Compositions for delivery of tRNA as nanoparticles and methods of use thereof

Abstract

Compositions for delivery of tRNA as nanoparticles and methods of use thereof. The present disclosure relates generally to the fields of genetic diseases and disorders and pharmaceutical formulations. In some aspects, the present disclosure provides nanoparticle compositions comprising a tRNA and an aminolipid delivery compound. The aminolipid delivery compound can be a dendrimer, a dendron or dendritic lipid, a polymer (e.g., a polyamide or polyester), or a lipid having one or more hydrophobic components. 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.

Description

[0001] This application is a divisional application of Chinese patent application No. 201780038893.0, entitled “Composition for delivering tRNA as nanoparticles and method of using thereof”, which is a PCT international patent application PCT / US2017 / 032967 filed on May 16, 2017, which entered the Chinese national phase.

[0002] This application claims priority to U.S. Provisional Application No. 62 / 337,096, filed May 16, 2016, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure generally relates to the fields of hereditary diseases and conditions, as well as pharmaceutical formulations. More specifically, it relates to a method of delivering tRNA as a nanoparticle composition. Background Technology

[0004] Protein synthesis in the body is guided by the genetic code, which consists of 61 three-base-pair codons encoding different amino acids and 3 three-base-pair codons that terminate protein synthesis. When the nucleic acid sequence encoding a protein mutates to contain a stop codon instead of the codon for the next amino acid, the resulting protein terminates prematurely and is usually nonfunctional. Such mutations, called nonsense mutations, lead to many different genetic diseases, including many cases of cystic fibrosis.

[0005] One potential treatment option is to treat these nonsense mutations with tRNA that allows the production of complete proteins. Unfortunately, efforts to develop tRNAs and tRNA compositions that can be administered to patients have only achieved limited success. Therefore, new compositions and methods for delivering tRNA to patients are of clinical importance. Summary of the Invention

[0006] In some aspects, this disclosure provides compositions that can be used to deliver tRNA or tRNA derivatives into cells. In some embodiments, the composition comprises:

[0007] (A) tRNA;

[0008] (B) Aminolipid delivery compounds;

[0009] The aminolipid delivery compound forms nanoparticles. In some embodiments, the aminolipid delivery compound is a dendrimer comprising a lipophilic group and a positively charged group at physiological pH, such as a dendrimer of the following formula or a pharmaceutically acceptable salt thereof:

[0010] Core - (Repeating Unit) n -Terminal group (I)

[0011] The core is connected to the repeating unit by removing one or more hydrogen atoms from the core and replacing them with repeating units, wherein:

[0012] The core has the following formula:

[0013]

[0014] in:

[0015] X1 is an amino or alkylamino group. (C≤12) Dialkylamino (C≤12) heterocyclic alkyl (C≤12) , heteroaryl (C≤12) or its substituted form;

[0016] R1 is an amino, hydroxyl, or mercapto group, or an alkylamino group. (C≤12) Dialkylamino (C≤12) Or either of these two groups in a substituted form; and

[0017] a is 1, 2, 3, 4, 5, or 6; or

[0018] The core has the following formula:

[0019]

[0020] in:

[0021] X2 is N(R5) y ;

[0022] R5 is hydrogen or alkyl (C≤18) or substituted alkyl (C≤18) ;and

[0023] y can be 0, 1, or 2, provided that the sum of y and z is 3;

[0024] R2 is an amino, hydroxyl, or mercapto group, or an alkylamino group. (C≤12) Dialkylamino (C≤12) Or a substituted form of either of these two groups;

[0025] b is 1, 2, 3, 4, 5, or 6; and

[0026] z can be 1, 2, or 3; provided that the sum of z and y is 3; or

[0027] The core has the following formula:

[0028]

[0029] in:

[0030] X3 is -NR6-, where R6 is hydrogen or alkyl.(C≤8) or substituted alkyl (C≤8) -O-, or alkylamine dimethyl (C≤8) Alkoxydiyl (C≤8) Arandibral (C≤8) Mixed aromatic dimethyl (C≤8) heterocyclic alkyl dimethyl (C≤8) Or a substituted form of any of these groups;

[0031] R3 and R4 are each independently an amino, hydroxyl, or mercapto group, or an alkylamino group. (C≤12) Dialkylamino (C≤12) Or a substituted form of either of these two groups; or a group of the following formula: -(CH2CH2N) e (R c )R d ;

