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000074.tif14128 formula, R1 is a group of the formula: TIFF2026034537000075.tif16128 formula, R5, R6, and R2 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z2A'R7; where Z2 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and R2 are each independently -Z3A''R8; Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6), or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; Alternatively, it is further defined as a compound of the formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000076.tif14128 formula, R1 is a group of the formula: TIFF2026034537000077.tif16128In formula, R5 is -(CH2) t CH(OH)R8, -(CH2) t C(O)OR8, -(CH2) t C(O)(NH)R8; t is 1 or 2; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; R6 is alkyl (C≦8) or substituted alkyl (C≦8) and; X1 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group, wherein: R' and R'' are each independently -(CH2) s CH(OH)R7, -(CH2) s C(O)OR7, or -(CH2) s C(O)(NH)R7; s is 1 or 2; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl(C6~24) , substituted alkenyl (C6~24) or q is 1 or 2; r is 1 or 2.

[0051] In other embodiments, the compound is further defined as the following formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000078.tif14128 formula, R1 is a group of the formula: TIFF2026034537000079.tif16128In formula, R5 is -Z3A''R8; where Z3 is alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; R6 is alkyl (C≦8) or substituted alkyl (C≦8) and; R2 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group, wherein: R′ and R″ are each independently —Z2A′R7; Z2 is alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHR j -, -C(O)O-, or -C(O)NRb - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or q is 1 or 2; r is 1 or 2; Alternatively, it is further defined as a compound of the formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000080.tif14128 formula, R1 is a group of the formula: TIFF2026034537000081.tif16128 formula, R5 is alkyl (C≦8) or substituted alkyl (C≦8) and; R6 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group, wherein: R' and R'' are each independently alkyl (C≦8) , substituted alkyl (C≦8) , -(CH2) s CH(OH)R7, -(CH2) s C(O)OR7, or -(CH2) s C(O)(NH)R7; s is 1 or 2; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; X1 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group, wherein: R' and R'' are each independently alkyl(C≦8) , substituted alkyl (C≦8) , -(CH2) s CH(OH)R7, -(CH2) s C(O)OR7, or -(CH2) s C(O)(NH)R7; s is 1 or 2; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1 or 2; r is 1 or 2.

[0052] In other embodiments, the compound is further defined as the following formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000082.tif14128 formula, R1 is a group of the formula: TIFF2026034537000083.tif16128In formula, R5 is alkyl (C≦8) or substituted alkyl (C≦8) and; R6 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group, wherein: R' and R'' are each independently alkyl (C≦8) , substituted alkyl (C≦8) , or -Z2A'R7; where Z2 is alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R2 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group, wherein: R' and R'' are each independently alkyl (C≦8) , substituted alkyl (C≦8) , or -Z2A'R7; where Z2 is alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; q is 1 or 2; r is 1 or 2; Alternatively, it is further defined as a compound of the formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000084.tif14128 formula, R1 is a group of the formula: TIFF2026034537000085.tif16128 formula, R5 is -(CH2) t CH(OH)R8, -(CH2) t C(O)OR8, -(CH2) t C(O)(NH)R8; t is 1 or 2; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; R6 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group; R' and R'' are each independently -(CH2) s CH(OH)R7, -(CH2) s C(O)OR7, or -(CH2) s C(O)(NH)R7; s is 1 or 2; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; X1 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group; R' and R'' are each independently -(CH2) s CH(OH)R7, -(CH2) s C(O)OR7, or -(CH2) s C(O)(NH)R7; s is 1 or 2; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1 or 2; r is 1 or 2.

[0053] In some embodiments, the compound is further defined as the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000086.tif14128In formula, R1 is a group of the formula: TIFF2026034537000087.tif16128 formula, R5 is -Z3A''R8; where Z3 is alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A'' is -CHR k-, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; R6 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group; R′ and R″ are each independently —Z2A′R7; Z2 is alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; R2 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group; R′ and R″ are each independently —Z2A′R7; Z2 is alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHRj -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1 or 2; r is 1 or 2; Alternatively, it is further defined as a compound of the formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000088.tif16128In formula, R1 is a group of the formula: TIFF2026034537000089.tif11128In formula, Y is Arenejiil (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) or a substituted form of any of these groups; R9, R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , -(CH2) u CH(OH)R 12 , -(CH2) u C(O)OR 12 , -(CH2) u C(O)(NR c )R 12 is selected from; where u is 1, 2, 3, or 4; R c is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R 12is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; x and y are 1, 2, 3, or 4; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6.

[0054] In other embodiments, the compound is further defined as the following formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000090.tif16128In formula, R1 is a group of the formula: TIFF2026034537000091.tif11128 formula, Y2 is Arrange (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) , alkoxydiyl (C≦12) or a substituted form of any of these groups; R9, R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z4A'''R 12 is selected from; where Z4 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A''' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24), alkenyl (C6~24) , substituted alkenyl (C6~24) and; x and y are 1, 2, 3, or 4; R a , R3, and R4 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) and; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6; Alternatively, it is further defined as a compound of the formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000092.tif14128 formula, R1 is a group of the formula: TIFF2026034537000093.tif11128 formula, Y is Arenejiil (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) or a substituted form of any of these groups; R9, R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , -Z4A'''R 12 is selected from; where Z4 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A''' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24), alkenyl (C6~24) , substituted alkenyl (C6~24) and; x and y are 1, 2, 3, or 4.

[0055] In other embodiments, the compound is further defined as the following formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000094.tif14128 formula, R1 is a group of the formula: TIFF2026034537000095.tif11128In formula, Y is heterocycloalkanediyl (C≦12) or substituted heterocycloalkanediyl (C≦12) and; R9, R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , -Z4A'''R 12 is selected from; where Z4 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A''' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; x and y are 1, 2, 3, or 4.

[0056] In other embodiments, the compound is further defined as the following formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000096.tif14128 formula, R1 is a group of the formula: TIFF2026034537000097.tif11128 formula, Y is heterocycloalkanediyl (C≦12) or substituted heterocycloalkanediyl (C≦12) and; R9, R 10 , and R 11 are each independently hydrogen, -Z4A'''R 12 is selected from; where Z4 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A''' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; x and y are 1, 2, 3, or 4.

[0057] R2 can be hydrogen. In other embodiments, R2 is alkyl. (C≦8) or substituted alkyl (C≦8) R3 can be hydrogen. In other embodiments, R3 is alkyl. (C≦8) or substituted alkyl (C≦8) In some embodiments, R3 is alkyl (C≦8)In some embodiments, R3 is hydrogen. In other embodiments, R4 is alkyl. (C≦8) or substituted alkyl (C≦8) R4 is alkyl (C≦8) , for example methyl.

[0058] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In other embodiments, m is 2. In some embodiments, n is 2 or 3. In some embodiments, n is 2. In other embodiments, n is 3. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1. In other embodiments, p is 2. In other embodiments, p is 3.

[0059] In some embodiments, R1 is a group of the formula: R1 is a group of the formula: TIFF2026034537000098.tif16128In formula, R5, R6, and R2 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , -Z2A'R7; where Z2 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; Rj is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and X1 are each independently -Z3A''R8; Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4.

[0060] In some embodiments, R1 is a group of the formula: TIFF2026034537000099.tif16128In formula, R5, R6, and X1 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6)-NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , -(CH2) s CH(OH)R7, -(CH2) s C(O)OR7, or -(CH2) s C(O)(NR a )R7; where: s is 1, 2, 3, or 4; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and X1 each independently represent -(CH2) t CH(OH)R8, -(CH2) t C(O)OR8, -(CH2) t C(O)(NR b )R8; where: t is 1, 2, 3, or 4; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or q is 1, 2, or 3; r is 1, 2, 3, or 4.

[0061] In some embodiments, q is 1 or 2. In some embodiments, q is 1. In other embodiments, q is 2. In some embodiments, r is 1 or 2. In some embodiments, r is 1. In other embodiments, r is 2. In some embodiments, R5 is hydrogen. In other embodiments, R5 is alkyl.(C≦8) or substituted alkyl (C≦8) In some embodiments, R5 is alkyl (C≦8) , for example methyl or isopropyl.

[0062] In some embodiments, R5 is further defined as -Z3A''R8, wherein: Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) is.

[0063] In some embodiments, Z3 is alkanediyl (C1~2) In one example, Z3 is -CH2-. In some embodiments, Z3 is a substituted alkanediyl (C1~2) In one example, Z is -CHCH(OH). In some embodiments, A" is -CHR k - In one example, R k is hydroxy. In some embodiments, R k is acyloxy (C≦24) or substituted acyloxy (C≦24) In some embodiments, R k is acyloxy (C1~8) or substituted acyloxy (C1~8) In some embodiments, R k is acyloxy (C≦12~24) or substituted acyloxy (C≦12~24)In one example, A" is -C(O)O-. In another example, A" is -C(O)NH-.

[0064] In other embodiments, R5 is -(CH2) t CH(OH)R8, -(CH2) t C(O)OR8, or -(CH2) t C(O)(NR b )R8; where: t is 1, 2, 3, or 4; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) is.

[0065] In some embodiments, R5 is -(CH2) t In other embodiments, R5 is -(CH2) t In other embodiments, R5 is -(CH2) t C(O)(NR b )R8. t can be 1 or 2. In some embodiments, t is 1. In other embodiments, t is 2. In some embodiments, R b is hydrogen. In other embodiments, R b is alkyl (C≦6) or substituted alkyl (C≦6) , e.g., alkyl (C6~24) or substituted alkyl (C6~24) is.

[0066] In some embodiments, R8 is alkyl (C6~24) In other embodiments, R8 is an alkenyl, for example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. (C6~24) or substituted alkenyl (C6~24) In some embodiments, R6 is hydrogen. In other embodiments, R6 is alkyl. (C≦8) or substituted alkyl(C≦8) R6 is alkyl (C≦8) , for example methyl or isopropyl.

[0067] In some embodiments, R6 is -Z3A''R8; Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) is.

[0068] In some embodiments, Z3 is alkanediyl (C1~2) In one example, Z3 is -CH2-. In some embodiments, Z3 is a substituted alkanediyl (C1~2) In one example, Z is -CHCH(OH). In some embodiments, A" is -CHR k - In one example, R k is hydroxy. In some embodiments, R k is acyloxy (C≦24) or substituted acyloxy (C≦24) In some embodiments, R k is acyloxy (C1~8) or substituted acyloxy (C1~8) In some embodiments, R k is acyloxy (C≦12~24) or substituted acyloxy (C≦12~24)In one example, A" is -C(O)O-. In another example, A" is -C(O)NH-. In some embodiments, R8 is alkyl (C6~24) or substituted alkyl (C6~24) R8 is alkyl (C6~24) In some embodiments, R8 can be an alkenyl, for example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. (C6~24) or substituted alkenyl (C6~24) is.

[0069] In other embodiments, R6 is -(CH2) t CH(OH)R8, -(CH2) t C(O)OR8, or -(CH2) t C(O)(NR b )R8; where: t is 1, 2, 3, or 4; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) is.

[0070] In some embodiments, R6 is -(CH2) t In other embodiments, R6 is -(CH2) t In other embodiments, R6 is -(CH2) t C(O)(NR b )R8. In some embodiments, t is 1 or 2. In some embodiments, t is 1. In other embodiments, t is 2. In some embodiments, R b is hydrogen. In other embodiments, R b is alkyl (C≦6) or substituted alkyl (C≦6) R8 is alkyl (C6~24) or substituted alkyl (C6~24) In some embodiments, R8 is alkyl (C6~24)In other embodiments, R8 is an alkenyl, for example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. (C6~24) or substituted alkenyl (C6~24) is.

[0071] In some embodiments, R6 is -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) or a substituted version of any of these groups. In some embodiments, R6 is -alkanediyl (C≦6) In another embodiment, R6 is -alkanediyl. (C≦6) -Alkylamino (C≦8) or substituted forms of this group, such as -CH2CH2NHMe or -CH2CH2NHiPr. In other embodiments, R6 is -alkanediyl (C≦6) -dialkylamino (C≦8) or a substituted form of this group.

[0072] In some embodiments, R2 is hydrogen. In other embodiments, R2 is alkyl. (C≦8) or substituted alkyl (C≦8) In some embodiments, R2 is alkyl (C≦8) In some embodiments, R2 is -Z3A''R8; Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24)and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) is.

[0073] In some embodiments, Z3 is alkanediyl (C1~2) In one example, Z3 is -CH2-. In some embodiments, Z3 is a substituted alkanediyl (C1~2) In one example, Z is -CHCH(OH). In some embodiments, A" is -CHR k - In one example, R k is hydroxy. In some embodiments, R k is acyloxy (C≦24) or substituted acyloxy (C≦24) In some embodiments, R k is acyloxy (C1~8) or substituted acyloxy (C1~8) In some embodiments, R k is acyloxy (C≦12~24) or substituted acyloxy (C≦12~24) In one example, A" is -C(O)O-. In another example, A" is -C(O)NH-. In some embodiments, R8 is alkyl (C6~24) or substituted alkyl (C6~24) R8 is alkyl (C6~24) In some embodiments, R8 can be an alkenyl, for example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. (C6~24) or substituted alkenyl (C6~24) is.

[0074] In other embodiments, R2 is -(CH2) t CH(OH)R8, -(CH2) t C(O)OR8, or -(CH2) t C(O)(NR b )R8; where: t is 1, 2, 3, or 4; R b is hydrogen, alkyl (C≦6), or substituted alkyl (C≦6) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) is.

[0075] In some embodiments, R2 is -(CH2) t In other embodiments, R2 is -(CH2) t In other embodiments, R2 is -(CH2) t C(O)(NR b )R8. t can be 1 or 2. In some embodiments, t is 1. In other embodiments, t is 2. In some embodiments, R b is hydrogen. In other embodiments, R b is alkyl (C≦6) or substituted alkyl (C≦6) R8 is alkyl (C6~24) or substituted alkyl (C6~24) In some embodiments, R8 is alkyl (C6~24) In some embodiments, R is an alkenyl, for example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. (C6~24) or substituted alkenyl (C6~24) is.

[0076] In other embodiments, R2 is -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) or a substituted version of any of these groups. In some embodiments, R2 is -alkanediyl (C≦6) In another embodiment, R2 is -alkanediyl. (C≦6) -Alkylamino (C≦8) or substituted forms of this group, such as -CH2CH2NHMe or -CH2CH2NHiPr. In other embodiments, R2 is -alkanediyl (C≦6)-dialkylamino (C≦8) or a substituted form of this group.

[0077] In another aspect, R1 is a group of the formula: TIFF2026034537000100.tif11128In formula, Y is Arenejiil (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) or a substituted form of any of these groups; R9, R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , -(CH2) u CH(OH)R 12 , -(CH2) u C(O)OR 12 , -(CH2) u C(O)(NR c )R 12 is selected from; where u is 1, 2, 3, or 4; R c is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; x and y are 1, 2, 3, or 4.

[0078] In another aspect, R1 is a group of the formula: TIFF2026034537000101.tif11128 formula, Y2 is Arrange (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) , alkoxydiyl (C≦12) or a substituted form of any of these groups; R9, R 10, and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z4A'''R 12 is selected from; where Z4 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A''' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; x and y are 1, 2, 3, or 4.

[0079] In some embodiments, Y is heterocycloalkanediyl (C≦12) or substituted heterocycloalkanediyl (C≦12) In some embodiments, Y is heterocycloalkanediyl (C≦12) In other embodiments, Y is heteroarenediyl, for example, piperazinediyl. (C≦12) or substituted heteroarenediyl (C≦12) In another embodiment, Y is arenediyl. (C≦12) or substituted arenediyl (C≦12) In some embodiments, x is 2 or 3. In one embodiment, x is 2. In another embodiment, x is 3. In some embodiments, y is 2 or 3. In one embodiment, y is 2. In another embodiment, y is 3.

[0080] In one aspect, R9 is —(CH2) uCH(OH)R 12 , -(CH2) u C(O)OR 12 , -(CH2) u C(O)(NR c )R 12 where: u is 1, 2, 3, or 4; R c is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) is.

[0081] In some embodiments, R9 is —(CH2) u CH(OH)R 12 In other embodiments, R9 is —(CH2) u C(O)OR 12 In some embodiments, R9 is -(CH2) u C(O)(NR c )R 12 u can be 1, 2, or 3. In some embodiments, u is 1 or 2. In one embodiment, u is 1. In another embodiment, u is 2. In some embodiments, R c is hydrogen. In other embodiments, R c is alkyl (C≦6) or substituted alkyl (C≦6) R 12 is alkyl (C6~24) or substituted alkyl (C6~24) In some embodiments, R 12 is alkyl (C6~24) , for example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. 12 is alkenyl (C6~24) or substituted alkenyl (C6~24) is.

[0082] In some embodiments, R 10 Ha-(CH2)u CH(OH)R 12 , -(CH2) u C(O)OR 12 , -(CH2) u C(O)(NR c )R 12 where: u is 1, 2, 3, or 4; R c is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) is.

[0083] In some embodiments, R 10 Ha-(CH2) u CH(OH)R 12 In another embodiment, R 10 Ha-(CH2) u C(O)OR 12 In another embodiment, R 10 Ha-(CH2) u C(O)(NR c )R 12 u can be 1, 2, or 3. In some embodiments, u is 1 or 2. In one embodiment, u is 1. In another embodiment, u is 2. In some embodiments, R c is hydrogen. In other embodiments, R c is alkyl (C≦6) or substituted alkyl (C≦6) R 12 is alkyl (C6~24) or substituted alkyl (C6~24) In some embodiments, R 12 is alkyl (C6~24) , for example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. 12 is alkenyl (C6~24) or substituted alkenyl (C6~24) is.

[0084] In some embodiments, R 11 Ha-(CH2) u CH(OH)R 12 , -(CH2) u C(O)OR 12 , -(CH2) u C(O)(NR c )R 12 where: u is 1, 2, 3, or 4; R c is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) is.

[0085] In some embodiments, R 11 Ha-(CH2) u CH(OH)R 12 In another embodiment, -(CH2) u C(O)OR 12 In another embodiment, R 11 Ha-(CH2) u C(O)(NR c )R 12 u can be 1, 2, or 3. In some embodiments, u is 1 or 2. In one embodiment, u is 1. In another embodiment, u is 2. In some embodiments, R c is hydrogen. In other embodiments, R c is alkyl (C≦6) or substituted alkyl (C≦6) R 12 is alkyl (C6~24) or substituted alkyl (C6~24) In some embodiments, R 12 is alkyl (C6~24) , for example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. 12 is alkenyl (C6~24) or substituted alkenyl (C6~24) is.

[0086] In other embodiments, the compound is further defined as the following formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000102.tif16128 formula, R1, R2, and R3 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000103.tif12128 formula, R7 and R8 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000104.tif11128In formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4; R5 and R6 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) and; m and n are each independently 1, 2, 3, 4, or 5.

[0087] In some embodiments, the compound is further defined as the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000105.tif16128 formula, R1, R2, and R3 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000106.tif12128 formula, R7 and R8 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000107.tif11128In formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4; R5 and R6 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) and; m is 1, 2, 3, 4, or 5.

[0088] In some embodiments, R2 is hydrogen. R2 is alkyl (C≦6) or substituted alkyl (C≦6) In some embodiments, R2 can be alkyl (C≦6) In another embodiment, R2 is a group of the formula: TIFF2026034537000108.tif12128In formula, R7 and R8 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000109.tif11128In formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4.

[0089] In some embodiments, R7 is hydrogen. In other embodiments, R7 is alkyl. (C≦6) or substituted alkyl (C≦6) R7 is alkyl (C≦6) In other embodiments, R7 is: TIFF2026034537000110.tif11128 formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group.

[0090] In some embodiments, R9 is halo, e.g., chloro or bromo. In other embodiments, R9 is hydroxy. In other embodiments, R9 is alkoxy. (C≦8) or substituted alkoxy (C≦8) R9 is alkoxy (C≦8) In other embodiments, R9 can be acyloxy. (C≦8) or substituted acyloxy (C≦8) R9 is acyloxy (C≦8) , for example, acetoxy or pivaloyloxy. 10 is alkyl (C≦24) or substituted alkyl (C≦24) , for example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. 10 is alkenyl (C≦24) or substituted alkenyl (C≦24) is.

[0091] In some embodiments, R8 is hydrogen. In other embodiments, R8 is alkyl. (C≦6) or substituted alkyl (C≦6)R8 is alkyl (C≦6) In other embodiments, R8 is: TIFF2026034537000111.tif11128In formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group.

[0092] In some embodiments, R9 is halo, e.g., chloro or bromo. In other embodiments, R9 is hydroxy. In other embodiments, R9 is alkoxy. (C≦8) or substituted alkoxy (C≦8) R9 is alkoxy (C≦8) In other embodiments, R9 can be acyloxy. (C≦8) or substituted acyloxy (C≦8) R9 is acyloxy (C≦8) , for example, acetoxy or pivaloyloxy. 10 is alkyl (C≦24) or substituted alkyl (C≦24) , for example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. 10 is alkenyl (C≦24) or substituted alkenyl (C≦24) is.

[0093] Alternatively, q can be 1 or 2. In some embodiments, q is 1. In other embodiments, q is 2. Similarly, r can be 1, 2, or 3. In some embodiments, r is 1. In other embodiments, r is 2. In other embodiments, r is 3. In some embodiments, R3 is hydrogen. In some embodiments, R3 is alkyl. (C≦6) or substituted alkyl (C≦6) R3 is alkyl (C≦6), for example methyl or ethyl.

[0094] In some embodiments, R4 is hydrogen. In other embodiments, R4 is alkyl. (C≦6) or substituted alkyl (C≦6) In some embodiments, R5 is hydrogen. In other embodiments, R5 is alkyl. (C≦6) or substituted alkyl (C≦6) R5 is alkyl (C≦6) In some embodiments, R6 is hydrogen. In other embodiments, R6 is alkyl. (C≦6) or substituted alkyl (C≦6) R6 is alkyl (C≦6) In some embodiments, m is 2, 3, or 4. In some embodiments, m is 2. In some embodiments, n is 3.