[0032] in:

[0033] e is 1, 2, or 3;

[0034] R c and R d Each is independently hydrogen or alkyl (C≤6) or substituted alkyl (C≤6) ;

[0035] c and d are each independently 1, 2, 3, 4, 5, or 6; or

[0036] The core is alkylamine (C≤18) dialkylamine (C≤36) Heterocyclic alkanes (C≤12) Or a substituted form of any of these groups;

[0037] The repeating unit contains a biodegradable diacyl group and a linker;

[0038] Degradable diacyl groups have the following formula:

[0039]

[0040] in:

[0041] A1 and A2 are independently -O-, -S-, or -NR. a -,in:

[0042] R a It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;

[0043] Y3 is an alkyldiyl group. (C≤12) alkenyl (C≤12) Arandibral (C≤12)Or a substituted form of any of these groups; or a group of the following formula:

[0044]

[0045] in:

[0046] X3 and X4 are alkyldiyl groups. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or a substituted form of any of these groups;

[0047] Y5 is a covalent bond, alkyl diol. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or the substituted form of any of these groups; and

[0048] R9 is an alkyl group. (C≤8) or substituted alkyl (C≤8) ;

[0049] The linker group has the following formula:

[0050]

[0051] in:

[0052] Y1 is an alkyldiyl group. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or the substituted form of any of these groups; and

[0053] When the repeating unit contains a linker group, the linker group is attached to both the nitrogen and sulfur atoms of the linker group, wherein the first group in the repeating unit is a degradable diacyl group, and for each linker group, the next group contains two degradable diacyl groups attached to the nitrogen atom of the linker group; and where n is the number of linker groups present in the repeating unit; and

[0054] Terminating groups have the following formula:

[0055]

[0056] in:

[0057] Y4 is an alkyldiyl group. (C≤18) alkenyl (C≤18) Or a substituted form of either of these two groups;

[0058] R 10 It is hydrogen, carboxyl, hydroxyl, or

[0059] Aryl(C≤12) alkylamino (C≤12) Dialkylamino (C≤12) N-heterocyclic alkyl (C≤12) -C(O)N(R) 11 )-alkyldiyl (C≤6) - Heterocyclic alkyl (C≤12) -C(O)-alkylamino (C≤12) -C(O)-dialkylamino (C≤12) -C(O)-N-heterocyclic alkyl (C≤12) ,in:

[0060] R 11 It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;

[0061] In this chain, the last degradable diacyl group is connected to a capping group;

[0062] n is 0, 1, 2, 3, 4, 5, or 6.

[0063] Aminolipid delivery compounds can be dendritic polymers of the following formula or pharmaceutically acceptable salts thereof:

[0064] The core has the following formula:

[0065]

[0066] in:

[0067] X1 is an amino or alkylamino group. (C≤12) Dialkylamino (C≤12) heterocyclic alkyl (C≤12) , heteroaryl (C≤12) or its substituted form;

[0068] R1 is an amino, hydroxyl, or mercapto group, or an alkylamino group. (C≤12) Dialkylamino (C≤12) Or either of these two groups in a substituted form; and

[0069] a is 1, 2, 3, 4, 5, or 6; and

[0070] The repeating unit contains a biodegradable diacyl group and a linker;

[0071] Degradable diacyl groups have the following formula:

[0072]

[0073] in:

[0074] A1 and A2 are independently -O- or -NR. a -,in:

[0075] R a It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;

[0076] Y3 is an alkyldiyl group. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or a substituted form of any of these groups; or a group of the following formula:

[0077]

[0078] in:

[0079] X3 and X4 are alkyldiyl groups. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or a substituted form of any of these groups;

[0080] Y5 is a covalent bond, alkyl diol. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or the substituted form of any of these groups; and

[0081] R9 is an alkyl group. (C≤8) or substituted alkyl (C≤8) ;

[0082] The linker group has the following formula:

[0083]

[0084] in:

[0085] Y1 is an alkyldiyl group. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or the substituted form of any of these groups; and

[0086] When the repeating unit contains a linker group, the linker group is attached to both the nitrogen and sulfur atoms of the linker group, wherein the first group in the repeating unit is a degradable diacyl group, and for each linker group, the next group contains two degradable diacyl groups attached to the nitrogen atom of the linker group; and where n is the number of linker groups present in the repeating unit; and

[0087] End-capping groups, wherein the end-capping groups have the following formula:

[0088]

[0089] in:

[0090] Y4 is an alkyldiyl group. (C≤18) alkenyl (C≤18) Or a substituted form of either of these two groups;

[0091] R 10 It is hydrogen, carboxyl, hydroxyl, or

[0092] Aryl (C≤12) alkylamino (C≤12) Dialkylamino (C≤12) N-heterocyclic alkyl (C≤12) -C(O)N(R) 11 )-alkyldiyl (C≤6) - Heterocyclic alkyl (C≤12) -C(O)-alkylamino (C≤12) -C(O)-dialkylamino (C≤12) -C(O)-N-heterocyclic alkyl (C≤12) ,in:

[0093] R 11 It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;

[0094] In this chain, the last degradable diacyl group is connected to a capping group;

[0095] n is 0, 1, 2, 3, 4, 5, or 6.

[0096] In some embodiments, the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0097] Core - (Repeating Unit) n -Terminal group (I)

[0098] The core is connected to the repeating unit by removing one or more hydrogen atoms from the core and replacing them with repeating units, wherein:

[0099] The core has the following formula:

[0100]

[0101] in:

[0102] X2 is N(R5) y ;

[0103] R5 is hydrogen or alkyl. (C≤8) or substituted alkyl (C≤18) ;and

[0104] y can be 0, 1, or 2, provided that the sum of y and z is 3;

[0105] R2 is an amino, hydroxyl, or mercapto group, or an alkylamino group. (C≤12) Dialkylamino (C≤12) Or a substituted form of either of these two groups;

[0106] b is 1, 2, 3, 4, 5, or 6; and

[0107] z can be 1, 2, or 3; provided that the sum of z and y is 3.

[0108] The repeating unit contains a biodegradable diacyl group and a linker;

[0109] Degradable diacyl groups have the following formula:

[0110]

[0111] in:

[0112] A1 and A2 are independently -O- or -NR. a -,in:

[0113] R a It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;

[0114] Y3 is an alkyldiyl group. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or a substituted form of any of these groups; or a group of the following formula:

[0115]

[0116] in:

[0117] X3 and X4 are alkyldiyl groups. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or a substituted form of any of these groups;

[0118] Y5 is a covalent bond, alkyl diol. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or the substituted form of any of these groups; and

[0119] R9 is an alkyl group. (C≤8) or substituted alkyl (C≤8) ;

[0120] The linker group has the following formula:

[0121]

[0122] in:

[0123] Y1 is an alkyldiyl group. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or the substituted form of any of these groups; and

[0124] When the repeating unit contains a linker group, the linker group is attached to both the nitrogen and sulfur atoms of the linker group, wherein the first group in the repeating unit is a degradable diacyl group, and for each linker group, the next group contains two degradable diacyl groups attached to the nitrogen atom of the linker group; and where n is the number of linker groups present in the repeating unit; and

[0125] End-capping groups, wherein the end-capping groups have the following formula:

[0126]

[0127] in:

[0128] Y4 is an alkyldiyl group. (C≤18) alkenyl (C≤18) Or a substituted form of either of these two groups;

[0129] R 10 It is hydrogen, carboxyl, hydroxyl, or

[0130] Aryl (C≤12) alkylamino (C≤12) Dialkylamino (C≤12) N-heterocyclic alkyl (C≤12) -C(O)N(R) 11 )-alkyldiyl (C≤6) - Heterocyclic alkyl (C≤12) -C(O)-alkylamino (C≤12) -C(O)-dialkylamino (C≤12) -C(O)-N-heterocyclic alkyl (C≤12) ,in:

[0131] In this chain, the last degradable diacyl group is connected to a capping group;

[0132] n is 0, 1, 2, 3, 4, 5, or 6.