[0095] In some embodiments, R1 is hydrogen. In other embodiments, R1 is alkyl. (C≦6) or substituted alkyl (C≦6) R1 is alkyl (C≦6) , for example, methyl or ethyl. In other embodiments, R1 is a group of the formula: TIFF2026034537000112.tif12128In formula, R7 and R8 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000113.tif11128In formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4.

[0096] In some embodiments, R7 is hydrogen. In other embodiments, R7 is alkyl. (C≦6) or substituted alkyl (C≦6) R7 is alkyl (C≦6) In other embodiments, R7 is: TIFF2026034537000114.tif11128 formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group.

[0097] In some embodiments, R9 is halo, e.g., chloro or bromo. In other embodiments, R9 is hydroxy. In other embodiments, R9 is alkoxy. (C≦8) or substituted alkoxy (C≦8) R9 is alkoxy (C≦8) In other embodiments, R9 can be acyloxy. (C≦8) or substituted acyloxy (C≦8) R9 is acyloxy (C≦8) , for example, acetoxy or pivaloyloxy. 10 is alkyl (C≦24) or substituted alkyl (C≦24) , for example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. 10 is alkenyl (C≦24) or substituted alkenyl (C≦24) is.

[0098] In some embodiments, R8 is hydrogen. In other embodiments, R8 is alkyl. (C≦6) or substituted alkyl (C≦6) R8 is alkyl (C≦6) In other embodiments, R8 is: TIFF2026034537000115.tif11128 formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group.

[0099] In some embodiments, R9 is halo, e.g., chloro or bromo. In other embodiments, R9 is hydroxy. In other embodiments, R9 is alkoxy. (C≦8) or substituted alkoxy (C≦8) R9 is alkoxy (C≦8) In other embodiments, R9 can be acyloxy. (C≦8) or substituted acyloxy (C≦8) R9 is acyloxy (C≦8) , for example, acetoxy or pivaloyloxy. 10 is alkyl (C≦24) or substituted alkyl (C≦24) , for example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. 10 is alkenyl (C≦24) or substituted alkenyl (C≦24) is.

[0100] In some embodiments, q is 1 or 2. In some embodiments, q is 1. In other embodiments, q is 2. In some embodiments, r is 1, 2, or 3. In some embodiments, r is 1. In other embodiments, r is 2. In other embodiments, r is 3.

[0101] In some embodiments, the tRNA is an unmodified tRNA. In other embodiments, the tRNA is a modified tRNA. In some embodiments, the tRNA is a suppressor tRNA. In some embodiments, the tRNA is a tRNA that delivers an amino acid into a protein instead of terminating translation. In some embodiments, the tRNA is a tRNA amber suppressor. In other embodiments, the tRNA is a tRNA opal suppressor. In other embodiments, the tRNA is a tRNA ochre suppressor. In some embodiments, the tRNA is a tRNA frameshift suppressor. tRNA arg / op An arginine residue can be added to a growing polypeptide using a tRNA such as

[0102] In some embodiments, the composition further comprises a steroid or steroid derivative. In some embodiments, the steroid or steroid derivative is a sterol, such as cholesterol. In some embodiments, the composition further comprises a phospholipid. In some embodiments, the phospholipid is a phosphatidylcholine. In other embodiments, the phospholipid is distearoylphosphatidylcholine. In some embodiments, the composition further comprises a PEG-lipid. In some embodiments, the PEG-lipid is a PEGylated diacylglycerol, such as PEGylated dimyristoyl-sn-glycerol. In other embodiments, the PEG-lipid is of the formula: TIFF2026034537000116.tif39128 formula, n1 is an integer from 1 to 250; n2 and n3 are each independently selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.

[0103] In some embodiments, n1 is 5 to 100. In some embodiments, n1 is 45. In some embodiments, n2 is 11, 12, 13, 14, 15, 16, or 17. In some embodiments, n2 is 15. In some embodiments, n3 is 11, 12, 13, 14, 15, 16, or 17. In some embodiments, n3 is 15.

[0104] In some embodiments, the compositions comprise a molar ratio of compound to nucleic acid of about 5:1 to about 1000:1. In some embodiments, the molar ratio of compound to nucleic acid is about 100:1 to about 1000:1. In some embodiments, the molar ratio is about 166:1. In other embodiments, the molar ratio is about 250:1 to about 750:1. In some embodiments, the compositions comprise a ratio of compound to steroid or steroid derivative of about 1:1 to about 20:1, e.g., about 1:1 to about 6:1. In some embodiments, the compositions comprise a ratio of compound to phospholipid of about 1:1 to about 9:1, e.g., about 2.5:1 to about 7.5:1. In some embodiments, the compositions comprise a ratio of compound to PEG lipid of about 2.5:1 to about 100:1, e.g., about 7.5:1 to about 50:1.

[0105] In some embodiments, the tRNA TIFF2026034537000117.tif11152. In other embodiments, the tRNA is TIFF2026034537000118.tif65150TIFF2026034537000119.tif189150.

[0106] In some embodiments, the tRNA corrects a nonsense mutation in the cystic fibrosis transmembrane conductance regulator protein.

[0107] In another aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: (A) a composition described herein; (B) excipients and The present invention provides a pharmaceutical composition comprising:

[0108] In some embodiments, the pharmaceutical composition is formulated for oral, intraadipose, intra-arterial, intra-articular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intravesicular, intravitreal, liposomal, topical, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, buccal, transdermal, vaginal, cream, lipid composition, catheter, irrigation, continuous infusion, drip, infusion, inhalation, injection, local delivery, or localized perfusion administration. In some embodiments, the pharmaceutical composition is formulated for administration by injection. In some embodiments, the pharmaceutical composition is formulated as a unit dose.

[0109] In yet another aspect, the present disclosure provides a method for treating a disease or disorder in a patient, comprising administering a therapeutically effective amount of a composition described herein to a patient in need thereof. In some embodiments, the disease or disorder is a genetic disease or disorder. In some embodiments, the genetic disease or disorder is cystic fibrosis. In some embodiments, the gene for cystic fibrosis transmembrane conductance regulator protein (CFTR) has a nonsense mutation. In some embodiments, the method results in a 25% increase in CFTR activity. In some embodiments, the method further comprises administering a second cystic fibrosis therapy.

[0110] In other embodiments, the genetic disease or disorder is Duchenne muscular dystrophy (DMD), a congenital glycosylation disorder, Dravet syndrome, a mucopolysaccharidosis type I (MPS I) disorder, an NGLY1 deficiency (N-glycanase deficiency) disorder, Rett syndrome, or cancer.

[0111] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma. In some embodiments, the cancer is bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, reproductive cancer, genitourinary cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosa cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, colon cancer, stomach cancer, testicular cancer, or thyroid cancer. In some embodiments, the cancer is lung cancer or colorectal cancer. In some embodiments, the lung cancer has a nonsense mutation in the p53 gene. In other embodiments, the colorectal cancer has a nonsense mutation in the APC gene. In some embodiments, the cancer comprises a genetic mutation in one or more tumor suppressor proteins, such as p53, APC, LKB1, ERCC3, WRN, BRCA2, IDH1, or ARID1A. In some embodiments, the cancer is a liver cancer, such as hepatitis B-derived hepatocellular carcinoma (HCC).

[0112] In other embodiments, the method further comprises administering a second cancer therapy, such as chemotherapy, surgery, immunotherapy, or radiation therapy. In some embodiments, the patient is a mammal, such as a human. In some embodiments, the composition is administered once. In other embodiments, the composition is administered two or more times.

[0113] As used herein, "a" or "an" may mean one or more. As used in the claims herein, when used in conjunction with the word "comprising," the words "a" or "an" may mean one, or more than one.

[0114] Use of the term "or" in the claims is used to mean "and / or," unless expressly indicated to refer to only certain alternatives or the alternatives are not mutually exclusive, although the present disclosure supports alternatives and a definition that refers only to "and / or." As used herein, "another" means at least a second or more.

[0115] Throughout this specification, the term "about" is used to indicate that a value includes the inherent variation of error for the device or the method being employed to determine the value, or the variation that exists among test subjects.