[0133] In some embodiments, the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0134] Core - (Repeating Unit) n -Terminal group (I)

[0135] The core is connected to the repeating unit by removing one or more hydrogen atoms from the core and replacing them with repeating units, wherein:

[0136] The core has the following formula:

[0137]

[0138] in:

[0139] X3 is -NR6-, where R6 is hydrogen or alkyl. (C≤8) or substituted alkyl (C≤8) -O-, or alkylamine dimethyl (C≤8) Alkoxydiyl (C≤8) Arandibral (C≤8) Mixed aromatic dimethyl (C≤8) heterocyclic alkyl dimethyl (C≤8) Or a substituted form of any of these groups;

[0140] R3 and R4 are each independently an amino, hydroxyl, or mercapto group, or an alkylamino group. (C≤12) Dialkylamino (C≤12) Or a substituted form of either of these two groups; or a group of the following formula: -(CH2CH2N) e (R c )R d ;

[0141] in:

[0142] e is 1, 2, or 3;

[0143] R c and R d Each is independently hydrogen or alkyl (C≤6) or substituted alkyl (C≤6) c and d are each independently 1, 2, 3, 4, 5, or 6; and

[0144] The repeating unit contains a biodegradable diacyl group and a linker;

[0145] Degradable diacyl groups have the following formula:

[0146]

[0147] in:

[0148] A1 and A2 are independently -O- or -NR. a -,in:

[0149] R a It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;

[0150] Y3 is an alkyldiyl group. (C≤12) alkenyl (C≤12) Arandibral (C≤12)Or a substituted form of any of these groups; or a group of the following formula:

[0151]

[0152] in:

[0153] X3 and X4 are alkyldiyl groups. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or a substituted form of any of these groups;

[0154] Y5 is a covalent bond, alkyl diol. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or the substituted form of any of these groups; and

[0155] R9 is an alkyl group. (C≤8) or substituted alkyl (C≤8) ;

[0156] The linker group has the following formula:

[0157]

[0158] in:

[0159] Y1 is an alkyldiyl group. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or the substituted form of any of these groups; and

[0160] When the repeating unit contains a linker group, the linker group is attached to both the nitrogen and sulfur atoms of the linker group, wherein the first group in the repeating unit is a degradable diacyl group, and for each linker group, the next group contains two degradable diacyl groups attached to the nitrogen atom of the linker group; and where n is the number of linker groups present in the repeating unit; and

[0161] End-capping groups, wherein the end-capping groups have the following formula:

[0162]

[0163] in:

[0164] Y4 is an alkyldiyl group. (C≤18) alkenyl (C≤18) Or a substituted form of either of these two groups;

[0165] R 10 It is hydrogen, carboxyl, hydroxyl, or

[0166] Aryl (C≤12) alkylamino(C≤12) Dialkylamino (C≤12) N-heterocyclic alkyl (C≤12) -C(O)N(R) 11 )-alkyldiyl (C≤6) - Heterocyclic alkyl (C≤12) -C(O)-alkylamino (C≤12) -C(O)-dialkylamino (C≤12) -C(O)-N-heterocyclic alkyl (C≤12) ,in:

[0167] R 11 It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;

[0168] In this chain, the last degradable diacyl group is connected to a capping group;

[0169] n is 0, 1, 2, 3, 4, 5, or 6.

[0170] Y4 can be an alkyldiyl group. (C≤18) Or the alkyl diyl group thereof (C≤18) Alkyl groups in which one or more hydrogen atoms have been replaced by -OH, -F, -Cl, -Br, -I, -SH, -OCH3, -OCH2CH3, -SCH3, or -OC(O)CH3 (C≤18) .

[0171] In other embodiments, the aminolipid delivery compound is an aminolipid comprising: an anionic carboxylate, sulfonate, or phosphate group; a quaternary amino group; a positively charged amino group at physiological pH; and a lipophilic group. In some embodiments, the aminolipid delivery compound is further defined as the following or pharmaceutically acceptable salts thereof:

[0172]

[0173] in:

[0174] X1 is -S(O)2O - -OP(O)OR e O - -(CHR) f ) z C(O)O - or -NR g R h R i + ,in:

[0175] R e R g R h and R iEach is independently hydrogen or alkyl (C≤6) or substituted alkyl (C≤6) ;

[0176] R f It is hydrogen, amino, hydroxyl, or alkyl (C≤12) aryl (C≤12) Aryl alkyl (C≤12) , heteroaryl (C≤12) acyl group (C≤12) alkoxy (C≤12) acyloxy (C≤12) acylamino (C≤12) alkoxy (C≤12) alkoxy (C≤12) Or the substituted form of any one of the last ten groups; and

[0177] z is 1, 2, 3, or 4;

[0178] Y1 is an alkyldiyl group. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Mixed aromatic dimethyl (C≤12) heterocyclic alkyl dimethyl (C≤12) ,-alkyldiyl (C≤8) -heterocyclic dimethyl (C≤12) ,-alkyldiyl (C≤8) -heterocyclic dimethyl (C≤12) -alkyldiyl (C≤8) ,-alkyldiyl (C≤8) -Diarylene aromatics (C≤12) ,-alkyldiyl (C≤8) -Diarylene aromatics (C≤12) -alkyldiyl (C≤8) Or a substituted form of any of these groups;

[0179] Z1 is -N + R3R4-or-OP(O)O - O-

[0180] A is -NR a -, -S-, or -O-; where:

[0181] R a It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) , or R a Combined with R3 or R4 and being an alkyldiyl group (C≤8) alkenyl (C≤8) Alkoxydiyl (C≤8) Alkylamine dimethyl (C≤8) Or a substituted form of any of these groups;

[0182] R1 is a group in the following formula:

[0183]

[0184] in:

[0185] R5, R6, and R2 are each independently hydrogen or alkyl. (C≤8) ,-alkyldiyl (C≤6) -NH2, -alkyldiyl (C≤6) -alkylamino (C≤8) ,-alkyldiyl (C≤6) -Dialkylamino (C≤12) ,-alkyldiyl (C≤6) -NR'R" or any of these groups in a substituted form, wherein:

[0186] R' and R” are independently hydrogen and alkyl groups, respectively. (C≤8) Substituted alkyl groups (C≤8) Or -Z2A'R7; where:

[0187] Z2 is an alkyldiyl group. (C≤6) Substituted alkyl diols (C≤6) Or the following groups:

[0188]

[0189] in:

[0190] Z5 and Z6 are each independently alkyldiyl groups. (C≤6) Or substituted alkyl diols (C≤6) ;

[0191] X2 and X3 are independently -O-, -S-, or -NR. m -;

[0192] in:

[0193] R m It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) And a is 0, 1, 2, 3, 4, 5, or 6;

[0194] A' is -CHR j -、-C(O)O- or -C(O)NR b -;

[0195] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0196] R j It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;

[0197] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0198] R5, R6, and R2 are each independently -Z3A"R8; where:

[0199] Z3 is an alkyldiyl group. (C≤6) Substituted alkyl diols (C≤6) Or the following groups:

[0200]

[0201] in:

[0202] Z7 and Z8 are each independently alkyldiyl groups. (C≤6) Or substituted alkyl diols (C≤6) ;

[0203] X4 and X5 are independently -O-, -S-, or -NR. n -;in:

[0204] R n It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) And b is 0, 1, 2, 3, 4, 5, or 6;

[0205] A” is -CHR k -、-S-、-C(O)O- or -C(O)NR1-;

[0206] R1 is hydrogen or alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0207] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0208] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;

[0209] q is 1, 2, or 3; and

[0210] r is 1, 2, 3, or 4;

[0211] R1 is a group in the following formula:

[0212]

[0213] in:

[0214] Y2 is an aryldimethyl group. (C≤12) heterocyclic alkyl dimethyl (C≤12) Mixed aromatic dimethyl (C≤12) Alkoxydiyl (C≤12) Or a substituted form of any of these groups;

[0215] R9, R 10 and R 11 Each is independently hydrogen or alkyl (C≤8) Substituted alkyl groups (C≤8) or -Z4A”'R 12 ;in:

[0216] Z4 is an alkyldiyl group. (C≤6) Substituted alkyl diols (C≤6) Or the following groups:

[0217]

[0218] in:

[0219] Z9 and Z 10 Each is an alkyl diene independently (C≤6) Or substituted alkyl diols (C≤6) ;

[0220] X6 and X7 are independently -O-, -S-, or -NR. o -;in:

[0221] R o It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) And c is 0, 1, 2, 3, 4, 5, or 6;

[0222] A”' is -CHR k -、-S-、-C(O)O- or -C(O)NR1-;

[0223] R1 is hydrogen or alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0224] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0225] R 12 It is an alkyl group (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24);and

[0226] x and y are 0, 1, 2, 3 or 4;

[0227] R3 and R4 are independently hydrogen and alkyl groups, respectively. (C≤6) or substituted alkyl (C≤6) Or R3 or R4 with R a Combined and is alkyldiyl (C≤8) alkenyl (C≤8) Alkoxydiyl (C≤8) Alkylamine dimethyl (C≤8) Or the substituted form of any of these groups; and

[0228] m, n, and p are each an integer selected independently from 0, 1, 2, 3, 4, 5, or 6;

[0229] The premise is that if X1 carries a positive charge, then Z1 carries a negative charge, and if X1 carries a negative charge, then Z1 carries a positive charge.