[0116] [The present invention 1001] (a) tRNA and; (b) nanoparticle-forming aminolipid delivery compounds and A composition comprising: [The present invention 1002] 1001. The composition of claim 1001, wherein the aminolipid delivery compound is a dendrimer comprising a group that is positively charged at physiological pH and a lipophilic group. [The present invention 1003] The composition of the present invention, wherein the aminolipid delivery compound is a dendrimer of the following formula or a pharmaceutically acceptable salt thereof: Core - (repeating unit) n -Terminal group (I) wherein the core is linked to the repeat unit by removing one or more hydrogen atoms from the core and replacing them with the repeat unit; The core has the formula: TIFF2026034537000120.tif10128 formula, X1 is amino or alkylamino (C≦12) , dialkylamino (C≦12) , heterocycloalkyl (C≦12) , heteroaryl (C≦12) , or a substituted form thereof; R1 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12)or a substituted form of either of these groups; a is 1, 2, 3, 4, 5, or 6; or The core has the formula: TIFF2026034537000121.tif12128 formula, X2 is N(R5) y and; R5 is hydrogen, alkyl (C≦18) , or substituted alkyl (C≦18) and; y is 0, 1, or 2, provided that the sum of y and z is 3; R2 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; b is 1, 2, 3, 4, 5, or 6; z is 1, 2, or 3, provided that the sum of z and y is 3; or The core has the formula: TIFF2026034537000122.tif11128 formula, X3 is -NR6-, where R6 is hydrogen, alkyl (C≦8) , or substituted alkyl (C≦8) , -O-, or alkylaminodiyl (C≦8) , alkoxydiyl (C≦8) , Arendjiil (C≦8) , heteroarenediyl (C≦8) , heterocycloalkanediyl (C≦8) or a substituted form of any of these groups; R3 and R4 are each independently amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or substituted forms of either of these groups, or a group of the formula -(CH2CH2N) e (R c )R d is the basis of; where: e is 1, 2, or 3; R cand R d are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; c and d are each independently 1, 2, 3, 4, 5, or 6; or The core is an alkylamine (C≦18) , dialkylamine (C≦36) , heterocycloalkane (C≦12) or a substituted form of any of these groups; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: TIFF2026034537000123.tif17128In formula, A1 and A2 each independently represent -O-, -S-, or -NR a -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; Y3 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: TIFF2026034537000124.tif11128In formula, X3 and X4 are alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R9 is alkyl (C≦8) or substituted alkyl (C≦8) and; The linker group has the formula: TIFF2026034537000125.tif16128 formula, Y1 is alkanediyl(C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: TIFF2026034537000126.tif12128In formula, Y4 is alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either group; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) where: R 11 is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6. [The present invention 1004] The composition of the present invention 1003, wherein the aminolipid delivery compound is a dendrimer of the following formula or a pharmaceutically acceptable salt thereof: The core has the formula: TIFF2026034537000127.tif10128 formula, X1 is amino or alkylamino (C≦12) , dialkylamino (C≦12) , heterocycloalkyl (C≦12) , heteroaryl (C≦12) , or a substituted form thereof; R1 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; a is 1, 2, 3, 4, 5, or 6; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: TIFF2026034537000128.tif17128In formula, A1 and A2 each independently represent -O- or -NR a -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; Y3 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: TIFF2026034537000129.tif11128In formula, X3 and X4 are alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R9 is alkyl (C≦8) or substituted alkyl (C≦8) and; The linker group has the formula: TIFF2026034537000130.tif16128 formula, Y1 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: TIFF2026034537000131.tif12128 formula, Y4 is alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either group; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) where: R 11 is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6. [The present invention 1005] The composition of the present invention 1003, wherein the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof: Core - (repeating unit) n -Terminal group (I) wherein the core is linked to the repeat unit by removing one or more hydrogen atoms from the core and replacing them with the repeat unit; The core has the formula: TIFF2026034537000132.tif12128 formula, X2 is N(R5) y and; R5 is hydrogen or alkyl (C≦8) , or substituted alkyl (C≦18) and; y is 0, 1, or 2, provided that the sum of y and z is 3; R2 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; b is 1, 2, 3, 4, 5, or 6; z is 1, 2, or 3, provided that the sum of z and y is 3; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: TIFF2026034537000133.tif17128 formula, A1 and A2 each independently represent -O- or -NR a -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; Y3 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: TIFF2026034537000134.tif11128 formula, X3 and X4 are alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y5 is a covalent bond, alkanediyl(C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R9 is alkyl (C≦8) or substituted alkyl (C≦8) and; The linker group has the formula: TIFF2026034537000135.tif16128 formula, Y1 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: TIFF2026034537000136.tif13128 formula, Y4 is alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either group; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) and The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6. [The present invention 1006] The composition of the present invention 1003, wherein the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof: Core - (repeating unit) n -Terminal group (I) wherein the core is linked to the repeat unit by removing one or more hydrogen atoms from the core and replacing them with the repeat unit; The core has the formula: TIFF2026034537000137.tif11128 formula, X3 is -NR6-, where R6 is hydrogen, alkyl (C≦8) , or substituted alkyl (C≦8) , -O-, or alkylaminodiyl (C≦8) , alkoxydiyl (C≦8) , Arendjiil (C≦8) , heteroarenediyl (C≦8) , heterocycloalkanediyl (C≦8) or a substituted form of any of these groups; R3 and R4 are each independently amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or substituted forms of either of these groups, or a group of the formula -(CH2CH2N) e (R c )R d is the basis of; where: e is 1, 2, or 3; R c and R d are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; c and d are each independently 1, 2, 3, 4, 5, or 6; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: TIFF2026034537000138.tif17128 formula, A1 and A2 each independently represent -O- or -NRa -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; Y3 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: TIFF2026034537000139.tif11128 formula, X3 and X4 are alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R9 is alkyl (C≦8) or substituted alkyl (C≦8) and; The linker group has the formula: TIFF2026034537000140.tif16128 formula, Y1 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: TIFF2026034537000141.tif12128 formula, Y4 is alkanediyl (C≦18) , Alkendiyl (C≦18)or a substituted form of either group; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) where: R 11 is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6. [The present invention 1007] Y4 is alkanediyl (C≦18) or alkanediyl (C≦18) Alkanediyl in which one or more hydrogen atoms are replaced by -OH, -F, -Cl, -Br, -I, -SH, -OCH3, -OCH2CH3, -SCH3, or -OC(O)CH3 (C≦18) The composition of any one of 1003 to 1006 of the present invention, [The present invention 1008] The composition of claim 1001, wherein the aminolipid delivery compound is an aminolipid comprising an anionic carboxylic acid group, a sulfonic acid group, or a phosphate group, a quaternary amino group, an amino group that is positively charged at physiological pH, and a lipophilic group. [The present invention 1009] The composition of the present invention 1008, wherein the aminolipid delivery compound is further defined as the following formula: TIFF2026034537000142.tif13128 formula, X1 is -S(O)2O - , -OP(O)OR e O- , -(CHR f ) z C(O)O - , or -NR g R h R i + where: R e , R g , R h , and R i are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R f is hydrogen, amino, hydroxy, or alkyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦12) , acyl (C≦12) , alkoxy (C≦12) , acyloxy (C≦12) , amide (C≦12) , alkoxy (C≦12) , alkoxy (C≦12) or a substituted form of any of the last ten groups; z is 1, 2, 3, or 4; Y1 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) , heteroarenediyl (C≦12) , heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) -Alkanediyl (C≦8) , -alkanediyl (C≦8) -heteroarenediyl (C≦12) , -alkanediyl (C≦8) -heteroarenediyl (C≦12) -Alkanediyl (C≦8) or a substituted form of any of these groups; Z1 is -N + R3R4- or -OP(O)O - O-; A is -NR a -, -S-, or -O-; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) or R a together with R3 or R4 to form an alkanediyl (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; R1 is a group of the formula: TIFF2026034537000143.tif16128 formula, R5, R6, and R2 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z2A'R7; where Z2 is alkanediyl (C≦6) , substituted alkanediyl (C≦6) or a group of the formula: TIFF2026034537000144.tif10128 formula, Z5 and Z6 are each independently alkanediyl (C≦6) or substituted alkanediyl (C≦6) and; X2 and X3 each independently represent -O-, -S-, or -NR m - and where: R m is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; a is 0, 1, 2, 3, 4, 5, or 6; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and R2 are each independently -Z3A''R8; Z3 is alkanediyl (C≦6) , substituted alkanediyl (C≦6) or a group of the formula: TIFF2026034537000145.tif10128 formula, Z7 and Z8 are each independently alkanediyl (C≦6) or substituted alkanediyl (C≦6) and; X4 and X5 each independently represent -O-, -S-, or -NR n - and where: R n is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; b is 0, 1, 2, 3, 4, 5, or 6; A'' is -CHR k -, -S-, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24), or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; R1 is a group of the formula: TIFF2026034537000146.tif11128 formula, Y2 is Arrange (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) , alkoxydiyl (C≦12) or a substituted form of any of these groups; R9, R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z4A'''R 12 where: Z4 is alkanediyl (C≦6) , substituted alkanediyl (C≦6) or a group of the formula: TIFF2026034537000147.tif10128 formula, Z9 and Z 10 are each independently an alkanediyl (C≦6) or substituted alkanediyl (C≦6) and; X6 and X7 each independently represent -O-, -S-, or -NR o - and where: R o is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; c is 0, 1, 2, 3, 4, 5, or 6; A''' is -CHR k -, -S-, -C(O)O-, or -C(O)NR l - and; R lis hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; x and y are 0, 1, 2, 3, or 4; R3 and R4 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) Alternatively, R3 or R4 is R a Together with (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6; However, when X1 is positively charged, Z1 is negatively charged, and when X1 is negatively charged, Z1 is positively charged. [The present invention 1010] 1001. The composition of claim 1001, wherein the aminolipid delivery compound is an aminolipid comprising an anionic sulfonic acid group and a quaternary amino group, a lipophilic group, and an amino group that is protonated at physiological pH. [The present invention 1011] The composition of the present invention, wherein the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000148.tif16128In formula, Y1 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) , heteroarenediyl (C≦12) , heterocycloalkanediyl(C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) -Alkanediyl (C≦8) , -alkanediyl (C≦8) -heteroarenediyl (C≦12) , -alkanediyl (C≦8) -heteroarenediyl (C≦12) -Alkanediyl (C≦8) or a substituted form of any of these groups; A is -NR a -, -S-, or -O-; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) or R a together with R3 or R4 to form an alkanediyl (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; R1 is a group of the formula: TIFF2026034537000149.tif16128In formula, R5, R6, and R2 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z2A'R7; where Z2 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and R2 are each independently -Z3A''R8; Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; R1 is a group of the formula: TIFF2026034537000150.tif11128 formula, Y2 is Arrange (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) , alkoxydiyl(C≦12) or a substituted form of any of these groups; R9, R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z4A'''R 12 is selected from; where Z4 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A''' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; x and y are 1, 2, 3, or 4; R3 and R4 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) Alternatively, R3 or R4 is R a Together with Alkandiil (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6. [The present invention 1012] The composition of the present invention, wherein the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000151.tif16128 formula, Y1 is alkanediyl (C≦12) , heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) -Alkanediyl (C≦8) or a substituted form of any of these groups; A is -NR a -, -S-, or -O-; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) or R a together with R3 or R4 to form an alkanediyl (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; R1 is a group of the formula: TIFF2026034537000152.tif16128 formula, R5, R6, and R2 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z2A'R7; where Z2 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j-, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and R2 are each independently -Z3A''R8; Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; R1 is a group of the formula: TIFF2026034537000153.tif11128 formula, Y2 is Arrange (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) , alkoxydiyl (C≦12)or a substituted form of any of these groups; R9, R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z4A'''R 12 is selected from; where Z4 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A''' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; x and y are 1, 2, 3, or 4; R3 and R4 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) Alternatively, R3 or R4 is R a Together with Alkandiil (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6. [The present invention 1013] The composition of the present invention, wherein the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000154.tif17128 formula, R1 is a group of the formula: TIFF2026034537000155.tif15128 formula, R5, R6, and R2 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z2A'R7; where Z2 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and R2 are each independently -Z3A''R8; Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l- and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; R a , R3, and R4 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) and; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6. [The present invention 1014] 1001. The composition of claim 1001, wherein the aminolipid delivery compound comprises a sulfonamide group, a quaternary ammonium group, an amino group that is protonated at physiological pH, and a lipophilic group. [The present invention 1015] The composition of the present invention, wherein the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000156.tif16128 formula, R1, R2, and R3 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000157.tif12128 formula, R7 and R8 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000158.tif11128 formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦24) , acyloxy (C≦24) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4; R4, R5, and R6 are each independently hydrogen, alkyl, (C≦6) , or substituted alkyl (C≦6) and; m and n are each independently 1, 2, 3, 4, or 5. [The present invention 1016] The composition of the present invention, wherein the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000159.tif16128 formula, R1, R2, and R3 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000160.tif12128 formula, R7 and R8 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000161.tif11128 formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦24) , acyloxy (C≦24) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4; R4, R5, and R6 are each independently hydrogen, alkyl, (C≦6) , or substituted alkyl (C≦6) and; m and n are each independently 1, 2, 3, 4, or 5. [The present invention 1017] 1001. The composition of claim 1001, wherein the amino lipid comprises a polyester group, a thioether group, and an amine group that is protonated at physiological pH. [The present invention 1018] 1001. The composition of claim 1001, wherein the amino lipid comprises a polyester group of the formula: TIFF2026034537000162.tif18128 formula, X1 is alkyl (C≦18) or substituted alkyl (C≦18) and; X2 is hydrogen, alkyl (C≦18) , or substituted alkyl (C≦18) and; R1 is -AZ; where: A is alkanediyl (C≦18) or substituted alkanediyl (C≦18) and; Z is -NR3R4; where: R3 and R4 are each independently hydrogen, alkyl, or (C≦18) , substituted alkyl (C≦18) or R3 and R4 together are selected from alkanediyl; (C≦18) or substituted alkanediyl (C≦18) and; R2 is alkyl (C≦24) , alkenyl (C≦24) , substituted alkyl (C≦24) , or substituted alkenyl (C≦24) and; x and y are each independently 0, 1, 2, 3, 4, or 5; m and n each independently represent an integer of 0 to 250, provided that at least one of m and n exceeds 1; The repeat units defined by m and n are randomly distributed throughout the polymer. [The present invention 1019] The composition of invention 1001 or 1017, wherein the compound is further defined as the following formula: or a pharmaceutically acceptable salt thereof: TIFF2026034537000163.tif36128 formula, R1, R2, and R3 are each independently hydrogen, alkyl, or (C≦8) , or substituted alkyl (C≦8) and; R4 is hydrogen, halo, hydroxy, alkyl (C≦8) , or substituted alkyl (C≦8) and; R5 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either of these groups; R6 is Y1-R7; where: Y1 is alkanediyl (C≦8) , substituted alkanediyl (C≦8) , -(CH2) r C(O)- or -(CH2) r C(O)NR a (CH2) s - and; where: r and s are each independently 1, 2, or 3; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R7 is amino or heteroaryl (C≦12) , heterocycloalkyl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , arylalkylamino (C≦12) or a substituted form of any of these groups; a, b, m, d, e, and n are each independently 1, 2, 3, or 4; c and f are each independently 1 to 10; x and y are each independently an integer of 0 to 250, provided that at least one of x and y exceeds 1. [The present invention 1020] The composition of claim 1003, wherein the dendrimer has the following formula: Core - (repeating unit) n -Terminal group (I) wherein the core is linked to the repeat unit by removing one or more hydrogen atoms from the core and replacing them with the repeat unit; The core is an alkylamine (C≦18) , dialkylamine (C≦36) , heterocycloalkane (C≦12) or a substituted form of any of these groups; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: TIFF2026034537000164.tif17128 formula, A1 and A2 each independently represent -O- or -NR a -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; Y3 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: TIFF2026034537000165.tif11128 formula, X3 and X4 are alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R9 is alkyl (C≦8)or substituted alkyl (C≦8) and; The linker group has the formula: TIFF2026034537000166.tif16128 formula, Y1 is alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: TIFF2026034537000167.tif13128 formula, Y4 is alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either of these groups; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) where: R 11 is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6. [The present invention 1021] 1006. The composition of any one of claims 1003 to 1006, wherein the end group is further defined by the formula: TIFF2026034537000168.tif12128 formula, Y4 is alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either of these groups; R 10 is hydrogen. [The present invention 1022] The composition of the present invention 1021, wherein the end group is further defined by the formula: TIFF2026034537000169.tif12128 formula, Y4 is alkanediyl (C≦18) and; R 10 is hydrogen. [The present invention 1023] Y4 is alkanediyl (C4~18) The composition of the present invention 1021 or 1022, [The present invention 1024] Compositions of any of 1003, 1005, and 1021-1023, wherein the core is further defined by the formula: TIFF2026034537000170.tif12128 formula, X2 is N(R5) y and; R5 is hydrogen or alkyl (C≦8) , or substituted alkyl (C≦18) and; y is 0, 1, or 2, provided that the sum of y and z is 3; R2 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; b is 1, 2, 3, 4, 5, or 6; z is 1, 2, or 3, provided that the sum of z and y is 3. [The present invention 1025] X2 is NR5, where R5 is hydrogen or alkyl (C≦8)The composition of the present invention 1024. [The present invention 1026] The composition of the present invention 1025, wherein R5 is methyl. [The present invention 1027] Any of compositions 1024 to 1026 of the present invention, wherein z is 3. [The present invention 1028] The composition of any one of claims 1024 to 1027, wherein R2 is amino. [The present invention 1029] R2 is alkylamino (C≦12) or substituted alkylamino (C≦12) Any of compositions 1024 to 1027 of the present invention, [The present invention 1030] R2 is dialkylamino (C≦12) or substituted dialkylamino (C≦12) Any of compositions 1024 to 1027 of the present invention, [The present invention 1031] The composition of claim 1024, wherein b is 2 or 3. [The present invention 1032] 10. The composition of any of claims 1024-1031, wherein the core is further defined as: TIFF2026034537000171.tif56150. [The present invention 1033] Compositions of any of 1003, 1006, and 1021-1023, wherein the core is further defined as: TIFF2026034537000172.tif11128 formula, X3 is -NR6-, where R6 is hydrogen, alkyl (C≦8) , or substituted alkyl (C≦8) , -O-, or alkylaminodiyl (C≦8) , alkoxydiyl (C≦8) , Arendjiil (C≦8) , heteroarenediyl (C≦8) , heterocycloalkanediyl (C≦8) or a substituted form of any of these groups; R3 and R4 are each independently amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or substituted forms of either of these groups, or a group of the formula -(CH2CH2N) e (R c )R d is the basis of; where: e is 1, 2, or 3; R c and R d are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; c and d are each independently 1, 2, 3, 4, 5, or 6. [The present invention 1034] X3 is alkylaminodiyl (C≦8) or substituted alkylaminodiyl (C≦8) The composition of the present invention 1033. [This invention 1035] X3 is heterocycloalkanediyl (C≦8) or substituted heterocycloalkanediyl (C≦8) The composition of the present invention 1033. [The present invention 1036] The composition of any one of claims 1033 to 1035, wherein R3 is amino. [This invention 1037] R3 is alkylamino (C≦12) or substituted alkylamino (C≦12) Any of compositions 1033 to 1035 of the present invention, [The present invention 1038] The composition of any one of claims 1033 to 1037, wherein R4 is amino. [This invention 1039] R4 is alkylamino (C≦12) or substituted alkylamino (C≦12) Any of compositions 1033 to 1037 of the present invention, [The present invention 1040] R4 is -(CH2CH2N) e (R c )Rd and; where: e is 1, 2, or 3; R c and R d are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) That is, Any of compositions 1033 to 1037 of the present invention. [The present invention 1041] 1033-1040. The composition of any of claims 1033-1040, wherein the core is further defined as: TIFF2026034537000173.tif89146. [The present invention 1042] Y3 is alkanediyl (C≦8) or substituted alkanediyl (C≦8) Any one of compositions 1001 to 1021 of the present invention, [This invention 1043] Y3 is alkanediyl (C≦8) The composition of the present invention 1042. [This invention 1044] A1 is -NR a - Any of compositions 1003 to 1006 or 1020 to 1043 of the present invention. [This invention 1045] A2 is -NR a Any of compositions 1003 to 1006 or 1020 to 1044 of the present invention, [The present invention 1046] R9 is alkyl (C≦8) The composition of any one of 1003 to 1006 or 1020 to 1045 of the present invention, [This invention 1047] Compositions 1003 to 1006 or 1020 to 1046 of the present invention, wherein n is 0 or 1. [This invention 1048] The composition of the present invention 1011 or 1012, further defined as the following formula: TIFF2026034537000174.tif16128 formula, R1 is a group of the formula: TIFF2026034537000175.tif15128 formula, R5, R6, and R2 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z2A'R7; where Z2 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and R2 are each independently -Z3A''R8; Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl(C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6. [This invention 1049] Compositions of any of 1011, 1012, or 1048 of the present invention further defined as the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000176.tif14128 formula, R1 is a group of the formula: TIFF2026034537000177.tif16128 formula, R5, R6, and R2 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z2A'R7; where Z2 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and R2 are each independently -Z3A''R8; Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4. [The present invention 1050] Compositions of any of 1011, 1012, 1048, or 1049 of the present invention further defined as the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000178.tif14128In formula, R1 is a group of the formula: TIFF2026034537000179.tif16128In formula, R5 is -Z3A''R8; where Z3 is alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; R6 is alkyl (C≦8) or substituted alkyl (C≦8) and; R2 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group, wherein: R′ and R″ are each independently —Z2A′R7; Z2 is alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or q is 1 or 2; r is 1 or 2. [This invention 1051] Composition of any of 1011, 1012, or 1048-1050, further defined as the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000180.tif14128 formula, R1 is a group of the formula: TIFF2026034537000181.tif16128In formula, R5 is alkyl (C≦8) or substituted alkyl (C≦8) and; R6 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group, wherein: R' and R'' are each independently alkyl (C≦8) , substituted alkyl (C≦8) , or -Z2A'R7; where Z2 is alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R2 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group, wherein: R' and R'' are each independently alkyl (C≦8) , substituted alkyl (C≦8), or -Z2A'R7; where Z2 is alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; q is 1 or 2; r is 1 or 2. [This invention 1052] Composition of any of 1011, 1012, or 1048-1050, further defined as the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000182.tif14128 formula, R1 is a group of the formula: TIFF2026034537000183.tif16128 formula, R5 is -Z3A''R8; where Z3 is alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24)and; R6 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group; R′ and R″ are each independently —Z2A′R7; Z2 is alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; R2 is -alkanediyl (C≦6) -NR'R'' or a substituted form of this group; R′ and R″ are each independently —Z2A′R7; Z2 is alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl(C6~24) and; q is 1 or 2; r is 1 or 2. [This invention 1053] The composition of the present invention 1011 or 1013, further defined as: TIFF2026034537000184.tif16128In formula, R1 is a group of the formula: TIFF2026034537000185.tif11128 formula, Y2 is Arrange (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) , alkoxydiyl (C≦12) or a substituted form of any of these groups; R9, R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z4A'''R 12 is selected from; where Z4 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A''' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; x and y are 1, 2, 3, or 4; R a, R3, and R4 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) and; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6. [This invention 1054] R3 is alkyl (C≦8) or substituted alkyl (C≦8) Compositions 1011 to 1013 or 1053 of the present invention, [This invention 1055] R4 is alkyl (C≦8) or substituted alkyl (C≦8) Compositions of any one of 1011 to 1013 or 1048 to 1054 of the present invention, [This invention 1056] Compositions 1011, 1012, 1013, and any one of 1048 to 1055, wherein m is 1 or 2. [This invention 1057] Compositions 1011, 1012, 1013, and any one of 1048 to 1056, wherein n is 2 or 3. [This invention 1058] Composition 1011, 1012, 1013, or any of compositions 1048 to 1057, wherein p is 1, 2, or 3. [This invention 1059] Compositions 1011, 1012, or 1048-1058 of the present invention, wherein R1 is a group of the formula: TIFF2026034537000186.tif16128 formula, R5, R6, and R2 are each independently hydrogen or alkyl. (C≦8) , -alkanediyl (C≦6) -NH2, -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl(C≦8) , substituted alkyl (C≦8) , -Z2A'R7; where Z2 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R7 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) or R5, R6, and X1 are each independently -Z3A''R8; Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4. [The present invention 1060] The composition of claim 1059, wherein q is 1 or 2. [This invention 1061] R5 is -Z3A''R8; where Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) That is, Any of the compositions of 1059 to 1060 of the present invention. [This invention 1062] R6 is -Z3A''R8; where Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) That is, Any of the compositions of 1059 to 1061 of the present invention. [This invention 1063] R2 is -Z3A''R8; where Z3 is alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R8 is alkyl (C6~24) , substituted alkyl (C6~24) , alkenyl (C6~24) , substituted alkenyl (C6~24) That is, Any of the compositions of 1059 to 1062 of the present invention. [This invention 1064] X1 is alkanediyl (C1~2) The composition of any one of claims 1061 to 1063, [This invention 1065] R8 is alkyl (C6~24) or substituted alkyl (C6~24) The composition of any one of claims 1061 to 1064 of the present invention, [The present invention 1066] The composition of the present invention 1015 or 1016, further defined as: TIFF2026034537000187.tif16128 formula, R1 is hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000188.tif12128In formula, R7 and R8 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000189.tif11128 formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4; R5 and R6 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) and; m and n are each independently 1, 2, 3, 4, or 5. [This invention 1067] Compositions of any of 1015, 1016, or 1066 of the present invention further defined as the following formula or a pharmaceutically acceptable salt thereof: TIFF2026034537000190.tif16128 formula, R1, R2, and R3 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000191.tif12128 formula, R7 and R8 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000192.tif11128In formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4; R5 and R6 are each independently hydrogen, alkyl, or (C≦6) , or substituted alkyl (C≦6) and; m is 1, 2, 3, 4, or 5. [The present invention 1068] R2 is alkyl (C≦6) or substituted alkyl (C≦6) The composition of any one of 1015, 1016, 1066 to 1067 of the present invention, [This invention 1069] Any of compositions 1015, 1016, 1066 to 1067 of the present invention, wherein R2 is a group of the following formula: TIFF2026034537000193.tif12128 formula, R7 and R8 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000194.tif11128 formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4. [The present invention 1070] R7 TIFF2026034537000195.tif11128, During the ceremony, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24)or a substituted form of either group, The composition of the present invention 1069. [This invention 1071] R8 TIFF2026034537000196.tif11128, During the ceremony, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group, Any of the compositions of 1069 to 1070 of the present invention. [This invention 1072] R3 is alkyl (C≦6) or substituted alkyl (C≦6) The composition of any one of 1015 and 1066 to 1071 of the present invention, [This invention 1073] Compositions 1015, 1016, and any of 1066 to 1072, wherein R4 is hydrogen. [This invention 1074] R5 is alkyl (C≦6) or substituted alkyl (C≦6) Any of compositions 1015, 1016, and 1066 to 1073 of the present invention, [This invention 1075] R6 is alkyl (C≦6) or substituted alkyl (C≦6) Any of compositions 1015, 1016, and 1066 to 1074 of the present invention, [This invention 1076] Compositions 1015, 1016, and 1066 to 1075 of the present invention, wherein m is 2, 3, or 4. [This invention 1077] Compounds of any of 1015, 1016, and 1066 to 1076 of the present invention, wherein n is 2, 3, or 4. [This invention 1078] Compositions 1015, 1016, and 1066 to 1077 of the present invention, wherein R1 is a group of the following formula: TIFF2026034537000197.tif12128 formula, R7 and R8 are each independently hydrogen, alkyl, or (C≦6) , substituted alkyl (C≦6) or a group of the formula: TIFF2026034537000198.tif11128In formula, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4. [This invention 1079] R7 TIFF2026034537000199.tif11128, During the ceremony, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group, Composition of the present invention 1078. [The present invention 1080] The composition of claim 1079, wherein R9 is hydroxy. [This invention 1081] R9 is acyloxy (C≦8) or substituted acyloxy (C≦8) The composition of the present invention 1079. [This invention 1082] R 10 is alkyl (C≦24) or substituted alkyl (C≦24)Any of the compositions of 1079 to 1081 of the present invention, [This invention 1083] R8 TIFF2026034537000200.tif11128, During the ceremony, R9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group, Any of the compositions of 1078 to 1082 of the present invention. [This invention 1084] The composition of claim 1083, wherein R9 is hydroxy. [This invention 1085] R9 is acyloxy (C≦8) or substituted acyloxy (C≦8) The composition of the present invention 1083. [This invention 1086] R 10 is alkyl (C≦24) or substituted alkyl (C≦24) The composition of any one of 1083 to 1085 of the present invention, [This invention 1087] Any of the compositions of 1078 to 1085 of the present invention, wherein q is 1 or 2. [This invention 1088] Any of the compositions of 1078 to 1087, wherein r is 1, 2, or 3. [This invention 1089] The composition of any of claims 1001 to 1088, wherein the tRNA is an unmodified tRNA. [The present invention 1090] The composition of any one of claims 1001 to 1088, wherein the tRNA is a modified tRNA. [This invention 1091] The composition of any one of claims 1001 to 1090, wherein the tRNA is a suppressor tRNA. [This invention 1092] The composition of invention 1091, wherein the tRNA is a tRNA that delivers an amino acid into a protein instead of terminating translation. [This invention 1093] The composition of the present invention 1091, wherein the tRNA is a tRNA amber suppressor, a tRNA opal suppressor, a tRNA ochre suppressor, or a tRNA frameshift suppressor. [This invention 1094] The composition of claim 1092, wherein the tRNA adds an arginine residue to the growing polypeptide. [This invention 1095] tRNA is tRNA arg / op The composition of the present invention 1094. [This invention 1096] The composition of claim 1092, wherein the tRNA adds a glycine residue to the growing polypeptide. [This invention 1097] tRNA is tRNA gly / op The composition of the present invention 1096. [This invention 1098] The composition of claim 1092, wherein the tRNA adds a tryptophan residue to the growing polypeptide. [This invention 1099] tRNA is tRNA trp / op The composition of the present invention 1098. [The present invention 1100] 1091. The composition of claim 1091, wherein the tRNA corrects a nonsense mutation in a cystic fibrosis transmembrane conductance regulator protein. [The present invention 1101] The composition of any one of claims 1001 to 1100, further comprising a steroid or a steroid derivative. [The present invention 1102] The composition of any one of claims 1001 to 1101, further comprising a phospholipid. [The present invention 1103] The composition of any one of claims 1001 to 1102, further comprising a PEG lipid. [The present invention 1104] The composition of the present invention 1103, wherein the PEG lipid is further defined as: TIFF2026034537000201.tif39128 formula, n1 is an integer from 1 to 250; n2 and n3 are each independently selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23. [This invention 1105] The composition of any of claims 1001 to 1104, comprising a ratio of the compound to a steroid or steroid derivative of about 1:1 to about 20:1. [The present invention 1106] 6. The composition of any one of claims 1001 to 1105, comprising a ratio of compound to phospholipid of about 1:1 to about 9:1. [This invention 1107] 1001-1106. The composition of any of claims 1001-1106, comprising a ratio of compound to PEG lipid of about 2.5:1 to about 100:1. [This invention 1108] 8. The composition of any one of claims 1001 to 1107, comprising a molar ratio of compound to nucleic acid of about 5:1 to about 1000:1. [This invention 1109] (A) any one of the compositions 1001 to 1108 of the present invention; (B) excipients and 10. A pharmaceutical composition comprising: [The present invention 1110] A pharmaceutical composition of the present invention 1109 formulated for administration by injection. [The present invention 1111] The pharmaceutical composition of any one of claims 1109 to 1110, which is formulated as a unit dose. [The present invention 1112] A method of treating a disease or disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of any of the compositions of present inventions 1001-1111. [The present invention 1113] The method of claim 1112, wherein the disease or disorder is a genetic disease or disorder. [This invention 1114] The method of claim 1113, wherein the genetic disease or disorder is cystic fibrosis. [This invention 1115] 1114. The method of claim 1114, wherein the gene for the cystic fibrosis transmembrane conductance regulator protein (CFTR) has a nonsense mutation. [The present invention 1116] 1113. The method of claim 1113, wherein the genetic disease or disorder is Duchenne muscular dystrophy (DMD), a congenital glycosylation disorder, Dravet syndrome, a mucopolysaccharidosis type I (MPS I) disorder, an NGLY1 deficiency (N-glycanase deficiency) disorder, Rett syndrome, or cancer. [This invention 1117] The method of claim 1112, wherein the disease or disorder is cancer. [This invention 1118] The method of any one of claims 1112 to 1117, wherein the patient is a mammal. [This invention 1119] The method of claim 1118, wherein the patient is a human. [The present invention 1120] The method of any of claims 1112 to 1119, wherein the composition is administered once. [This invention 1121] The method of any of claims 1112 to 1119, wherein the composition is administered more than once. Other objects, features, and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples indicating preferred embodiments of the present disclosure are given by way of illustration only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description. [Brief explanation of the drawings]

[0117] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The present disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0118] [Figure 1] A schematic representation of the consequences of a nonsense mutation is shown. [Figure 2A] Western blot analysis of CFTR mutations after 72 hours of transfection in 293 cells. G418 and PTC124 were added 24 hours after transfection. [Figure 2B] Figure 1 shows Western blot analysis of CFTR in IB3-1 cells after increasing concentrations of PTC124 and G418 for 48 hours. Calu-3 cells were used as antibody control. [Figure 2C] 1 shows a schematic diagram of the effect of a readthrough agent on a nonsense mutation. [Figure 3A] Western blot analysis of CFTR mutants after 48 hours of transfection in 293 cells. [Figure 3B] Transepithelial electrical resistance measurements of transiently transfected FRT monolayers performed using a TECC 24 (EP instrument) after addition of the indicated compounds are shown. [Figure 4A] Representative single-channel recordings of wild-type (WT) and W1282L-CFTR in inside-out membrane patches excised from transiently transfected CHO cells are shown. ATP (1 mM) and PKA (75 nM) were continuously present in the intracellular solution. The dotted line indicates the closed channel state, and downward deflection corresponds to channel opening. The lower bar graphs show the single-channel current amplitude (i), single-channel slope conductance (γ), and open probability (Po) of WT and W1282L-CFTR. Data are shown as mean ± SEM (n > 3); * > 0.05 vs. WT. [Figure 4B] Representative recordings are shown showing the effect of VX-770 (0.05, 0.2, and 1 μM) on single-channel activity of W1282L-CFTR in inside-out membrane patches excised from CHO cells. ATP (1 mM) and PKA (75 nM) were continuously present in the intracellular solution. [Figure 5A]Western blot analysis of CFTR mutants after 48 hours of transfection with the indicated plasmids in 293 cells is shown. [Figure 5B] Quantification of full-length CFTR after Sup-tRNAArg expression normalized to WT CFTR levels by LiCOR Image Studio software is shown. [Figure 5C] Representative whole-cell current recordings from 293 cells transfected with the indicated plasmids under basal and flow-stimulated conditions are shown. [Figure 6A] Representative images of fluorescently labeled tRNA delivered by nanoparticles after 24 hours of exposure in Hela cells are shown. [Figure 6B] Western blot analysis of nmP53(R196X) rescue by the indicated carriers after 48 h exposure in Calu6 cells. [Figure 6C] 1 shows a schematic representation of the consequences of nonsense mutations after delivery of modified tRNA. [Figure 7] 1 shows the fractional tRNA binding for various different nanoparticle compositions. [Figure 8] 1 shows the particle size and polydispersity index of various different nanoparticle compositions. [Figure 9-1] 1 shows the amount of p53 rescue by Western blot analysis of different nanoparticle compositions. [Figure 9-2] See description of Figure 9-1. [Figure 10] This shows that composition RCT-Z100 induces p53 expression events at half the amount. Both G418 and PTC124 showed minimal p53 expression compared to RCT-Z100. [Figure 11] Figure 1 shows that RCT-Z100 nanoparticles were readily taken up by Calu6 cells after incubation, as monitored by fluorescence microscopy. [Figure 12] We show that zwitterionic amino lipids and cationic sulfonamide amino lipids can deliver suppressor tRNAs, thereby restoring p53 expression. [Figure 13] 1 shows the results of luciferase response assays and viability of cells treated with tRNA-containing nanoparticles prepared using manual or microfluidic mixing, and dilution or swelling. [Figure 14] The components of ZAL used in these studies are shown below. [Figure 15] The components of CSAL used in these studies are shown below. DETAILED DESCRIPTION OF THE INVENTION

[0119] DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS In some aspects, the present disclosure provides compositions, comprising tRNA or modified tRNA or tRNA derivative and aminolipid delivery compound that supports the delivery of said tRNA to cells.These compositions can be administered to patients to correct nonsense mutation in genome.Therefore, in some embodiments, this composition can be administered to treat genetic disorders such as but not limited to cystic fibrosis, cancer or Duchenne muscular dystrophy.

[0120] I. Aminolipid Delivery Compounds In some aspects, the present disclosure provides compositions comprising aminolipid delivery compounds. The aminolipid delivery compounds are compounds comprising one or more hydrophobic components and one or more amine groups that can be protonated at physiological pH. In some embodiments, the aminolipid delivery compounds can be dendrimers (also known as dendrons or dendritic lipids). In other embodiments, the aminolipid delivery compounds are polymers having positively charged amine groups and one or more hydrophobic components. In some embodiments, the polymers can be degradable in vivo. Some non-limiting examples of polymers that can be used in the compositions include polyamides and polyesters. In other embodiments, the aminolipid delivery compounds are zwitterionic compounds having a negatively charged group, a positively charged amine group, and one or more hydrophobic components. Some non-limiting examples of possible negatively charged groups that the compositions can contain include sulfonic acid, phosphorous acid, or carboxylic acid. In some embodiments, the negatively charged group is sulfonic acid. In yet another embodiment, the aminolipid carrier is a positively charged amine group, a sulfonamide functional group, a tetraalkylamine functional group, and one or more hydrophobic components. These compounds have a net positive charge, a dimethyl quaternary amine functional group, and one or more lipid components.

[0121] In some embodiments, the present disclosure relates to compounds such as the polyesters in Table 1 and the dendrimers in Table 2. Within the polyesters, the number of repeat units is measured based on the average molecular weight of the compound. Further information regarding these compounds can be found in Yan et al., 2016. Further details regarding amino lipid components can be found in WO 2016 / 094342, WO 2017 / 048789, and International Application PCT / US2017 / 032950, ​​the contents of which are incorporated herein by reference in their entireties. Additional structures include zwitterionic and cationic compositions prepared using the components set forth in Figures 14 and 15, respectively.

[0122] Table 1: Polyester polymers used in the compositions described herein TIFF2026034537000202.tif232140TIFF2026034537000203.tif232141TIFF2026034537000204.tif232145TIFF2026034537000205.tif232141

[0123] Table 2: Dendrimers used in the compositions described herein TIFF2026034537000206.tif232140TIFF2026034537000207.tif232140TIFF2026034537000208. tif232122TIFF2026034537000209.tif232149TIFF2026034537000210.tif23279TIFF202603453 7000211.tif232150TIFF2026034537000212.tif23298TIFF2026034537000213.tif23275TIFF20 26034537000214.tif23296TIFF2026034537000215.tif232150TIFF2026034537000216.tif23240

[0124] The aminolipid delivery compounds provided by the present disclosure are shown, for example, in the summary section above and in the claims below.They can be prepared using the methods outlined in the examples section.These methods can be further modified and optimized by those skilled in the art using the principles and techniques of organic chemistry.For example, such principles and techniques are taught in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (2007), which is incorporated herein by reference.

[0125] The compounds described herein may contain one or more asymmetrically substituted carbon or nitrogen atoms and may be isolated as optically active or racemic forms. Therefore, unless a specific stereochemical configuration or isomer is specifically indicated, all chiral forms, diastereomeric forms, racemic forms, epimeric forms, and all geometric isomers of a given chemical formula are intended. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. In some embodiments, single diastereomers are obtained. The chiral centers of the compounds of the present disclosure may have an S or R configuration.

[0126] The chemical formula used to represent the aminolipid delivery compound of the present disclosure usually only shows one of possibly several different tautomers.For example, it is known that many kinds of ketone groups exist in equilibrium with corresponding enol groups.Similarly, many kinds of imine groups exist in equilibrium with enamine groups.No matter which tautomer is shown for a given compound, and no matter which tautomer is most predominant, all tautomers of a given chemical formula are intended.

[0127] Additionally, the compounds of the present disclosure, whether used in the indications described herein or otherwise, may have the advantage that they may be more effective, less toxic, longer acting, more potent, produce fewer side effects, be more readily absorbed, and / or exhibit a favorable pharmacokinetic profile (e.g., high oral bioavailability and / or low clearance), and / or exhibit other useful pharmacological, physical, or chemical properties than compounds known in the prior art.

[0128] Furthermore, atoms constituting the compounds of the present disclosure are intended to include all isotopic forms of such atoms. As used herein, isotopes include atoms with the same atomic number but different mass numbers. By way of general example and without limitation, hydrogen isotopes include tritium and deuterium, and carbon isotopes include tetrahydrogen and tetrahydrofuran. 13 C and 14C is one example.

[0129] It should be recognized that the particular anion or cation forming part of any salt form of the compounds provided herein is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Further examples of pharmaceutically acceptable salts and methods for their preparation and use are provided in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.

[0130] II. tRNA In some aspects, the composition includes transfer RNA (also known as tRNA). As used herein, the term transfer RNA or tRNA refers to both traditional tRNA molecules and tRNA molecules with one or more modifications, unless otherwise specified. Transfer RNA is an RNA polymer approximately 70-100 nucleotides in length. During protein synthesis, tRNA delivers amino acids to the ribosome for addition to a growing peptide chain. Active tRNAs have a 3' CCA tail, which may be transferred to the tRNA during its synthesis or added later during post-translational processing. An amino acid is covalently attached to the 2' or 3' hydroxyl group of the 3'-terminal ribose to form an aminoacyl-tRNA (aa-tRNA). Although the amino acid can spontaneously migrate from the 2'-OH to the 3'-OH or vice versa, it is incorporated into the growing protein chain at the ribosome from the 3'-OH position. The loop at the other end of the folded aa-tRNA molecule contains a three-base sequence known as the anticodon. If this anticodon sequence base-pairs with a three-base codon sequence in the ribosome-bound messenger RNA (mRNA), the aa-tRNA binds to the ribosome and that amino acid is incorporated into the nascent protein chain. Translation of the genetic code is carried out by tRNAs, since all tRNAs that base-pair with a particular codon are aminoacylated with a single, specific amino acid. Each of the 61 non-terminating codons in an mRNA directs the binding of its cognate aa-tRNA and the addition of a single, specific amino acid to the growing protein polymer. In some embodiments, the tRNA can contain a mutation in the anticodon region of the tRNA such that the aa-tRNA base-pairs with a different codon on the mRNA. In certain embodiments, the mutant tRNA introduces an amino acid into the growing protein chain that is different from the amino acid encoded by the mRNA. In other embodiments, the mutant tRNA base-pairs with a stop codon, introducing an amino acid instead of terminating protein synthesis, thereby allowing the nascent peptide to continue growing. In some embodiments, the wild-type or mutant tRNA is capable of reading through a stop codon and incorporating an amino acid instead of terminating protein synthesis.In some embodiments, the tRNA can include a full-length tRNA that includes a 3'-terminal CCA nucleotide. In other embodiments, a tRNA lacking a 3'-terminal A, CA, or CCA is converted to a full-length tRNA in vivo by a CCA-adding enzyme.

[0131] In other aspects, the composition may further comprise one or more modified tRNA molecules, including: acylated tRNA; alkylated tRNA; tRNA containing one or more bases other than adenine, cytosine, guanine, or uracil; tRNA that is covalently modified by the attachment of a specific ligand or antigen probe moiety, a fluorescent probe moiety, an affinity probe moiety, a reactive probe moiety, a spectral probe moiety, or other probe moiety; tRNA containing one or more ribose moieties that are methylated or otherwise modified; aa-tRNA aminoacylated with an amino acid other than the 20 natural amino acids, including unnatural amino acids, that functions as a carrier of a reagent or specific ligand, or as an antigen probe, a fluorescent probe, a reactive probe, an affinity probe, a spectral probe, or other probe; or any combination of these compositions. Some examples of modified tRNA molecules are taught by Soll, et al., 1995; El Yacoubi, et al., 2012; Grosjean and Benne, et al., 1998; Hendrickson, et al., 2004; Ibba and Soll, 2000; Johnson, et al., 1995; Johnson, et al., 1982; Crowley, et al., 1994; Beier and Grimm, 2001; Torres, et al., 2014; and Bjork, et al., 1987, all of which are incorporated herein by reference.

[0132] III. Genetic disorders In some aspects, the present disclosure provides compositions that can be used to treat one or more genetic disorders.One example of a genetic disorder is cystic fibrosis.Some cases of cystic fibrosis are caused by a mutation that causes the deletion of phenylalanine at position 508, but about 10% of cases are caused by a mutation that generates a stop codon that replaces the codon of the adjacent amino acid in the protein sequence.This mutation is called a nonsense mutation, and it causes a truncated non-functional cystic fibrosis transmembrane conductance regulator (CFTR) protein.

[0133] Mutations in the CFTR protein impair chloride ion transport, and therefore, patients with cystic fibrosis exhibit salty skin, poor growth, poor weight gain, mucus accumulation, especially in the lungs, frequent chest infections, and persistent cough. Because cystic fibrosis is a genetic disorder, treatment options are often related to treating symptoms rather than the underlying pathology. Such treatments include treating infections, therapies to remove mucus accumulation, and organ transplants, such as lung transplants. Therefore, attempts to address the underlying pathology are crucial.

[0134] In another aspect, the present disclosure contemplates the treatment of cancer, particularly cancers with nonsense mutations in one or more tumor suppressor genes.Some non-limiting types of cancer include bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal tract cancer, reproductive cancer, genitourinary cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosa cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, colon cancer, stomach cancer, testicular cancer, or thyroid cancer, or carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma. A non-limiting list of possible tumor suppressor proteins includes p53, pRb, PTEN, SWI, SNF, pVHL, APC, CD95, ST5, YPEL3, ST7, and ST14. In addition to the compositions described herein, patients can be treated with one or more additional anti-cancer therapies, including chemotherapy, surgery, immunotherapy, or radiation therapy.

[0135] IV.Treatment A. Pharmaceutical Formulations and Routes of Administration When clinical use is envisaged, pharmaceutical compositions need to be prepared in a form suitable for intended use.In some embodiments, such formulations with the compounds of the present disclosure are envisaged.Generally, this involves preparing compositions that are essentially free of pyrogens and other impurities that may be harmful to humans or animals.

[0136] Generally, it is desirable to use appropriate salts and buffers to stabilize the delivery vector and enable uptake by target cells. Buffers are also used when introducing recombinant cells into a patient. The aqueous compositions of the present disclosure contain a cell-effective amount of the vector, dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. Such compositions are also referred to as inocula. The phrase "pharmaceutically or pharmacologically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans. As used herein, "pharmaceutically acceptable carrier" includes any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional media or agent is contemplated for use in therapeutic compositions, except insofar as it is incompatible with the vectors or cells of the present disclosure. Supplementary active ingredients can also be incorporated into the compositions.

[0137] The active compositions of the present disclosure may include classical pharmaceutical formulations. These compositions of the present disclosure may be administered via any common route, provided that the target tissue is accessible by that route. Such routes include oral, nasal, buccal, vaginal, or topical routes. Alternatively, administration may be via orthotopic, intradermal, subcutaneous, intramuscular, intratumoral, intraperitoneal, or intravenous injection. Typically, such compositions are administered as pharmaceutically acceptable compositions as described above.

[0138] The active compound can be administered parenterally or intraperitoneally.The solution of the active compound as a free base or pharmacologically acceptable salt can be prepared in water, suitably mixed with a surfactant such as hydroxypropyl cellulose.Dispersions can also be prepared in glycerin, liquid polyethylene glycol and their mixtures, and in oil.These preparations contain preservatives to prevent the growth of microorganisms under normal storage and use conditions.

[0139] Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid to the extent that easy syringability exists. The form must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerin, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, the maintenance of the required particle size in the case of dispersions, and the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0140] Sterile injectable solution is prepared by incorporating required amount of active compound in suitable solvent with various other components as listed above as necessary, then sterilizing by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into the sterile medium that contains basic dispersion medium and other components that are required among the components listed above.For the sterile powder that is used to prepare sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains the powder of active ingredient and any other desired components from the solution that has already been sterilized and filtered.

[0141] As used herein, "pharmaceutically acceptable carrier" includes any solvent, dispersion medium, coating, antibacterial and antifungal agent, isotonic agent, absorption delaying agent, etc. The use of such media and agents for pharmaceutical active substances is well known in the art. Any conventional media or agent is contemplated for use in therapeutic compositions, except insofar as it is incompatible with the active ingredient. Supplementary active ingredients can also be incorporated into the composition.

[0142] For oral administration, the compositions described herein can be incorporated into excipients and used in the form of non-oral mouthwashes and dentifrices. Mouthwashes can be prepared by incorporating the required amount of active ingredient into a suitable solvent, such as sodium borate solution (Dobell's solution). Alternatively, the active ingredient can be incorporated into an antiseptic rinse containing sodium borate, glycerin, and potassium bicarbonate. The active ingredient can also be dispersed in dentifrices, including gels, pastes, powders, and slurries. A therapeutically effective amount of the active ingredient can be added to a paste dentifrice, which can contain water, binders, abrasives, flavorings, foaming agents, and humectants.

[0143] The compositions of the present disclosure can be formulated in neutral or salt form.Pharmaceutically acceptable salts include acid addition salts (formed with the free amino groups of protein and) with inorganic acids such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, mandelic acid, etc. Also, salts formed with free carboxyl groups can be derived from inorganic bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or ferric hydroxide, and organic bases such as isopropylamine, trimethylamine, histidine, procaine, etc.

[0144] Upon formulation, solutions are administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. The formulations are easily administered in a variety of dosage forms, such as injectable solutions, drug-release capsules, and the like. For example, for parenteral administration in aqueous solutions, the solution should be suitably buffered, if necessary, and the liquid diluent should first be rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. In this regard, usable sterile aqueous vehicles will be apparent to those skilled in the art in light of the present disclosure. For example, a dose can be dissolved in 1 ml of isotonic NaCl solution and added to 1000 ml of hypodermic infusion fluid or injected at the intended injection site (see, e.g., "Remington's Pharmaceutical Sciences," 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual administering the solution will, in any event, determine the appropriate dose for the individual subject. Moreover, for human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologics standards.

[0145] I. Steroids and Steroid Derivatives In some aspects of the present disclosure, aminolipids are mixed with one or more steroids or steroid derivatives to form nanoparticle compositions.In some embodiments, steroids or steroid derivatives include any steroids or steroid derivatives.In some embodiments, the term "steroid" used herein refers to a class of compounds with a 4-ring, 17-carbon ring structure, and this ring structure can further include one or more substituents, including alkyl groups, alkoxy groups, hydroxy groups, oxo groups, acyl groups, or double bonds between two or more carbon atoms.In one aspect, the ring structure of steroids includes three fused cyclohexyl rings and one fused cyclopentyl ring, as shown in the following formula: TIFF2026034537000217.tif18128.

[0146] In some embodiments, the steroid derivative comprises the above ring structure with one or more non-alkyl substituents. In some embodiments, the steroid or steroid derivative is a sterol, the formula of which is further defined as: TIFF2026034537000218.tif19128.

[0147] In some embodiments of the present disclosure, the steroid or steroid derivative is cholestane or a cholestane derivative, in which the ring structure is further defined by the formula: TIFF2026034537000219.tif36128.

[0148] As described above, the cholestane derivative contains one or more non-alkyl substituents on the ring system. In some embodiments, the cholestane or cholestane derivative is cholestene or a cholestene derivative, or a sterol or a sterol derivative. In other embodiments, the cholestane or cholestane derivative is both cholestene and sterol, or a derivative thereof.

[0149] In some embodiments, the compositions comprise a ratio of compound or aminolipid to steroid or steroid derivative of about 1:3 to about 30:1 or about 1:1 to about 20:1. The ratio can be about 1:1 to 6:1, e.g., about 1.3:1. In some embodiments, the ratio is about 1:3, 1:2, 1:1, 1.25:1, 1.5:1, 2:1, 3:1, 5:1, 8:1, 10:1, 12.5:1, 15:1, 17.5:1, 20:1, 25:1 to about 30:1, or any range derivable therein.

[0150] II. PEG or PEGylated lipids In some aspects of the present disclosure, an amino lipid (or compound) and one or more PEGylated lipids (or PEG lipids) are mixed to create a nanoparticle composition. In some embodiments, the present disclosure includes using any lipid with a PEG group attached. In some embodiments, the PEG lipid is a diglyceride that also contains a PEG chain attached to a glycerol group. In other embodiments, the PEG lipid is a compound containing one or more C6-C24 long-chain alkyl or alkenyl groups or C6-C24 fatty acid groups attached to a linker group to the PEG chain. Some non-limiting examples of PEG lipids include PEG-modified phosphatidylethanolamine and phosphatidic acid, PEG-ceramide conjugates, PEG-modified dialkylamines and PEG-modified 1,2-diacyloxypropan-3-amines, PEG-modified diacylglycerols and dialkylglycerols. In some embodiments, the PEG-modified distearoylphosphatidylethanolamine or PEG-modified dimyristoyl-sn-glycerol. In some embodiments, the PEG modification is measured by the molecular weight of the PEG component of the lipid. In some embodiments, the PEG modification has a molecular weight of about 100 to about 5,000. In some embodiments, the molecular weight is about 200 to about 500 or about 1,200 to about 3,000. Some non-limiting examples of lipids that can be used in the present disclosure are taught by U.S. Pat. No. 5,820,873, WO 2010 / 141069, or U.S. Pat. No. 8,450,298, which are incorporated herein by reference.

[0151] In another aspect, the PEG lipid has the formula: TIFF2026034537000220.tif39128 wherein n1 is an integer between 1 and 100, and n2 and n3 are each independently selected from integers between 1 and 29. In some embodiments, n1 is 5, 10, 15, 20, 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100, or any range derivable therein. In some embodiments, n1 is about 30 to about 50. In some embodiments, n2 is 5 to 23. In some embodiments, n2 is 11 to about 17. In some embodiments, n3 is 5 to 23. In some embodiments, n3 is 11 to about 17.

[0152] In some embodiments, the compositions comprise a ratio of compound or amino lipid to PEG lipid of about 1:1 to about 150:1 or about 2.5:1 to about 100:1. The ratio can be about 7.5:1 to 50:1, e.g., about 33.3:1. In some embodiments, the ratio is about 5:1, 10:1, 20:1, 25:1, 30:1, 35:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 120:1, 140:1, to about 150:1, or any range derivable therein.

[0153] III. Phospholipids In some aspects of the present disclosure, an amino lipid and one or more phospholipids are mixed to create a nanoparticle composition. In some embodiments, the phospholipid is any lipid that also contains a phosphate group. In some embodiments, the phospholipid is a structure comprising one or two long-chain C6-C24 alkyl or alkenyl groups, glycerol or sphingosine, one or two phosphate groups, and optionally a small organic molecule. In some embodiments, the small organic molecule is an amino acid, a sugar, or an amino-substituted alkoxy group, such as choline or ethanolamine. In some embodiments, the phospholipid is a phosphatidylcholine. In some embodiments, the phospholipid is distearoylphosphatidylcholine.

[0154] In some embodiments, the compositions include a ratio of compound or aminolipid to phospholipid of about 1:1 to about 15:1, or about 1:1 to about 9:1. The ratio can be about 2.5:1 to 7.5:1, e.g., about 5:1. In some embodiments, the ratio is about 1:1, 2:1, 3:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 14:1 to about 15:1, or any range derivable therein.

[0155] B. Treatment Method In particular, compositions usable for treating genetic diseases and cancer in subjects (e.g., human subjects) are disclosed herein. The compositions described above are preferably administered to mammals (e.g., rodents, humans, non-human primates, dogs, cattle, sheep, horses, cats, etc.) in effective amounts, i.e., amounts capable of producing the desired results in the treated subject. The toxicity and therapeutic efficacy of the compositions utilized in the disclosed methods can be determined by standard pharmaceutical procedures. As is well known in the medical and veterinary fields, the dosage for any single animal depends on many factors, including the subject's size, body surface area, weight, age, the specific composition to be administered, the time and route of administration, general health, clinical symptoms of genetic disease or cancer, and other co-administered drugs. In some embodiments, these dosages can be reduced or increased based on biological factors related to a particular patient, such as increased or decreased metabolic degradation of the drug or decreased uptake by the gastrointestinal tract when administered orally. Furthermore, the effective compositions may be more effective, thus requiring fewer doses to achieve the same effect. Typically, such doses are administered once daily for several weeks or until a sufficient reduction in cancer cells is achieved.

[0156] Generally, the therapeutic methods (including prophylactic treatments) of the present disclosure involve administering a therapeutically effective amount of a composition described herein to a subject in need thereof, including a mammal, particularly a human. Such treatments may be suitably carried out on subjects, particularly humans, suffering from, having, susceptible to, or at risk for a disease, disorder, or symptom thereof. The determination of a subject "at risk" may be made by any objective or subjective determination, such as by diagnostic testing or the opinion of the subject or a health care provider (e.g., genetic testing, enzyme or protein markers, markers (as defined herein), family history, etc.).

[0157] C. Combination Therapy It is assumed that the effective composition described herein can be used in combination with one or more therapeutic methods.In some aspects, in the field of cancer treatment, it is common to combine therapeutic methods.The following is a general description of the therapeutic methods that can be used in combination with the therapeutic methods of the present disclosure.

[0158] For example, to treat cancer using the methods and compositions of the present disclosure, tumor cells or a subject are typically contacted with a compound and at least one other therapeutic agent, which are administered in a combined amount effective to achieve a reduction in one or more disease parameters. This process can involve contacting the cells / subject with both agents / therapeutics simultaneously, for example, by using a single composition or pharmacological formulation containing both agents, or by contacting the cells / subject with two separate compositions or formulations, one containing the compound and the other containing the other agent.

[0159] Alternatively, the active compositions described herein may precede or follow the other therapeutic agent by intervals ranging from minutes to weeks. Generally, it is ensured that no significant period of time passes between each delivery so that the therapeutic agents can still exert their beneficial combined effect on the cell / subject. In such cases, it is contemplated that contact of the cells with both modalities may occur about 12 to 24 hours apart, about 6 to 12 hours apart, or with a delay of only about 1 to 2 hours. However, in some situations, it may be desirable to significantly extend the treatment period, allowing several days (2, 3, 4, 5, 6, or 7 days) to several weeks (1, 2, 3, 4, 5, 6, 7, or 8 weeks) to pass between each administration.

[0160] It may also be desirable to administer more than one dose of the compound or the other therapeutic agent. Various combinations can be used, as exemplified below, where the compound of the present disclosure is designated "A" and the other therapeutic agent is designated "B": TIFF2026034537000221.tif17128.

[0161] Other combinations are contemplated. The following is a general description of cancer treatments that can be used in combination with the compounds of the present disclosure.

[0162] 1. Chemotherapy The term "chemotherapy" refers to the use of drugs to treat cancer. "Chemotherapeutic agent" is used to imply a compound or composition administered in the treatment of cancer. These agents or drugs are classified by their mode of action within cells, for example, whether and at what stage they affect the cell cycle. Alternatively, agents can be characterized based on their ability to directly cross-link DNA, intercalate DNA, or affect nucleic acid synthesis to induce chromosomal and mitotic abnormalities. Most chemotherapeutic agents fall into the following categories: alkylating agents, antimetabolites, antitumor antibiotics, mitotic inhibitors, and nitrosoureas.

[0163] Examples of chemotherapeutic agents include: alkylating agents, e.g., thiotepa and cyclophosphamide; alkylsulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its adozelesin, carzelesin, and biceresin synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; Duocarmycins (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatins; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobuenbiquine, fenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics, for example, enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma 1 and calicheamicin omega 1; dynemicins, including dynemicin A; uncialamicin and its derivatives; Bisphosphonates such as clodronate; esperamicin;and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycins, actinomycins, anthramycins, azaserine, bleomycins, cactinomycins, carabicins, carminomycins, carzinophilins, chromomycins, dactinomycins, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (morpholino-doxorubicin, cyano ... sorbicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalarnycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozotocin, tubercidin, ubenimex, zinostatin, or zorubicin; Antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; and Bestravcil; Bisantrene; edatrexate; defofamine; demecolcine; diaziquone; eflornithine; elformithine; elliptinium acetate; epothilone;Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidainine; Maytansinoids such as maytansine and ansamitocins; Mitoguazone; Mitoxantrone; Mopidanmol; Nitraerine; Pentostatin; Fenamet; Pirarubicin; Losoxantrone; Podophyllinic acid; 2-Ethylhydrazide; Procarbazine; PSK polysaccharide complex; Razoxane; Rhizoxin; Sizofiran; Spirogermanium; Tenuazonic acid; Triazicone; 2,2',2''-Trichlorotriethylamine; Trichothecines (especially T-2 toxin, verracurin A, roridin A, and anguidine); Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Taxoids, such as paclitaxel and docetaxel; Chlorambucil; Gemcitabine; 6-thioguanine; Mercaptopurine; Methotrexate; Platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine; Vinorelbine; Novantrone; Teniposide; Edatrexate; Daunomycin; Aminopterin; Xeloda; Ibandronate; Irinotecan (e.g., CPT-11); Topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine;Cisplatin (CDDP), carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosoureas, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, raloxifene, estrogen receptor binding agents, taxol, paclitaxel, docetaxel, gemcitabine, navelbine, farnesyl-protein transferase inhibitors, transplatinum, 5-fluorouracil, vincristine, vinblastin, and methotrexate, and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing;

[0164] 2. Radiation therapy Radiotherapy, also known as radiation therapy, is the treatment of cancer and other diseases with ionizing radiation. Ionizing radiation applies energy that injures or destroys cells in an area, treating the area by damaging genetic material so that these cells cannot continue to grow. Radiation damages both cancer cells and normal cells, but the latter are able to repair themselves and function properly.

[0165] Radiation therapy used in accordance with the present disclosure can include, but is not limited to, the use of gamma rays, X-rays, and / or the direct delivery of radioisotopes to tumor cells. Other forms of DNA-damaging agents, such as microwave and ultraviolet radiation, are also contemplated. Arguably, all of these agents induce widespread damage to DNA, DNA precursors, DNA replication and repair, and chromosome assembly and maintenance. X-ray doses range from daily doses of 50-200 roentgens for prolonged periods (3-4 weeks) to single doses of 2000-6000 roentgens. Dosage ranges for radioisotopes vary widely and depend on the half-life of the isotope, the strength and type of radiation emitted, and uptake by neoplastic cells.

[0166] Radiation therapy can involve the use of radiolabeled antibodies (radioimmunotherapy) to deliver radiation doses directly to the cancer site. Antibodies are highly specific proteins made by the body in response to the presence of antigens (substances recognized as foreign by the immune system). Some tumor cells contain specific antigens that trigger the production of tumor-specific antibodies. Large quantities of these antibodies can be produced in the laboratory and attached to radioactive materials (a process known as radiolabeling). When injected into the body, the antibodies actively seek out cancer cells, which are then destroyed by the cell-killing (cytotoxic) effects of the radiation. This approach can minimize the risk of radiation damage to healthy cells.

[0167] Conformal radiation therapy uses the same radiation therapy equipment, a linear accelerator, as conventional radiation therapy treatments, but a metal block is placed in the path of the x-ray beam to modify its shape to match the shape of the cancer. This ensures a higher radiation dose is delivered to the tumor. Healthy surrounding tissue and nearby structures receive a lower radiation dose, thus reducing the likelihood of side effects. A device called a multi-leaf collimator has been developed and can be used as an alternative to the metal block. The multi-leaf collimator consists of several metal sheets fixed to the linear accelerator. Each layer can be adjusted so that the radiation therapy beam can be shaped to the treatment area without the need for a metal block. Precise positioning of the radiation therapy equipment is critical to conformal radiation therapy treatments, and special scanning equipment can be used to check the position of internal organs at the start of each treatment.

[0168] High-resolution intensity-modulated radiation therapy also uses a multi-leaf collimator, whose layers move during treatment while the treatment is being administered. This method likely provides more accurate shaping of the treatment beam, resulting in a consistent radiation therapy dose throughout the treatment area.

[0169] Although research studies have shown that conformal radiation therapy and intensity-modulated radiation therapy can reduce the side effects of radiation therapy treatment, the very precise shaping of the treatment area can cause tiny cancer cells to stop just outside the treatment area where they are destroyed, meaning that the risk of cancer recurrence in the future may be increased by these specialized radiation therapy techniques.

[0170] Scientists are also exploring ways to increase the effectiveness of radiation therapy. Two types of investigational drugs are being tested for their effect on irradiated cells: radiosensitizers, which make tumor cells more susceptible to damage, and radioprotectors, which protect normal tissue from the effects of radiation. Hyperthermia, or the use of heat, is also being tested for its effectiveness in sensitizing tissue to radiation.

[0171] 3. Immunotherapy Generally, in cancer treatment, immunotherapeutics rely on the use of immune effector cells and molecules to target and destroy cancer cells. Trastuzumab (Herceptin™) is one such example. For example, the immune effector can be an antibody specific for some marker on the surface of tumor cells. The antibody can act alone as a therapeutic effector or can assist other cells in actually influencing cell death. The antibody can also be conjugated to a drug or toxin (e.g., a chemotherapeutic agent, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc.) and simply act as a targeting agent. Alternatively, the effector can be a lymphocyte bearing a surface molecule that interacts directly or indirectly with a tumor cell target. Various effector cells include cytotoxic T cells and NK cells. Combining therapeutic modalities, i.e., direct cytotoxic activity combined with ErbB2 inhibition or reduction, offers therapeutic benefits in the treatment of ErbB2-overexpressing cancers.

[0172] In one aspect of immunotherapy, tumor cells necessarily bear some marker that is amenable to targeting, i.e., some marker that is not present on the majority of other cells. Many tumor markers exist, any of which may be suitable for targeting in the present disclosure. Common tumor markers include carcinoembryonic antigen, prostate-specific antigen, urinary tract tumor-associated antigen, fetal antigen, tyrosinase (p97), gp68, TAG-72, HMFG, sialyl Lewis antigen, MucA, MucB, PLAP, estrogen receptor, laminin receptor, erb B, and p155. An alternative aspect of immunotherapy is to combine anti-cancer effects with immunostimulatory effects. There are also immunostimulatory molecules, including cytokines such as IL-2, IL-4, IL-12, GM-CSF, and γ-IFN; chemokines such as MIP-1, MCP-1, and IL-8; and growth factors such as FLT3 ligand. Combining immunostimulatory molecules with tumor suppressors, either as proteins or using gene delivery, has been shown to enhance antitumor effects (Ju et al., 2000). Furthermore, antibodies against any of these compounds can be used as targets for the anticancer drugs described herein.

[0173] Examples of immunotherapeutic agents currently under investigation or in use include immune enhancers such as Mycobacterium bovis, Plasmodium falciparum, dinitrochlorobenzene, and aromatic compounds (U.S. Patent Nos. 5,801,005 and 5,739,169; Hui and Hashimoto, 1998; Christodoulides et al., 1998), cytokine therapeutics such as interferon α, β, and γ; IL-1, GM-CSF, and TNF (Bukowski et al., 1998; Davidson et al., 1998; Hellstrand et al., 1998), gene therapy agents such as TNF, IL-1, IL-2, p53 (Qin et al., 1998; Austin-Ward and Villaseca, 1998; U.S. Patent Nos. 5,830,880 and 5,846,945), and monoclonal antibodies, such as anti-ganglioside GM2, anti-HER-2, and anti-p185 (Pietras et al., 1998; Hanibuchi et al., 1998; U.S. Patent No. 5,824,311). It is contemplated that one or more anti-cancer therapeutic agents can be used in the gene silencing treatments described herein.

[0174] In active immunotherapy, antigenic peptides, polypeptides, or proteins, or autologous or allogeneic tumor cell compositions, or "vaccines," are generally administered together with a separate bacterial adjuvant (Ravindranath and Morton, 1991; Morton et al., 1992; Mitchell et al., 1990; Mitchell et al., 1993).

[0175] In adoptive immunotherapy, the patient's circulating or tumor-infiltrating lymphocytes are isolated in vitro, activated with lymphokines such as IL-2 or subjected to transduction with tumor necrosis genes, and readministered (Rosenberg et al., 1988; 1989).

[0176] 4. Surgery Approximately 60% of individuals with cancer will undergo some type of surgery, including preventative surgery, diagnostic or staging surgery, curative surgery, and palliative surgery. Curative surgery is a cancer treatment that can be used in combination with other therapies, such as the treatments disclosed herein, chemotherapy, radiation therapy, hormone therapy, gene therapy, immunotherapy, and / or alternative therapies.

[0177] Curative surgery includes resection, in which all or part of the cancerous tissue is physically removed, excised, and / or destroyed. Tumor resection refers to the physical removal of at least part of a tumor. In addition to tumor resection, surgical procedures include laser surgery, cryosurgery, electrosurgery, and microscopically controlled surgery (Mohs surgery). It is further contemplated that the present disclosure can be used in combination with the removal of superficial cancers, pre-cancers, or incidental amounts of normal tissue.

[0178] When cancerous cells, tissues, or tumors are completely or partially removed, a cavity may be formed in the body.Treatment can be achieved by perfusion, direct injection, or local application of additional anti-cancer therapeutic agents to the area.Such treatment can be repeated, for example, every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, 4, and 5 weeks, or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.In addition, these treatments can be treatments with variable dosages.

[0179] In some specific aspects, adjuvant treatment with compounds of the present disclosure following tumor removal is believed to be particularly effective in reducing tumor recurrence. Additionally, compounds of the present disclosure can also be used in a neoadjuvant setting.

[0180] 5. Cystic Fibrosis Treatment There is no cure for cystic fibrosis, and therefore, most treatment options address the symptoms rather than the underlying pathology of the disease. Some therapies involve reducing mucus deposition in the airways. Treatments can be physical therapy, exercise, manual expectoration, or medication. These medications include saline, DNases such as dornase alfa, mucolytic agents such as acetylcysteine, bronchodilators such as albuterol or salmeterol, or anticholinergics. In other aspects, the cystic fibrosis treatment is an antibiotic, such as, but not limited to, gentamicin, piperacillin, tazobactam, aztreonam, ciprofloxacin, tobramycin, ceftazidime, amikacin, meropenem, or azithromycin. In yet another aspect, the cystic fibrosis treating agent can be an anti-inflammatory agent such as an NSAID, a membrane stabilizer such as cromolyn, or a corticosteroid such as fluticasone or prednisone, hi other aspects, the cystic fibrosis treating agent is another therapeutic agent such as ivacaftor.

[0181] V. Definition When used in the context of chemical groups: "hydrogen" means -H; "hydroxy" means -OH; "oxo" means =O; "carbonyl" means -C(=O)-; "carboxy" means -C(=O)OH (also written -COOH or -COH); "halo" means, independently, -F, -Cl, -Br, or -I; "amino" means -NH; "hydroxyamino" means -NHOH; "nitro" means -NO; imino means =NH; "cyano" means -CN; "isocyanato" means -N=C=O; "azido" means -N; in the monovalent context, "phosphate" means -OP(O)(OH) or its deprotonated form; in the divalent context, "phosphate" means -OP(O)(OH)O- or its deprotonated form; "mercapto" means -SH; and "thio" means =S; "Sulfonyl" means -S(O)2-; "hydroxysulfonyl" means -S(O)2OH; "sulfonamido" means -S(O)2NH2; and "sulfinyl" means -S(O)-.

[0182] In the context of chemical formulas, the symbol "-" means a single bond, "=" means a double bond, and "≡" means a triple bond. TIFF2026034537000222.tif3128 represents any bond, which, if present, may be either a single or double bond. TIFF2026034537000223.tif3128 represents a single or double bond. Thus, for example, the formula TIFF2026034537000224.tif10128 TIFF2026034537000225.tif11128. It is understood that such ring atoms do not form part of more than one double bond. Furthermore, it should be noted that the covalent bond symbol "-" does not indicate any preferred stereochemistry when linking one or two stereogenic atoms. Rather, it encompasses all stereoisomers and mixtures thereof. TIFF2026034537000226.tif3128 when drawn perpendicularly across the bond TIFF2026034537000227.tif6128, showing the point of attachment of the group. Note that points of attachment are typically only identified in this manner for larger groups to aid the reader in unambiguously identifying the point of attachment. TIFF2026034537000228.tif3128 represents a single bond in which the group attached to the thick end of the wedge "juts out from the page." TIFF2026034537000229.tif3128 represents a single bond in which the group attached to the thick end of the wedge "goes deep into the page." TIFF2026034537000230.tif3128 refers to a single bond where the geometry around the double bond (e.g., either E or Z) is undefined. Therefore, both options, and combinations thereof, are contemplated. Any undefined valence on an atom of a structure shown in this application implies a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen bonded to that carbon is oriented out of the plane of the paper.

[0183] The group "R" may, for example, be of the formula: In TIFF2026034537000231.tif13128, if depicted as a "floating group" on a ring system, R may replace any hydrogen atom attached to any ring atom, including drawn, implied, or explicitly defined hydrogens, as long as a stable structure is formed. When depicted as a "floating group" on a fused ring system, as in TIFF2026034537000232.tif17128, R may replace any hydrogen bonded to any ring atom of any of the fused rings, unless otherwise specified. Substitutable hydrogens include drawn hydrogens (e.g., hydrogens bonded to nitrogen in the formula above), implied hydrogens (e.g., hydrogens in the formula above that are not shown but are understood to be present), explicitly defined hydrogens, and any hydrogens whose presence depends on the identity of the ring atom (e.g., hydrogens bonded to group X when X is equal to -CH-), so long as a stable structure is formed. In the depicted example, R may be present on either the 5-membered or 6-membered ring of the fused ring system. In the formula above, the subscript "y" immediately following the parenthesized group "R" represents a numerical variable. Unless otherwise specified, this variable can be 0, 1, 2, or any integer greater than 2, limited only by the maximum number of substitutable hydrogen atoms in the ring or ring system.

[0184] In the case of chemical groups and compound classes, the number of carbon atoms in the group or class is indicated as follows: "Cn" defines the exact number (n) of carbon atoms in the group / class. "C≦n" defines the maximum number (n) of carbon atoms that can be in the group / class, the minimum number being as small as possible for the group / class in question, e.g., the group "alkenyl (C≦8) " or class "Alkene (C≦8) " is understood to be the minimum number of carbon atoms in "alkoxy" which refers to an alkoxy group having 1 to 10 carbon atoms. (C≦10) "Cn-n'" defines both the minimum (n) and maximum (n') number of carbon atoms in the group. (C2~10) " denotes an alkyl group having 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical group or class that they modify, and may or may not be enclosed in parentheses without indicating any change in meaning. Thus, "C5 olefin," "C5-olefin," "olefin (C5) " and "Olefins C5" are all synonymous. When any chemical group or class of compounds defined herein is modified by the term "substituted," any carbon atoms in the moiety that replace a hydrogen atom are not counted. Thus, methoxyhexyl is a substituted alkyl. (C1~6) This is an example.

[0185] The term "saturated," when used to modify a compound or chemical group, means that the compound or chemical group has no carbon-carbon double bonds and no carbon-carbon triple bonds, except as noted below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bonds. In substituted forms of saturated groups, one or more carbon-oxygen or carbon-nitrogen double bonds may be present. If such bonds are present, carbon-carbon double bonds that may occur as part of keto-enol or imine / enamine tautomerism are not excluded. When the term "saturated" is used to modify a solution of a substance, it means that the substance is no longer soluble in the solution.

[0186] The term "aliphatic," when used without the "substituted" modifier, indicates that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic, hydrocarbon compound or group. In an aliphatic compound / group, the carbon atoms can be linked together in a straight chain, a branched chain, or a non-aromatic ring (alicyclic). An aliphatic compound / group can be saturated (alkane / alkyl) linked by a single carbon-carbon bond, or unsaturated by one or more carbon-carbon double bonds (alkene / alkenyl) or one or more carbon-carbon triple bonds (alkyne / alkynyl).

[0187] The term "aromatic," when used to modify a compound or chemical group, refers to a planar, unsaturated ring of atoms with 4n+2 electrons in a fully conjugated cyclic π system.

[0188] The term "alkyl," when used without the "substituted" modifier, refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a straight or branched acyclic structure, and no atoms other than carbon and hydrogen. Examples include the groups -CH3(Me), -CH2CH3(Et), -CH2CH2CH3(n-Pr or propyl), -CH(CH3)2(i-Pr, i Pr or isopropyl), -CH2CH2CH2CH3(n-Bu), -CH(CH3)CH2CH3(sec-butyl), -CH2CH(CH3)2(isobutyl), -C(CH3)3(tert-butyl, t-butyl, t-Bu or tBu), and -CHC(CH)(neo-pentyl) are non-limiting examples of alkyl groups. The term "alkanediyl," when used without the "substituted" modifier, refers to a divalent saturated aliphatic group having one or two saturated carbon atoms as points of attachment, a straight or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups -CH- (methylene), -CHCH-, -CHC(CH)CH-, and -CHCHCH- are non-limiting examples of alkanediyl groups. The term "alkylidene," when used without the "substituted" modifier, refers to the divalent group =CRR', where R and R' are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include =CH, =CH(CHCH), and =C(CH). "Alkane" refers to the class of compounds having the formula H-R, where R is alkyl, as that term is defined above. When any of these terms are used with the "substituted" modifier, one or more hydrogen atoms are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -SH, -OCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)OH, or -S(O)NH. The following groups are non-limiting examples of substituted alkyl groups: -CHOH, -CHCl, -CF, -CHCN, -CHC(O)OH, -CHC(O)OCH, -CHC(O)NH, -CHC(O)CH, -CHOCH, -CHOC(O)CH, -CHNH, -CHN(CH), and -CHCHCl. ​​The term "haloalkyl" refers to a substituted alkyl group limited to the replacement of hydrogen atoms by halo (i.e., -F, -Cl, -Br, or -I) such that no other atoms other than carbon, hydrogen, and halogen are present. The group -CHCl is a non-limiting example of a haloalkyl.The term "fluoroalkyl" refers to a substituted alkyl group limited to fluoro replacement of hydrogen atoms, such that no other atoms are present other than carbon, hydrogen, and fluorine. The groups -CHF, -CF, and -CHCF are non-limiting examples of fluoroalkyl groups.

[0189] The term "cycloalkyl," when used without the "substituted" modifier, refers to a monovalent saturated aliphatic group having a carbon atom as the point of attachment, the carbon atom forming part of one or more non-aromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include -CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). The term "cycloalkanediyl," when used without the "substituted" modifier, refers to a divalent saturated aliphatic group having two carbon atoms as the point of attachment, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Group TIFF2026034537000233.tif8128 is a non-limiting example of a cycloalkanediyl group. "Cycloalkane" refers to the class of compounds having the formula HR, where R is cycloalkyl, as that term is defined above. When any of these terms are used with the "substituted" modifier, one or more hydrogen atoms are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -SH, -OCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)OH, or -S(O)NH.

[0190] The term "alkenyl," when used without the "substituted" modifier, refers to a monovalent unsaturated aliphatic group having a carbon atom as a point of attachment, a straight-chain or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bond, and no atoms other than carbon and hydrogen. Non-limiting examples include -CH=CH2 (vinyl), -CH=CHCH3, -CH=CHCH2CH3, -CH2CH=CH2 (allyl), -CH2CH=CHCHCH3, and -CH=CHCH=CH2. The term "alkenediyl," when used without the "substituted" modifier, refers to a divalent unsaturated aliphatic group having two carbon atoms as points of attachment, a straight-chain or branched, straight-chain or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bond, and no atoms other than carbon and hydrogen. The groups -CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2-, and -CH2CH=CHCH2- are non-limiting examples of alkenediyl groups. It is noted that although alkenediyl groups are aliphatic, when joined at both ends, this does not preclude the group from forming part of an aromatic structure. The terms "alkene" and "olefin" are synonymous and refer to the class of compounds having the formula HR, where R is alkenyl as defined above. Similarly, the terms "terminal alkene" and "α-olefin" are synonymous and refer to an alkene that has only one carbon-carbon double bond, which bond is part of a vinyl group at the end of the molecule. When any of these terms are used in conjunction with the "substituted" modifier, one or more hydrogen atoms are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -SH, -OCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)OH, or -S(O)NH. The groups -CH=CHF, -CH=CHCl, and -CH=CHBr are non-limiting examples of substituted alkenyl groups.

[0191] The term "alkynyl," when used without the "substituted" modifier, refers to a monovalent unsaturated aliphatic group having a carbon atom as the point of attachment, a straight or branched acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not preclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups -C≡CH, -C≡CCH, and -CHC≡CCH are non-limiting examples of alkynyl groups. "Alkyne" refers to the class of compounds having the formula HR, where R is alkynyl. When any of these terms are used in conjunction with the "substituted" modifier, one or more hydrogen atoms are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -SH, -OCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)OH, or -S(O)NH.

[0192] The term "aryl," when used without the modifier "substituted," refers to a monovalent unsaturated aromatic group having an aromatic carbon atom as the point of attachment, the carbon atom forming part of one or more six-membered aromatic ring structures, all ring atoms being carbon, and the group consisting of atoms other than carbon and hydrogen. When two or more rings are present, the rings may be fused or unfused. As used herein, this term does not exclude the presence of one or more alkyl or aralkyl groups (carbon number limitations permitting) attached to the first aromatic ring or any additional aromatic rings present. Non-limiting examples of aryl groups include monovalent groups derived from phenyl (Ph), methylphenyl, (dimethyl)phenyl, -CHCHCH(ethylphenyl), naphthyl, and biphenyl. The term "arenediyl," when used without the "substituted" modifier, refers to a divalent aromatic group having two aromatic carbon atoms as attachment points, the carbon atoms forming part of one or more six-membered aromatic ring structures, the ring atoms being all carbon, and the monovalent group consisting of no atoms other than carbon and hydrogen. As used herein, this term does not exclude the presence of one or more alkyl, aryl, or aralkyl groups (carbon number limitations permitting) attached to the first aromatic ring or any additional aromatic rings present. When two or more rings are present, the rings may be fused or unfused. Non-fused rings may be linked via one or more of the following: a covalent bond, an alkanediyl, or an alkenediyl group (carbon number limitations permitting). Non-limiting examples of arenediyl groups include: TIFF2026034537000234.tif33128 is an example.

[0193] "Arene" refers to the class of compounds having the formula H-R, where R is aryl, as that term is defined above. Benzene and toluene are non-limiting examples of arenes. When any of these terms are used with the "substituted" modifier, one or more hydrogen atoms are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -SH, -OCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)OH, or -S(O)NH.

[0194] The term "aralkyl," when used without the "substituted" modifier, refers to the monovalent group -alkanediyl-aryl, where the terms alkanediyl and aryl are each used in a manner consistent with the above definitions. Non-limiting examples are phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl. When the term aralkyl is used with the "substituted" modifier, one or more hydrogen atoms from the alkanediyl and / or aryl group are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -SH, -OCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)OH, or -S(O)NH. Non-limiting examples of substituted aralkyls are (3-chlorophenyl)-methyl and 2-chloro-2-phenyl-eth-1-yl.

[0195] The term "heteroaryl," when used without the "substituted" modifier, refers to a monovalent aromatic group having an aromatic carbon or nitrogen atom as the point of attachment, the carbon or nitrogen atom forming part of one or more aromatic ring structures, at least one of the ring atoms being nitrogen, oxygen, or sulfur, and the heteroaryl group consisting of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. When more than one ring is present, the rings may be fused or unfused. As used herein, the term does not exclude the presence of one or more alkyl, aryl, and / or aralkyl groups (where carbon number limitations permit) attached to the aromatic ring or aromatic ring system. Non-limiting examples of heteroaryl groups include furanyl, imidazolyl, indolyl, indazolyl (Im), isoxazolyl, methylpyridinyl, oxazolyl, phenylpyridinyl, pyridinyl (pyridyl), pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term "heteroarenediyl", when used without the modifier "substituted", refers to a divalent aromatic group having two aromatic carbon atoms, two aromatic nitrogen atoms, or one aromatic carbon atom and one aromatic nitrogen atom as two attachment points, which atoms form part of one or more aromatic ring structures, and at least one ring atom is nitrogen, oxygen, or sulfur, and the divalent group does not consist of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. When there are two or more rings, the rings can be fused or not fused. Non-fused rings may be linked via one or more of the following: a covalent bond, an alkanediyl, or an alkenediyl group (where the carbon number limit permits). As used herein, the term does not exclude the presence of one or more alkyl, aryl, and / or aralkyl groups (where the carbon number limit permits) attached to the aromatic ring or aromatic ring system. Non-limiting examples of heteroarenediyl groups include: TIFF2026034537000235.tif15128 is an example. The term "N-heteroaryl" refers to a heteroaryl group having a nitrogen atom as the point of attachment. "Heteroarene" refers to the class of compounds having the formula HR where R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes. When these terms are used in conjunction with the "substituted" modifier, one or more hydrogen atoms are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -SH, -OCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)OH, or -S(O)NH.

[0196] The term "heterocycloalkyl," when used without the "substituted" modifier, refers to a monovalent non-aromatic group having a carbon or nitrogen atom as the point of attachment, the carbon or nitrogen atom forming part of one or more non-aromatic ring structures, at least one of the ring atoms being nitrogen, oxygen, or sulfur, and the heterocycloalkyl group consisting of atoms other than carbon, hydrogen, nitrogen, oxygen, and sulfur. When more than one ring is present, the rings may be fused or unfused. As used herein, the term does not exclude the presence of one or more alkyl groups (carbon number limitations permitting) attached to a ring or ring system. Similarly, the term does not exclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, pyranyl, oxiranyl, and oxetanyl. The term "heterocycloalkanediyl," when used without the "substituted" modifier, refers to a divalent ring group having two carbon atoms, two nitrogen atoms, or one carbon atom and one nitrogen atom as two attachment points, which form part of one or more ring structures, at least one ring atom being nitrogen, oxygen, or sulfur, and the divalent group consisting of atoms other than carbon, hydrogen, nitrogen, oxygen, and sulfur. When two or more rings are present, the rings may be fused or unfused. Non-fused rings may be connected via one or more of the following: a covalent bond, an alkanediyl, or an alkenediyl group (where carbon number limitations permit). As used herein, this term does not exclude the presence of one or more alkyl groups (carbon number limitations permitting) attached to the ring or ring system. Likewise, this term does not exclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkanediyl groups include: TIFF2026034537000236.tif14128 is an example. The term "N-heterocycloalkyl" refers to a heterocycloalkyl group having a nitrogen atom as the point of attachment. N-pyrrolidinyl is an example of such a group. When these terms are used with the "substituted" modifier, one or more hydrogen atoms are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -SH, -OCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)OH, or -S(O)NH.

[0197] The term "acyl," when used without the "substituted" modifier, refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heteroaryl, as those terms are defined above. The groups -CHO, -C(O)CH(acetyl, Ac), -C(O)CHCH, -C(O)CHCHCH, -C(O)CH(CH), -C(O)CH(CH), -C(O)CH(CH), -C(O)CHH, -C(O)CHCHCH, -C(O)CHCH, -C(O)(imidazolyl) are non-limiting examples of acyl groups. A "thioacyl" is defined in a similar manner, except that the oxygen atom of the group -C(O)R is replaced with a sulfur atom, and is -C(S)R. The term "aldehyde" corresponds to an alkane, as defined above, in which at least one of the hydrogen atoms has been replaced with a -CHO group. When any of these terms are used with the "substituted" modifier, one or more hydrogen atoms (including the hydrogen atom directly bonded to the carbon atom of the carbonyl or thiocarbonyl group, if any) are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -SH, -OCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)OH, or -S(O)NH. The groups -C(O)CH2CF3, -CO2H (carboxyl), -CO2CH3 (methylcarboxyl), -CO2CH2CH3, -C(O)NH2 (carbamoyl), and -CON(CH3)2 are non-limiting examples of substituted acyl groups.

[0198] The term "alkoxy" when used without the "substituted" modifier refers to the group -OR, where R is alkyl, as that term is defined above. Non-limiting examples include -OCH(methoxy), -OCHCH(ethoxy), -OCHCHCH, -OCH(CH)(isopropoxy), -OC(CH)(tert-butoxy), -OCH(CH), -O-cyclopentyl, and -O-cyclohexyl. The terms "cycloalkoxy," "alkenyloxy," "alkynyloxy," "aryloxy," "aralkoxy," "heteroaryloxy," "heterocycloalkoxy," and "acyloxy," when used without the "substituted" modifier, refer to the group defined as -OR, where R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The term "alkoxydiyl" refers to the divalent group -O-alkanediyl-, -O-alkanediyl-O-, or -alkanediyl-O-alkanediyl-. The terms "alkylthio" and "acylthio," when used without the "substituted" modifier, refer to the group -SR, where R is alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane, as defined above, in which at least one of the hydrogen atoms has been replaced with a hydroxy group. The term "ether" corresponds to an alkane, as defined above, in which at least one of the hydrogen atoms has been replaced with an alkoxy group. When any of these terms are used in conjunction with the "substituted" modifier, one or more hydrogen atoms are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -SH, -OCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)OH, or -S(O)NH.

[0199] The term "alkylamino," when used without the "substituted" modifier, refers to the group -NHR, where R is alkyl, as that term is defined above. Non-limiting examples include -NHCH and -NHCHCH. The term "dialkylamino," when used without the "substituted" modifier, refers to the group -NRR', where R and R' can be the same or different alkyl groups, or R and R' together can represent an alkanediyl. Non-limiting examples of dialkylamino groups include -N(CH) and -N(CH)(CHCH). The terms "cycloalkylamino," "alkenylamino," "alkynylamino," "arylamino," "aralkylamino," "heteroarylamino," "heterocycloalkylamino," "alkoxyamino," and "alkylsulfonylamino," when used without the "substituted" modifier, refer to the group defined as -NHR, where R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, alkoxy, and alkylsulfonyl, respectively. A non-limiting example of an arylamino group is -NHC6H5. The term "amido" (acylamino), when used without the "substituted" modifier, refers to the group -NHR, where R is acyl, as that term is defined above. A non-limiting example of an amido group is -NHC(O)CH3. The term "alkylimino," when used without the "substituted" modifier, refers to the divalent group =NR, where R is alkyl, as that term is defined above. The term "alkylaminodiyl" refers to the divalent group -NH-alkanediyl-, -NH-alkanediyl-NH-, or -alkanediyl-NH-alkanediyl-.When any of these terms are used in conjunction with the "substituted" modifier, one or more hydrogen atoms bonded to a carbon atom are independently replaced with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -SH, -OCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)OH, or -S(O)NH. The groups NHC(O)OCH and -NHC(O)NHCH are non-limiting examples of substituted amide groups.

[0200] The use of the words "a" or "an," when used in conjunction with the word "comprising" in the claims and / or this specification, can mean "one," but is also consistent with the meanings of "one or more," "at least one," and "one or more."

[0201] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among test subjects.

[0202] The terms "comprise," "have," and "include" are open-ended linking verbs. Any form or tense of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes," and "including," is also open-ended. For example, any method that "comprises," "has," or "includes" one or more steps is not limited to having only those one or more steps, but also covers other unlisted steps.

[0203] The term "effective," as that term is used in the specification and / or claims, means sufficient to achieve a desired, expected, or intended result. An "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount," when used in the context of treating a patient or subject with a compound, means the amount of a compound that, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease.

[0204] As used herein, "IC 50 The term "inhibitory dose" refers to an inhibitory dose that is 50% of the maximal response obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological, biochemical, or chemical process (or component of a process, i.e., an enzyme, cell, cell receptor, or microorganism) by half.

[0205] An "isomer" of a first compound is a distinct chemical compound whose each molecule contains the same constituent atoms as the first compound, but differs in the three-dimensional arrangement of those atoms.

[0206] As used herein, the term "patient" or "subject" refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human subjects are adults, juveniles, infants, and fetuses.

[0207] As generally used herein, "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and / or body fluids of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0208] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure that are pharmaceutically acceptable, as defined above, and possess the desired pharmacological activity. Such salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts with 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, and the like. Pharmaceutically acceptable salts include acid addition salts formed with organic acids such as gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts that can be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It should be understood that the particular anion or cation forming a part of any salt of the present disclosure is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Further examples of pharmaceutically acceptable salts and their methods of preparation and use are provided in Handbook of Pharmaceutical Salts: Properties, and Use (PH Stahl & CG Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

[0209] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a chemical substance.

[0210] "Prevention" or "preventing" includes (1) inhibiting the onset of disease in a subject or patient who may be at risk and / or predisposed to the disease, but who has not yet experienced or displayed any or all of the symptoms or symptomatology of the disease, and / or (2) delaying the onset of symptoms or symptomatology of the disease in a subject or patient who may be at risk and / or predisposed to the disease, but who has not yet experienced or displayed any or all of the symptoms or symptomatology of the disease.

[0211] "Stereoisomers" or "optical isomers" are isomers of a given compound that have the same atoms bonded to the same other atoms but differ in the three-dimensional arrangement of those atoms. "Enantiomers" are stereoisomers of a given compound that are mirror images of each other, like left and right hands. "Diastereomers" are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain chiral centers, also called stereogenic centers or stereogenic centers, which are any points, but not necessarily atoms, in a molecule that bear groups such that the interchange of any two groups leads to a stereoisomer. In organic compounds, chiral centers are typically carbon, phosphorus, or sulfur atoms, although other atoms can be stereocenters in organic and inorganic compounds. Molecules can have multiple stereocenters, resulting in many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbon), the total number of hypothetical possible stereoisomers is 2. nwhere n is the number of tetrahedral stereocenters. Molecules with symmetry often have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is called a racemic mixture. Alternatively, a mixture of enantiomers may be enantiomerically enriched, such that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. For any stereocenter or axis of chirality where stereochemistry is not defined, it is contemplated that that stereocenter or axis of chirality may exist as its R-, S-, or mixtures of R- and S-forms, including racemic and non-racemic mixtures. As used herein, the phrase "substantially free of other stereoisomers" means that the composition contains ≦15%, more preferably ≦10%, even more preferably ≦5%, or most preferably ≦1% of another stereoisomer.

[0212] "Treatment" or "treating" includes (1) inhibiting a disease (e.g., halting further development of the pathology and / or symptomatology) in a subject or patient experiencing or exhibiting the pathology or symptomatology of the disease, (2) ameliorating a disease (e.g., reversing the pathology and / or symptomatology) in a subject or patient experiencing or exhibiting the pathology or symptomatology of the disease, and / or (3) making any measurable reduction in a disease in a subject or patient experiencing or exhibiting the pathology or symptomatology of the disease.

[0213] The preceding definitions supersede any conflicting definitions in any reference incorporated herein by reference. However, the fact that certain terms are defined should not be considered to indicate that any undefined term is unclear. Rather, all terms used are considered to describe the present disclosure in terms such that one skilled in the art can understand the scope of the disclosure and practice the invention. [Example]

[0214] V. Working Example The following examples are included to demonstrate preferred embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques discovered by the inventors to work well in the practice of the present disclosure, and can therefore be considered to constitute preferred modes for its practice. However, those skilled in the art should, in light of the present disclosure, recognize that many changes can be made in the specific embodiments disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.

[0215] Example 1 – Methods and Materials A. Cell culture Calu-6 and Calu-3 cells were obtained from the American Type Culture Collection and cultured in RMP1 1640 (Corning) medium with L-glutamine and 25 mM HEPES, supplemented with 5% FBS (Gemini Bio-Products). IB3-1 cells were kindly provided by Harvey Pollard and cultured in serum-free LHC-8 (Invitrogen) medium. HEK 293 cells were obtained from the American Type Culture Collection and cultured in DMEM (Invitrogen) supplemented with 10% FBS (Gemini Bio-Products).

[0216] B. Antibodies and Reagents p53 DO-1 (#sc-126) and GFP C2 (#sc-390394) antibodies were purchased from Santa Cruz Biotechnology, Inc. Actin antibody (MAB1501) was purchased from EMD Millipore. CFTR 596 antibody was purchased from the UNC Antibody Distribution Program. Non-acylated E. coli tRNA Phe -F 8 (P-05) was purified by chromatography as described in Johnson et al., 1982.Phe tRNAs were prepared by chemical modification with a fluorescein dye reagent. For other tRNAs, DNA fragments encoding specific tRNA sequences followed by a T7 RNA polymerase promoter sequence were chemically synthesized. Using standard techniques such as those described in Green and Sambrook, 2012; Rio et al., 2011; Flanagan et al., 2003; and Janiak et al., 1992, the T7 promoter-tRNA DNA sequences were amplified by PCR and then transcribed in vitro with T7 RNA polymerase. The resulting tRNA transcripts were extracted with phenol, precipitated in high salt and ethanol, and purified by HPLC using a MonoQ ion-exchange column. The purified tRNA was precipitated, resuspended, and dialyzed into water. RNAiMax and Lipofectamine 2000 were purchased from Invitrogen and used according to the supplier's recommended protocols. G418 (sc-29065) was purchased from Santa Cruz. PTC124 (S6003) and VX-770 (S1144) were purchased from Selleck Chemicals. 3-Isobutyl-1-methylxanthine (IBMX) (I5879) and forskolin (F3917) were purchased from Sigma-Aldrich. CFTR-Inh172 was obtained from CFFT (Cystic Fibrosis Foundation Therapeutics, Inc.). Compositions were formulated according to Tables 3 to 6 shown below.

[0217] Table 3. Formulations using polyester polymers TIFF2026034537000237.tif23255

[0218] Table 4. Formulations using dendrimers TIFF2026034537000238.tif23270TIFF2026034537000239.tif232146TIFF2026034537000240.tif232146TIFF2026034537000241.tif232108

[0219] Table 5. Formulations using zwitterionic amino lipids (ZAL) TIFF2026034537000242.tif22223TIFF2026034537000243.tif222147TIFF2026034537000244.tif22282

[0220] Table 6. Formulations using cationic sulfonamide amino lipids (CSAL) TIFF2026034537000245.tif21956

[0221] C. Plasmids and Site-Directed CFTR Mutagenesis The expression plasmid for full-length wild-type CFTR (pBI-CFTR) was purchased from Clontech and mutagenized using standard site-directed mutagenesis protocols (Sambrook et al., 1989). Site-directed mutagenesis was performed by PCR using PfuUltra high-fidelity DNA polymerase (Stratagene, Santa Clara, CA). All mutations were confirmed by DNA sequencing. Sup-tRNA Arg was a gift from Carla Oliveira (Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal).

[0222] D. Methods for Quantifying Mature CFTR HEK293 cells were seeded (9 x 10 cells) 5 CFTR plasmid (2 μg) and Sup-tRNA were transfected. Arg500 ng of ATP was cotransfected in a 6-well format using 4 μl of Lipofectamine 2000. 24 hours after transfection, G418 (200 μg) or PTC124 (40 μM) was added to the medium and left undisturbed for 48 hours. IB3-1 cells were seeded, and 24 hours later, G418 (0–400 μg) or PTC124 (0–20 μM) was added. After 48 hours, cells were lysed directly in 2x sample buffer (Tris-HCl 250 mM, pH 6.8, 20% glycerol, 2.5% SDS, 0.1% bromophenol blue). Cell lysate proteins were separated by electrophoresis on a 7% / 10% step (wt / vol) polyacrylamide gel using a Tris-glycine buffer system and transferred to a polyvinylidene fluoride Immobilon membrane (EMD Millipore). Western blot analysis was performed using primary CFTR antibody (596) (University of North Carolina School of Medicine, Chapel Hill, NC), actin antibody (EMD Millipore), and secondary antibody IRdye-680RD (Li-Cor) and imaged / quantified using a Li-Cor Odyssey CLx (Li-Cor). Data were plotted using Prism 6 (Graphpad).

[0223] E. CFTR-dependent whole-cell currents in HEK293 cells HEK293 cells were transfected with the plasmids used in the CFTR maturation experiments: 2 μg of CFTR plasmid and Sup-tRNA. Arg500 ng of each sample was cotransfected in a 6-well format using 4 μl of Lipofectamine 2000. 24 h after transfection, Cl- currents were measured using the whole-cell configuration of the patch clamp technique. The pipette solution contained 145 mM NMDG+-Cl-, 1 mM MgCl2, 2 mM EGTA, 5 mM ATP, and 10 mM HEPES (pH 7.3 with Tris). The bath solution contained 145 mM NMDG+-Cl-, 1 mM MgCl2, 1 mM CaCl2, 10 mM HEPES, and 10 mM glucose (pH 7.4 with Tris). Currents were recorded using an Axopatch 200B patch clamp amplifier and digitized at 2 kHz. Membrane conductance was investigated by stepping the membrane potential from a holding potential of 0 mV to membrane potentials of -40 mV and +40 mV for 200 ms. Whole-cell current responses to 10 μM forskolin, 100 μM IBMX, and 10 μM CFTRInh-172 (Inh-172) were measured. Pipettes exhibited resistances of 3–5 MΩ when filled with pipette solution, with seal resistances exceeding 8 GU. Current recording and analysis were performed using pClamp 9.2 software and analyzed using Origin 8 software.

[0224] F. Uptake Test Cellular uptake studies were performed using the top-performing materials from the screening. Calu6 cells were seeded onto 8-chamber coverglass slides (Nunc) at a density of 40,000 cells per well and allowed to attach for 24 hours. NP formulations were prepared by manual mixing using fluorescein-labeled tRNA using a protocol similar to that used in the in vitro transfection assay described above. Formulations were performed in 10 mM citrate buffer, pH 4.3, at a final carrier:siRNA molar ratio of 25:1. The carrier mixture for the formulation consisted of carrier:cholesterol:DSPC:PEG lipids in a molar ratio of 50:38:10:2. Nanoparticles were added to the cells at a final tRNA amount of 0.9 μg / well. After 6 hours of incubation, the medium was aspirated and washed with PBS. Cell membrane staining was performed using the manufacturer's protocol (Molecular Probes, Cell Mask Red). Cell nuclei were stained with DAPI (Sigma-Aldrich). Confocal microscopic imaging was performed using a Nikon Eclipse TE2000-E, and images were analyzed using ImageJ (NIH).

[0225] G. Nanoparticle Carrier Screening in Calu6 Cells Calu6 cells were seeded in a 6-well format at a density of 500,000 cells per well and allowed to attach overnight. For plasmid DNA, 1 μg was transfected using 3 μl of Lipofectamine 2000 using the manufacturer's recommended protocol. tRNA Arg / OpFor RNAiMax, 4 μg was transfected using 3 μl of RNAiMax using the manufacturer's recommended protocol. Particles were diluted in Opti-MEM (Invitrogen). G418 (50 μg) and PTC124 (10 μl) were added directly to the medium. Nanoparticles were prepared by mixing all delivery components in ethanol and then rapidly mixing with tRNA in 10 mM citrate buffer, pH 4.3, to a final carrier:siRNA molar ratio of 25:1. The carrier mixture for the formulation consisted of a 50:38:10:2 molar ratio of carrier:cholesterol:DSPC:PEG lipid. The nanoparticles were then diluted in sterile PBS to raise the pH and added to the cells. After 48 hours, cells were lysed directly in 2x sample buffer (Tris-HCl 250 mM, pH 6.8, 20% glycerol, 2.5% SDS, 0.1% bromophenol blue). Cell lysate proteins were separated by electrophoresis on a 10% (wt / vol) polyacrylamide gel using a Tris-glycine buffer system and transferred to a polyvinylidene difluoride Immobilon membrane (EMD Millipore). Western blot analysis was performed using a primary p53 antibody (Santa Cruz Biotechnology, Inc.), an actin antibody (EMD Millipore), and a secondary antibody IRdye-680RD (Li-Cor), and imaged / quantified using a Li-Cor Odyssey CLx (Li-Cor).

[0226] H. NP particle size analysis Particle size was measured by dynamic light scattering (DLS) using a Malvern Zetasizer Nano ZS (He-Ne laser, λ = 632 nm).

[0227] Example 2 – tRNA delivery As shown in Figure 1, nonsense mutations terminate synthesis at mutations that result in premature stop codons in mRNA, resulting in nonfunctional proteins. As can be seen in Figures 2A-2C, attempts to correct these mutations in proteins with readthrough agents failed to restore activity in the cystic fibrosis transmembrane conductance regulator protein. As shown in Figures 3A and 3B, correction of mutations by any amino acid does not result in a functional protein. Similarly, even if a mutation results in folding, the resulting protein may be functionally defective (Figures 4A and 4B). Therefore, readthrough approaches to correcting genetic mutations may not be sufficient to restore protein activity. On the other hand, as can be seen in Figures 5A-5C, introduction of modified tRNA restores CFTR folding and function. Similarly, introduction of modified tRNA into nanoparticle formulations results in delivery of tRNA into cells (Figure 6A) and the production of functional p53 through the incorporation of specific amino acids into the growing peptide chain (Figures 6B and 6C).

[0228] A variety of different aminolipid delivery compositions were tested to determine the amount of tRNA bound to nanoparticles. Figure 7 shows that most of the test materials bound with tRNA binding fractions greater than 0.8. Similarly, Figure 8 shows the characteristics of these tRNA compositions, including particle size and polydispersity index. These compositions were tested for their ability to restore p53 expression in Calu6 cells by combining exogenous tRNA. Arg / OpThe compositions were tested using a Western blot analysis shown in Figure 9. One composition that showed restoration of p53 expression was tested at various concentrations, and two other agents that showed only a slight restoration of p53 expression were tested in comparison with the composition (Figure 10). To confirm cellular uptake of the tRNA compositions, fluorescent microscopy was performed using labeled tRNA. As can be seen in Figure 11, tRNA was taken up by Calu6 cells after 6 hours of incubation. Furthermore, Figure 12 shows tRNA uptake using zwitterionic and cationic sulfonamide amino lipids. Finally, the data in Figure 13 demonstrate the effects of different nanoparticle preparation methods on both response in the luciferase assay and viability.

[0229] All methods disclosed and claimed herein can be implemented and executed without undue experimentation in light of this disclosure.Although the compositions and methods of the present disclosure have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that modifications can be made to the methods and to the steps or order of steps of the methods described herein without departing from the concept, spirit, and scope of the present disclosure.More specifically, it will be apparent that certain chemically and physiologically related agents can be substituted for the agents described herein while achieving the same or similar results.All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the present disclosure, as defined by the appended claims.

[0230] References The following references, to the extent that they provide exemplary procedural or other details supplementary to those disclosed herein, are specifically incorporated herein by reference. WO 2016 / 094342 WO 2017 / 048789 International application number PCT / US2017 / 032950 TIFF2026034537000246.tif107137

[0231] Array information SEQUENCE LISTING <110> The Board of Regents of the University of Texas System <120> COMPOSITIONS FOR THE DELIVERY OF TRNA AS NANOPARTICLES AND METHODS OF USE THEREWITH <150> US 62 / 337,096 <151> 2016-05-16 <160> 20 <170> PatentIn version 3.5 <210> 1 <211> 76 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 1 ggccgcgtgg cctaatggat aaggcgtctg acttcagatc agaagattgc aggttcgagt 60 cctgccgcgg tcgcca 76 <210> 2 <211> 76 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo "<400> 2 ggccgcgugg ccuaauggau aaggcgucug acuucagauc agaagauugc agguucgagu 60 ccugccgcgg ucgcca 76 <210> 3 <211> 75 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 3 ggccucgugg cgcaacggua gcgcgucuga cuucagauca gaagguugcg uguucaaauc 60 acgucggggu cacca 75 <210> 4 <211> 75 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 4 gcguuggugg uauagugguu agcauagcug ccuucaaagc aguugacccg gguucgauuc 60 ccggccaacg cacca 75 <210> 5 <211> 85 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 5 gcagcgaugg ccgagugguu aaggcguugg acuucaaauc caaugggguc uccccgcgca 60 gguucgaacc cugcucgcug cgcca 85 <210> 6 <211> 75 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 6 ggucccaugg uguaaugguu agcacucugg acuuuaaauc cagcgauccg aguucaaauc 60 ucggugggac cucca 75 <210> 7 <211> 76 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 7 gcccggauag cucagucggu agagcaucag acuuuaaauc ugagggucca ggguucaagu 60 cccuguucgg gcgcca 76 <210> 8 <211> 86 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 8 accaggaugg ccgagugguu aaggcguugg acuuuagauc caauggacau auguccgcgu 60 ggguucgaac cccacuccug guacca 86 <210> 9 <211> 76 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 9 gcccggcuag cucagucggu agagcauggg acucuaaauc ccagggucgu ggguucgagc 60 cccacguugg gcgcca 76 <210> 10 <211> 75 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 10 ucccuggugg ucuagugguu aggauucggc gcuaucaccg ccgcggcccg gguucgauuc 60 ccggucaggg aacca 75 <210> 11 <211> 75 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 11 ucccuggugg ucuagugguu aggauucggc gcuaucaccg ccgcggcccg gguucgauuc 60 ccggucaggg aacca 75 <210> 12 <211> 87 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 12 gucaggaugg ccgagugguc uaaggcgcca gacucuaguu cuggucuccg uauggaggcg 60 uggguucgaa ucccacuucu gacacca 87 <210> 13 <211> 86 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 13 accaggaugg ccgagugguu aaggcguugg acuucagauc caauggacau auguccgcgu 60 ggguucgaac cccacuccug guacca 86 <210> 14 <211> 76 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 14 ccuucaauag uucagcuggu agagcagagg acucuagguc cuuagguugc ugguucgauu 60 ccagcuugaa ggacca 76 <210> 15 <211> 76 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 15 ccuucaauag uucagcuggu agagcagagg acuuuagguc cuuagguugc ugguucgauu 60 ccagcuugaa ggacca 76 <210> 16 <211> 75 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 16 ggccucgugg cgcaacggua gcgcgucuga cucuagauca gaagguugcg uguucaaauc 60 acgucggggu cacca 75 <210> 17 <211> 85 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 17 gcugugaugg ccgagugguu aaggcguugg acucgaaauc caaugggguc uccccgcgca 60 gguucgaauc cugcucacag cgcca 85 <210> 18 <211> 85 <212> DNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 18 gcagcgaugg ccgagugguu aaggcguugg acuuuaaauc caaugggguc uccccgcgca 60 gguucgaacc cugcucgcug cgcca 85 <210> 19 <211> 75 <212> RNA <213> Artificial sequence <220> <223> Synthetic oligo <400> 19 gcguuggugg uauaguggg agcauagcug ccucciaagc agugacccg gguucgauuc 60 ccggccaacg shit 75 <210> 20 <211> 75 <212> RNA <213> Artificial Sequence <220> <223> Synthetic oligo <400> 20 gcguuggugg uauaguggua agcauagcug ccucciaagc agugacccg gguucgauuc 60 ccggccaacg shit 75

Claims

1. (a) tRNA and; (b) nanoparticle-forming aminolipid delivery compounds and A composition comprising:

2. 10. The composition of claim 1, wherein the aminolipid delivery compound is a dendrimer comprising a group that is positively charged at physiological pH and a lipophilic group.

3. 10. The composition of claim 1, wherein the aminolipid delivery compound is a dendrimer of the formula: Core - (repeating unit) n -Terminal group (I) wherein the core is linked to the repeat unit by removing one or more hydrogen atoms from the core and replacing them with the repeat unit; The core has the formula: During the ceremony, X 1 is amino or alkylamino (C≦12) , dialkylamino (C≦12) , heterocycloalkyl (C≦12) , heteroaryl (C≦12) , or a substituted form thereof; R 1 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; a is 1, 2, 3, 4, 5, or 6; or The core has the formula: During the ceremony, X 2 is N(R 5 ) y and; R 5 is hydrogen, alkyl (C≦18) , or substituted alkyl (C≦18) and; y is 0, 1, or 2, provided that the sum of y and z is 3; R 2 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; b is 1, 2, 3, 4, 5, or 6; z is 1, 2, or 3, provided that the sum of z and y is 3; or The core has the formula: During the ceremony, X 3 Ha-NR 6 - where R 6 is hydrogen, alkyl (C≦8) , or substituted alkyl (C≦8) , -O-, or alkylaminodiyl (C≦8) , alkoxydiyl (C≦8) , Arendjiil (C≦8) , heteroarenediyl (C≦8) , heterocycloalkanediyl (C≦8) or a substituted form of any of these groups; R 3 and R 4 each independently represents amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or substituted forms of either of these groups, or a group of the formula -(CH 2 CH 2 N) e (R c )R d is the basis of; where: e is 1, 2, or 3; R c and R d are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; c and d are each independently 1, 2, 3, 4, 5, or 6; or The core is an alkylamine (C≦18) , dialkylamine (C≦36) , heterocycloalkane (C≦12) or a substituted form of any of these groups; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: During the ceremony, A 1 and A 2 each independently represents -O-, -S-, or -NR a -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; Y 3 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: During the ceremony, X 3 and X 4 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y 5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R 9 is alkyl (C≦8) or substituted alkyl (C≦8) and; The linker group has the formula: During the ceremony, Y 1 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: During the ceremony, Y 4 Alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either group; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) where: R 11 is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6.

4. 4. The composition of claim 3, wherein the aminolipid delivery compound is a dendrimer of the formula: The core has the formula: During the ceremony, X 1 is amino or alkylamino (C≦12) , dialkylamino (C≦12) , heterocycloalkyl (C≦12) , heteroaryl (C≦12) , or a substituted form thereof; R 1 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; a is 1, 2, 3, 4, 5, or 6; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: During the ceremony, A 1 and A 2 are each independently -O- or -NR a -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; Y 3 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: During the ceremony, X 3 and X 4 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y 5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R 9 is alkyl (C≦8) or substituted alkyl (C≦8) and; The linker group has the formula: During the ceremony, Y 1 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: During the ceremony, Y 4 Alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either group; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) where: R 11 is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6.

5. 4. The composition of claim 3, wherein the aminolipid delivery compound is a compound of the following formula: Core - (repeating unit) n -Terminal group (I) wherein the core is linked to the repeat unit by removing one or more hydrogen atoms from the core and replacing them with the repeat unit; The core has the formula: During the ceremony, X 2 is N(R 5 ) y and; R 5 is hydrogen or alkyl (C≦8) , or substituted alkyl (C≦18) and; y is 0, 1, or 2, provided that the sum of y and z is 3; R 2 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; b is 1, 2, 3, 4, 5, or 6; z is 1, 2, or 3, provided that the sum of z and y is 3; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: During the ceremony, A 1 and A 2 are each independently -O- or -NR a -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; Y 3 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: During the ceremony, X 3 and X 4 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y 5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R 9 is alkyl (C≦8) or substituted alkyl (C≦8) and; The linker group has the formula: During the ceremony, Y 1 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: During the ceremony, Y 4 Alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either group; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) and The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6.

6. 4. The composition of claim 3, wherein the aminolipid delivery compound is a compound of the following formula: Core - (repeating unit) n -Terminal group (I) wherein the core is linked to the repeat unit by removing one or more hydrogen atoms from the core and replacing them with the repeat unit; The core has the formula: During the ceremony, X 3 Ha-NR 6 - where R 6 is hydrogen, alkyl (C≦8) , or substituted alkyl (C≦8) , -O-, or alkylaminodiyl (C≦8) , alkoxydiyl (C≦8) , Arendjiil (C≦8) , heteroarenediyl (C≦8) , heterocycloalkanediyl (C≦8) or a substituted form of any of these groups; R 3 and R 4 each independently represents amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or substituted forms of either of these groups, or a group of the formula -(CH 2 CH 2 N) e (R c )R d is the basis of; where: e is 1, 2, or 3; R c and R d are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; c and d are each independently 1, 2, 3, 4, 5, or 6; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: During the ceremony, A 1 and A 2 are each independently -O- or -NR a -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; Y 3 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: During the ceremony, X 3 and X 4 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y 5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R 9 is alkyl (C≦8) or substituted alkyl (C≦8) and; The linker group has the formula: During the ceremony, Y 1 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: During the ceremony, Y 4 Alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either group; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) where: R 11 is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6.

7. Y 4 But alkanediyl (C≦18) or alkanediyl (C≦18) One or more of the hydrogen atoms above are -OH, -F, -Cl, -Br, -I, -SH, -OCH 3 , -OCH 2 CH 3 , -SCH 3 , or -OC(O)CH 3 Alkanediyl replaced by (C≦18) The composition according to any one of claims 3 to 6, wherein

8. 10. The composition of claim 1, wherein the aminolipid delivery compound is an aminolipid comprising an anionic carboxylic acid group, a sulfonic acid group, or a phosphate group, a quaternary amino group, an amino group that is positively charged at physiological pH, and a lipophilic group.

9. 10. The composition of claim 8, wherein the aminolipid delivery compound is further defined as the following formula: During the ceremony, X 1 -S(O) 2 O - , -OP(O)OR e O - , -(CHR f ) z C(O)O - , or -NR g R h R i + where: R e , R g , R h , and R i are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R f is hydrogen, amino, hydroxy, or alkyl (C≦12) , aryl (C≦12) , aralkyl (C≦12) , heteroaryl (C≦12) , acyl (C≦12) , alkoxy (C≦12) , acyloxy (C≦12) , amide (C≦12) , alkoxy (C≦12) , alkoxy (C≦12) or a substituted form of any of the last ten groups; z is 1, 2, 3, or 4; Y 1 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) , heteroarenediyl (C≦12) , heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) -Alkanediyl (C≦8) , -alkanediyl (C≦8) -heteroarenediyl (C≦12) , -alkanediyl (C≦8) -heteroarenediyl (C≦12) -Alkanediyl (C≦8) or a substituted form of any of these groups; Z 1 Ha-N + R 3 R 4 -or-OP(O)O - O-; A is -NR a -, -S-, or -O-; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) or R a is R 3 or R 4 Together with (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; R 1 is a group of the formula: During the ceremony, R 5 , R 6 , and R 2 are each independently hydrogen or alkyl (C≦8) , -alkanediyl (C≦6) -NH 2 , -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z 2 A'R 7 where: Z 2 Alkanediyl (C≦6) , substituted alkanediyl (C≦6) or a group of the formula: During the ceremony, Z 5 and Z 6 are each independently an alkanediyl (C≦6) or substituted alkanediyl (C≦6) and; X 2 and X 3 each independently represents -O-, -S-, or -NR m - and where: R m is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; a is 0, 1, 2, 3, 4, 5, or 6; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 7 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) or R 5 , R 6 , and R 2 are each independently -Z 3 A''R 8 where: Z 3 Alkanediyl (C≦6) , substituted alkanediyl (C≦6) or a group of the formula: During the ceremony, Z 7 and Z 8 are each independently an alkanediyl (C≦6) or substituted alkanediyl (C≦6) and; X 4 and X 5 each independently represents -O-, -S-, or -NR n - and where: R n is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; b is 0, 1, 2, 3, 4, 5, or 6; A'' is -CHR k -, -S-, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 8 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; R 1 is a group of the formula: During the ceremony, Y 2 Arena Jill (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) , alkoxydiyl (C≦12) or a substituted form of any of these groups; R 9 , R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z 4 A'''R 12 where: Z 4 Alkanediyl (C≦6) , substituted alkanediyl (C≦6) or a group of the formula: During the ceremony, Z 9 and Z 10 are each independently an alkanediyl (C≦6) or substituted alkanediyl (C≦6) and; X 6 and X 7 each independently represents -O-, -S-, or -NR o - and where: R o is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; c is 0, 1, 2, 3, 4, 5, or 6; A''' is -CHR k -, -S-, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; x and y are 0, 1, 2, 3, or 4; R 3 and R 4 are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) or R 3 or R 4 is R a Together with (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6; However, X 1 If is positively charged, Z 1 is negatively charged, and X 1 If is negatively charged, Z 1 is positively charged.

10. 10. The composition of claim 1, wherein the aminolipid delivery compound is an aminolipid comprising an anionic sulfonic acid group and a quaternary amino group, a lipophilic group, and an amino group that is protonated at physiological pH.

11. 10. The composition of claim 1, wherein the aminolipid delivery compound is a compound of the following formula: During the ceremony, Y 1 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) , heteroarenediyl (C≦12) , heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) -Alkanediyl (C≦8) , -alkanediyl (C≦8) -heteroarenediyl (C≦12) , -alkanediyl (C≦8) -heteroarenediyl (C≦12) -Alkanediyl (C≦8) or a substituted form of any of these groups; A is -NR a -, -S-, or -O-; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) or R a is R 3 or R 4 Together with Alkandiil (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; R 1 is a group of the formula: During the ceremony, R 5 , R 6 , and R 2 are each independently hydrogen or alkyl (C≦8) , -alkanediyl (C≦6) -NH 2 , -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z 2 A'R 7 where: Z 2 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 7 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) or R 5 , R 6 , and R 2 are each independently -Z 3 A''R 8 where: Z 3 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 8 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; R 1 is a group of the formula: During the ceremony, Y 2 Arena Jill (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) , alkoxydiyl (C≦12) or a substituted form of any of these groups; R 9 , R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z 4 A'''R 12 is selected from; where Z 4 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A''' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; x and y are 1, 2, 3, or 4; R 3 and R 4 are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) or R 3 or R 4 is R a Together with Alkandiil (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6.

12. 12. The composition of claim 11, wherein the aminolipid delivery compound is a compound of the following formula: During the ceremony, Y 1 Alkanediyl (C≦12) , heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) , -alkanediyl (C≦8) -heterocycloalkanediyl (C≦12) -Alkanediyl (C≦8) or a substituted form of any of these groups; A is -NR a -, -S-, or -O-; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) or R a is R 3 or R 4 Together with Alkandiil (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; R 1 is a group of the formula: During the ceremony, R 5 , R 6 , and R 2 are each independently hydrogen or alkyl (C≦8) , -alkanediyl (C≦6) -NH 2 , -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z 2 A'R 7 where: Z 2 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 7 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) or R 5 , R 6 , and R 2 are each independently -Z 3 A''R 8 where: Z 3 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 8 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; R 1 is a group of the formula: During the ceremony, Y 2 Arena Jill (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) , alkoxydiyl (C≦12) or a substituted form of any of these groups; R 9 , R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z 4 A'''R 12 is selected from; where Z 4 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A''' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; x and y are 1, 2, 3, or 4; R 3 and R 4 are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) or R 3 or R 4 is R a Together with Alkandiil (C≦8) , Alkendiyl (C≦8) , alkoxydiyl (C≦8) , alkylaminodiyl (C≦8) or a substituted form of any of these groups; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6.

13. 12. The composition of claim 11, wherein the aminolipid delivery compound is a compound of the following formula: During the ceremony, R 1 is a group of the formula: During the ceremony, R 5 , R 6 , and R 2 are each independently hydrogen or alkyl (C≦8) , -alkanediyl (C≦6) -NH 2 , -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z 2 A'R 7 where: Z 2 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 7 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) or R 5 , R 6 , and R 2 are each independently -Z 3 A''R 8 where: Z 3 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 8 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; R a , R 3 , and R 4 are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6.

14. 10. The composition of claim 1, wherein the aminolipid delivery compound comprises a sulfonamide group, a quaternary ammonium group, an amino group that is protonated at physiological pH, and a lipophilic group.

15. 10. The composition of claim 1, wherein the aminolipid delivery compound is a compound of the following formula: During the ceremony, R 1 , R 2 , and R 3 are each independently hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) or a group of the formula: During the ceremony, R 7 and R 8 are each independently hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) or a group of the formula: During the ceremony, R 9 is hydrogen, halo, or hydroxy, or alkoxy (C≦24) , acyloxy (C≦24) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4; R 4 , R 5 , and R 6 are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; m and n are each independently 1, 2, 3, 4, or 5.

16. 16. The composition of claim 15, wherein the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof: During the ceremony, R 1 , R 2 , and R 3 are each independently hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) or a group of the formula: During the ceremony, R 7 and R 8 are each independently hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) or a group of the formula: During the ceremony, R 9 is hydrogen, halo, or hydroxy, or alkoxy (C≦24) , acyloxy (C≦24) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4; R 4 , R 5 , and R 6 are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; m and n are each independently 1, 2, 3, 4, or 5.

17. 10. The composition of claim 1, wherein the amino lipid comprises a polyester group, a thioether group, and an amine group that is protonated at physiological pH.

18. 10. The composition of claim 1, wherein the amino lipid comprises a polyester group of the formula: During the ceremony, X 1 is alkyl (C≦18) or substituted alkyl (C≦18) and; X 2 is hydrogen, alkyl (C≦18) , or substituted alkyl (C≦18) and; R 1 is -AZ; where: A is alkanediyl (C≦18) or substituted alkanediyl (C≦18) and; Z is -NR 3 R 4 and; where: R 3 and R 4 are each independently hydrogen, alkyl (C≦18) , substituted alkyl (C≦18) Alternatively, R 3 and R 4 Together we create alkanediyl (C≦18) or substituted alkanediyl (C≦18) and; R 2 is alkyl (C≦24) , alkenyl (C≦24) , substituted alkyl (C≦24) , or substituted alkenyl (C≦24) and; x and y are each independently 0, 1, 2, 3, 4, or 5; m and n are each independently an integer from 0 to 250, provided that at least one of m and n is greater than 1; The repeat units defined by m and n are randomly distributed throughout the polymer.

19. 20. The composition of claim 1 or 17, wherein the compound is further defined as the following formula: During the ceremony, R 1 , R 2 , and R 3 are each independently hydrogen, alkyl (C≦8) , or substituted alkyl (C≦8) and; R 4 is hydrogen, halo, hydroxy, alkyl (C≦8) , or substituted alkyl (C≦8) and; R 5 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either of these groups; R 6 is Y 1 -R 7 and; where: Y 1 Alkanediyl (C≦8) , substituted alkanediyl (C≦8) , -(CH 2 ) r C(O)-, or -(CH 2 ) r C(O)NR a (CH 2 ) s - and; where: r and s are each independently 1, 2, or 3; R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R 7 is amino, or heteroaryl (C≦12) , heterocycloalkyl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , arylalkylamino (C≦12) or a substituted form of any of these groups; a, b, m, d, e, and n are each independently 1, 2, 3, or 4; c and f are each independently 1 to 10; x and y are each independently an integer of 0 to 250, provided that at least one of x and y is greater than 1.

20. 4. The composition of claim 3, wherein the dendrimer has the formula: Core - (repeating unit) n -Terminal group (I) wherein the core is linked to the repeat unit by removing one or more hydrogen atoms from the core and replacing them with the repeat unit; The core is an alkylamine (C≦18) , dialkylamine (C≦36) , heterocycloalkane (C≦12) or a substituted form of any of these groups; The repeat unit comprises a degradable diacyl and a linker; The degradable diacyl group has the formula: During the ceremony, A 1 and A 2 are each independently -O- or -NR a -where: R a is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; Y 3 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups, or a group of the formula: During the ceremony, X 3 and X 4 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; Y 5 is a covalent bond, alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; R 9 is alkyl (C≦8) or substituted alkyl (C≦8) and; The linker group has the formula: During the ceremony, Y 1 Alkanediyl (C≦12) , Alkendiyl (C≦12) , Arendjiil (C≦12) or a substituted form of any of these groups; When the repeat unit comprises a linker group, the linker group is attached to the degradable diacyl group at both the nitrogen atom and the sulfur atom of the linker group, the first group in the repeat unit is a degradable diacyl group, and for each linker group, adjacent groups comprise two degradable diacyl groups attached to nitrogen atoms of the linker group; n is the number of linker groups present in the repeat unit; The end group has the formula: During the ceremony, Y 4 Alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either of these groups; R 10 is hydrogen, carboxy, hydroxy, or aryl (C≦12) , alkylamino (C≦12) , dialkylamino (C≦12) , N-heterocycloalkyl (C≦12) , -C(O)N(R 11 )-Alkanediyl (C≦6) -heterocycloalkyl (C≦12) , -C(O)-alkylamino (C≦12) , -C(O)-dialkylamino (C≦12) , —C(O)—N-heterocycloalkyl (C≦12) where: R 11 is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; The last degradable diacyl in the chain is attached to the terminal group; n is 0, 1, 2, 3, 4, 5, or 6.

21. The composition of any one of claims 3 to 6, wherein the terminal group is further defined by the formula: During the ceremony, Y 4 Alkanediyl (C≦18) , Alkendiyl (C≦18) or a substituted form of either of these groups; R 10 is hydrogen.

22. 22. The composition of claim 21, wherein the terminal group is further defined by the formula: During the ceremony, Y 4 Alkanediyl (C≦18) and; R 10 is hydrogen.

23. Y 4 Alkandiyl (C4～18) 23. The composition of claim 21 or 22, wherein

24. 24. The composition of any one of claims 3, 5, and 21-23, wherein the core is further defined by the formula: During the ceremony, X 2 is N(R 5 ) y and; R 5 is hydrogen or alkyl (C≦8) , or substituted alkyl (C≦18) and; y is 0, 1, or 2, provided that the sum of y and z is 3; R 2 is amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or a substituted form of either of these groups; b is 1, 2, 3, 4, 5, or 6; z is 1, 2, or 3, provided that the sum of z and y is 3.

25. X 2 NR 5 where R 5 is hydrogen or alkyl (C≦8) 25. The composition of claim 24, wherein

26. R 5 26. The composition of claim 25, wherein is methyl.

27. 27. The composition of any one of claims 24 to 26, wherein z is 3.

28. R 2 The composition of any one of claims 24 to 27, wherein is amino.

29. R 2 is alkylamino (C≦12) or substituted alkylamino (C≦12) 28. The composition of any one of claims 24 to 27, wherein

30. R 2 Dialkylamino (C≦12) or substituted dialkylamino (C≦12) 28. The composition of any one of claims 24 to 27, wherein

31. 25. The composition of claim 24, wherein b is 2 or 3.

32. The composition of any one of claims 24 to 31, wherein the core is further defined as: 。

33. 24. The composition of any one of claims 3, 6, and 21-23, wherein the core is further defined as: During the ceremony, X 3 Ha-NR 6 - where R 6 is hydrogen, alkyl (C≦8) , or substituted alkyl (C≦8) , -O-, or alkylaminodiyl (C≦8) , alkoxydiyl (C≦8) , Arendjiil (C≦8) , heteroarenediyl (C≦8) , heterocycloalkanediyl (C≦8) or a substituted form of any of these groups; R 3 and R 4 each independently represents amino, hydroxy, or mercapto, or alkylamino (C≦12) , dialkylamino (C≦12) or substituted forms of either of these groups, or a group of the formula -(CH 2 CH 2 N) e (R c )R d is the basis of; where: e is 1, 2, or 3; R c and R d are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; c and d are each independently 1, 2, 3, 4, 5, or 6.

34. X 3 Alkylaminodiyl (C≦8) or substituted alkylaminodiyl (C≦8) 34. The composition of claim 33, wherein

35. X 3 Heterocycloalkanediyl (C≦8) or substituted heterocycloalkanediyl (C≦8) 34. The composition of claim 33, wherein

36. R 3 The composition of any one of claims 33-35, wherein is amino.

37. R 3 is alkylamino (C≦12) or substituted alkylamino (C≦12) 36. The composition of any one of claims 33 to 35, wherein

38. R 4 The composition of any one of claims 33-37, wherein is amino.

39. R 4 is alkylamino (C≦12) or substituted alkylamino (C≦12) The composition of any one of claims 33 to 37, wherein

40. R 4 Ga-(CH 2 CH 2 N) e (R c )R d and; where: e is 1, 2, or 3; R c and R d are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) That is, The composition of any one of claims 33 to 37.

41. The composition of any one of claims 33 to 40, wherein the core is further defined as: 。

42. Y 3 Alkandiyl (C≦8) or substituted alkanediyl (C≦8) 22. The composition of any one of claims 1 to 21, wherein

43. Y 3 Alkandiyl (C≦8) 43. The composition of claim 42, wherein

44. A 1 Ga-NR a The composition of any one of claims 3 to 6 or 20 to 43, wherein

45. A 2 Ga-NR a The composition of any one of claims 3 to 6 or 20 to 44, wherein

46. R 9 is alkyl (C≦8) 46. ​​The composition of any one of claims 3 to 6 or 20 to 45, wherein

47. 47. The composition of any one of claims 3-6 or 20-46, wherein n is 0 or 1.

48. 13. The composition of claim 11 or 12, further defined as the following formula: or a pharmaceutically acceptable salt thereof: During the ceremony, R 1 is a group of the formula: During the ceremony, R 5 , R 6 , and R 2 are each independently hydrogen or alkyl (C≦8) , -alkanediyl (C≦6) -NH 2 , -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z 2 A'R 7 where: Z 2 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 7 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) or R 5 , R 6 , and R 2 are each independently -Z 3 A''R 8 where: Z 3 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 8 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6.

49. 49. The composition of any one of claims 11, 12, or 48, further defined as: During the ceremony, R 1 is a group of the formula: During the ceremony, R 5 , R 6 , and R 2 are each independently hydrogen or alkyl (C≦8) , -alkanediyl (C≦6) -NH 2 , -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z 2 A'R 7 where: Z 2 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 7 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) or R 5 , R 6 , and R 2 are each independently -Z 3 A''R 8 where: Z 3 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 8 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4.

50. 50. The composition of any one of claims 11, 12, 48, or 49, further defined as: During the ceremony, R 1 is a group of the formula: During the ceremony, R 5 Ha-Z 3 A''R 8 where: Z 3 Alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 8 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; R 6 is alkyl (C≦8) or substituted alkyl (C≦8) and; R 2 Ha-alkanediyl (C≦6) -NR'R'' or a substituted form of this group, wherein: R' and R'' are each independently -Z 2 A'R 7 where: Z 2 Alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 7 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) or q is 1 or 2; r is 1 or 2.

51. 51. The composition of any one of claims 11, 12, or 48-50, further defined as: During the ceremony, R 1 is a group of the formula: During the ceremony, R 5 is alkyl (C≦8) or substituted alkyl (C≦8) and; R 6 Ha-alkanediyl (C≦6) -NR'R'' or a substituted form of this group, wherein: R' and R'' are each independently alkyl (C≦8) , substituted alkyl (C≦8) , or -Z 2 A'R 7 where: Z 2 Alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; R 7 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) or R 2 Ha-alkanediyl (C≦6) -NR'R'' or a substituted form of this group, wherein: R' and R'' are each independently alkyl (C≦8) , substituted alkyl (C≦8) , or -Z 2 A'R 7 where: Z 2 Alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; q is 1 or 2; r is 1 or 2.

52. 51. The composition of any one of claims 11, 12, or 48-50, further defined as: During the ceremony, R 1 is a group of the formula: During the ceremony, R 5 Ha-Z 3 A''R 8 where: Z 3 Alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; R 8 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; R 6 Ha-alkanediyl (C≦6) -NR'R'' or a substituted form of this group; R' and R'' are each independently -Z 2 A'R 7 where: Z 2 Alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; R 7 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; R 2 Ha-alkanediyl (C≦6) -NR'R'' or a substituted form of this group; R' and R'' are each independently -Z 2 A'R 7 where: Z 2 Alkanediyl (C≦2) or substituted alkanediyl (C≦2) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, hydroxy, acyloxy (C≦6) , or substituted acyloxy (C≦6) and; R 7 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; q is 1 or 2; r is 1 or 2.

53. 14. The composition of claim 11 or 13, further defined as: During the ceremony, R 1 is a group of the formula: During the ceremony, Y 2 Arena Jill (C≦12) , heterocycloalkanediyl (C≦12) , heteroarenediyl (C≦12) , alkoxydiyl (C≦12) or a substituted form of any of these groups; R 9 , R 10 , and R 11 are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , or -Z 4 A'''R 12 is selected from; where Z 4 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A''' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 12 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; x and y are 1, 2, 3, or 4; R a , R 3 , and R 4 are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6.

54. R 3 is alkyl (C≦8) or substituted alkyl (C≦8) 54. The composition of any one of claims 11-13, or 53, wherein

55. R 4 is alkyl (C≦8) or substituted alkyl (C≦8) 55. The composition of any one of claims 11-13 or 48-54, wherein

56. 56. The composition of any one of claims 11, 12, 13, or 48-55, wherein m is 1 or 2.

57. 57. The composition of any one of claims 11, 12, 13, or 48-56, wherein n is 2 or 3.

58. 58. The composition of any one of claims 11, 12, 13, or 48-57, wherein p is 1, 2, or 3.

59. R 1 The composition of any one of claims 11, 12, or 48-58, wherein is a group of the formula: During the ceremony, R 5 , R 6 , and R 2 are each independently hydrogen or alkyl (C≦8) , -alkanediyl (C≦6) -NH 2 , -alkanediyl (C≦6) -Alkylamino (C≦8) , -alkanediyl (C≦6) -dialkylamino (C≦12) , -alkanediyl (C≦6) -NR'R'', or a substituted version of any of these groups, wherein: R' and R'' are each independently hydrogen, alkyl (C≦8) , substituted alkyl (C≦8) , -Z 2 A'R 7 where: Z 2 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A' is -CHR j -, -C(O)O-, or -C(O)NR b - and; R b is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R j is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 7 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) or R 5 , R 6 , and X 1 are each independently -Z 3 A''R 8 where: Z 3 Alkanediyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 8 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) and; q is 1, 2, or 3; r is 1, 2, 3, or 4.

60. 60. The composition of claim 59, wherein q is 1 or 2.

61. R 5 Ga-Z 3 A''R 8 where: Z 3 Alkandiyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 8 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) That is, 61. The composition of any one of claims 59-60.

62. R 6 Ga-Z 3 A''R 8 where: Z 3 Alkandiyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 8 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) That is, 62. The composition of any one of claims 59 to 61.

63. R 2 Ga-Z 3 A''R 8 where: Z 3 Alkandiyl (C≦4) or substituted alkanediyl (C≦4) and; A'' is -CHR k -, -C(O)O-, or -C(O)NR l - and; R l is hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; R k is hydrogen, halo, hydroxy, acyloxy (C≦24) , or substituted acyloxy (C≦24) and; R 8 is alkyl (C6～24) , substituted alkyl (C6～24) , alkenyl (C6～24) , substituted alkenyl (C6～24) That is, 63. The composition of any one of claims 59 to 62.

64. X 1 Alkandiyl (C1～2) 64. The composition of any one of claims 61 to 63, wherein

65. R 8 is alkyl (C6～24) or substituted alkyl (C6～24) 65. The composition of any one of claims 61 to 64, wherein

66. 17. The composition of claim 15 or 16, further defined as: During the ceremony, R 1 is hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) or a group of the formula: During the ceremony, R 7 and R 8 are each independently hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) or a group of the formula: During the ceremony, R 9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4; R 5 and R 6 are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; m and n are each independently 1, 2, 3, 4, or 5.

67. 67. The composition of any one of claims 15, 16, or 66, further defined as: During the ceremony, R 1 , R 2 , and R 3 are each independently hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) or a group of the formula: During the ceremony, R 7 and R 8 are each independently hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) or a group of the formula: During the ceremony, R 9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4; R 5 and R 6 are each independently hydrogen, alkyl (C≦6) , or substituted alkyl (C≦6) and; m is 1, 2, 3, 4, or 5.

68. R 2 is alkyl (C≦6) or substituted alkyl (C≦6) 68. The composition of any one of claims 15, 16, 66 to 67, wherein

69. R 2 The composition of any one of claims 15, 16, 66-67, wherein is a group of the formula: During the ceremony, R 7 and R 8 are each independently hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) or a group of the formula: During the ceremony, R 9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4.

70. R 7 but and During the ceremony, R 9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group, 70. The composition of claim 69.

71. R 8 but and During the ceremony, R 9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group, The composition of any one of claims 69-70.

72. R 3 is alkyl (C≦6) or substituted alkyl (C≦6) 72. The composition of any one of claims 15 and 66-71, wherein

73. R 4 73. The composition of any one of claims 15, 16, and 66-72, wherein is hydrogen.

74. R 5 is alkyl (C≦6) or substituted alkyl (C≦6) 74. The composition of any one of claims 15, 16, and 66-73, wherein

75. R 6 is alkyl (C≦6) or substituted alkyl (C≦6) 75. The composition of any one of claims 15, 16, and 66-74, wherein

76. 76. The composition of any one of claims 15, 16, and 66-75, wherein m is 2, 3, or 4.

77. 77. The compound of any one of claims 15, 16, and 66-76, wherein n is 2, 3, or 4.

78. R 1 The composition of any one of claims 15, 16, 66-77, wherein is a group of the formula: During the ceremony, R 7 and R 8 are each independently hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) or a group of the formula: During the ceremony, R 9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group; q is 1, 2, or 3; r is 0, 1, 2, 3, or 4.

79. R 7 but and During the ceremony, R 9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group, 79. The composition of claim 78.

80. R 9 80. The composition of claim 79, wherein is hydroxy.

81. R 9 Acyloxy (C≦8) or substituted acyloxy (C≦8) 80. The composition of claim 79, wherein

82. R 10 is alkyl (C≦24) or substituted alkyl (C≦24) 82. The composition of any one of claims 79 to 81, wherein

83. R 8 but and During the ceremony, R 9 is hydrogen, halo, or hydroxy, or alkoxy (C≦8) , acyloxy (C≦8) or a substituted form of either of these groups; R 10 is alkyl (C≦24) , alkenyl (C≦24) or a substituted form of either group, 83. The composition of any one of claims 78-82.

84. R 9 84. The composition of claim 83, wherein is hydroxy.

85. R 9 Acyloxy (C≦8) or substituted acyloxy (C≦8) 84. The composition of claim 83, wherein

86. R 10 is alkyl (C≦24) or substituted alkyl (C≦24) 86. The composition of any one of claims 83 to 85, wherein

87. 86. The composition of any one of claims 78-85, wherein q is 1 or 2.

88. 88. The composition of any one of claims 78-87, wherein r is 1, 2, or 3.

89. 89. The composition of any one of claims 1-88, wherein the tRNA is an unmodified tRNA.

90. 89. The composition of any one of claims 1-88, wherein the tRNA is a modified tRNA.

91. 91. The composition of any one of claims 1 to 90, wherein the tRNA is a suppressor tRNA.

92. 92. The composition of claim 91, wherein the tRNA is a tRNA that delivers an amino acid into a protein instead of terminating translation.

93. 92. The composition of claim 91, wherein the tRNA is a tRNA amber suppressor, a tRNA opal suppressor, a tRNA ochre suppressor, or a tRNA frameshift suppressor.

94. 93. The composition of claim 92, wherein the tRNA adds an arginine residue to the growing polypeptide.

95. tRNA is tRNA arg / op 95. The composition of claim 94, wherein

96. 93. The composition of claim 92, wherein the tRNA adds a glycine residue to the growing polypeptide.

97. tRNA is tRNA gly / op 97. The composition of claim 96, wherein

98. 93. The composition of claim 92, wherein the tRNA adds a tryptophan residue to the growing polypeptide.

99. tRNA is tRNA trp / op 99. The composition of claim 98, wherein

100. 92. The composition of claim 91, wherein said tRNA corrects a nonsense mutation in a cystic fibrosis transmembrane conductance regulator protein.

101. 101. The composition of any one of claims 1 to 100, further comprising a steroid or steroid derivative.

102. 102. The composition of any one of claims 1-101, further comprising a phospholipid.

103. 103. The composition of any one of claims 1-102, further comprising a PEG lipid.

104. 104. The composition of claim 103, wherein the PEG lipid is further defined as: During the ceremony, n 1 is an integer between 1 and 250; n 2 and n 3 are each independently selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.

105. 105. The composition of any one of claims 1-104, comprising a ratio of the compound to steroid or steroid derivative of about 1:1 to about 20:

1.

106. 106. The composition of any one of claims 1-105, comprising a ratio of compound to phospholipid of about 1:1 to about 9:

1.

107. 107. The composition of any one of claims 1-106, comprising a ratio of compound to PEG lipid of about 2.5:1 to about 100:

1.

108. 108. The composition of any one of claims 1-107, comprising a molar ratio of compound to nucleic acid of about 5:1 to about 1000:

1.

109. (A) a composition according to any one of claims 1 to 108; (B) excipients and 10. A pharmaceutical composition comprising:

110. 110. The pharmaceutical composition of claim 109, formulated for administration by injection.

111. 111. The pharmaceutical composition of any one of claims 109-110, formulated as a unit dose.

112. 112. A method of treating a disease or disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of the composition of any one of claims 1-111.

113. 113. The method of claim 112, wherein the disease or disorder is a genetic disease or disorder.

114. 114. The method of claim 113, wherein the genetic disease or disorder is cystic fibrosis.

115. 115. The method of claim 114, wherein the gene for cystic fibrosis transmembrane conductance regulator protein (CFTR) has a nonsense mutation.

116. 114. The method of claim 113, wherein the genetic disease or disorder is Duchenne muscular dystrophy (DMD), a congenital glycosylation disorder, Dravet syndrome, a mucopolysaccharidosis type I (MPS I) disorder, an NGLY1 deficiency (N-glycanase deficiency) disorder, Rett syndrome, or cancer.

117. 113. The method of claim 112, wherein the disease or disorder is cancer.

118. The method of any one of claims 112-117, wherein the patient is a mammal.

119. 119. The method of claim 118, wherein the patient is a human.

120. 120. The method of any one of claims 112-119, wherein the composition is administered once.

121. 120. The method of any one of claims 112-119, wherein the composition is administered more than once.

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