[0230] In other embodiments, the aminolipid delivery compound is an aminolipid comprising an anionic sulfonate group and a quaternary amino group, a lipophilic group, and a protonated amino group at physiological pH. In some embodiments, the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0231]

[0232] in:

[0233] Y1 is an alkyldiyl group. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Mixed aromatic dimethyl (C≤12) heterocyclic alkyl dimethyl (C≤12) ,-alkyldiyl (C≤8) -heterocyclic dimethyl (C≤12) ,-alkyldiyl (C≤8) -heterocyclic dimethyl (C≤12) -alkyldiyl (C≤8) ,-alkyldiyl (C≤8) -Diarylene aromatics (C≤12) ,-alkyldiyl (C≤8) -Diarylene aromatics (C≤12) -alkyldiyl (C≤8) Or a substituted form of any of these groups;

[0234] A is -NR a -, -S-, or -O-; where:

[0235] R a It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6)Or Ra combined with R3 or R4 and is an alkyldiyl group. (C≤8) alkenyl (C≤8) Alkoxydiyl (C≤8) Alkylamine dimethyl (C≤8) Or a substituted form of any of these groups;

[0236] R1 is a group in the following formula:

[0237]

[0238] in:

[0239] R5, R6, and R2 are each independently hydrogen or alkyl. (C≤8) ,-alkyldiyl (C≤6) -NH2, -alkyldiyl (C≤6) -alkylamino (C≤8) ,-alkyldiyl (C≤6) -Dialkylamino (C≤12) ,-alkyldiyl (C≤6) -NR'R" or any of these groups in a substituted form, wherein:

[0240] R' and R” are independently hydrogen and alkyl groups, respectively. (C≤8) Substituted alkyl groups (C≤8) Or -Z2A'R7; where:

[0241] Z2 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0242] A' is -CHR j -、-C(O)O- or -C(O)NR b -;

[0243] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0244] R j It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;

[0245] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0246] R5, R6, and R2 are each independently -Z3A"R8; where:

[0247] Z3 is an alkyldiyl group. (C≤4)Or substituted alkyl diols (C≤4) ;

[0248] A” is -CHR k -、-C(O)O- or -C(O)NR1-;

[0249] R1 is hydrogen or alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0250] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0251] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;

[0252] q is 1, 2, or 3; and

[0253] r is 1, 2, 3, or 4;

[0254] R1 is a group in the following formula:

[0255]

[0256] in:

[0257] Y2 is an aryldimethyl group. (C≤12) heterocyclic alkyl dimethyl (C≤12) Mixed aromatic dimethyl (C≤12) Alkoxydiyl (C≤12) Or a substituted form of any of these groups;

[0258] R9, R 10 and R 11 Each is independently selected from hydrogen and alkyl groups. (C≤8) Substituted alkyl groups (C≤8) or -Z4A”'R 12 ;in:

[0259] Z4 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0260] A”' is -CHR k -、-C(O)O- or -C(O)NR1-;

[0261] R1 is hydrogen or alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0262] Rk It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0263] R 12 It is an alkyl group (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;and

[0264] x and y are 1, 2, 3 or 4;

[0265] R3 and R4 are independently hydrogen and alkyl groups, respectively. (C≤6) or substituted alkyl (C≤6) Or R3 or R4 with R a Combined and is alkyldiyl (C≤8) alkenyl (C≤8) Alkoxydiyl (C≤8) Alkylamine dimethyl (C≤8) Or the substituted form of any of these groups; and

[0266] m, n, and p are each an integer selected independently from 0, 1, 2, 3, 4, 5, or 6;

[0267] Alternatively, compounds of the following formula or their pharmaceutically acceptable salts:

[0268]

[0269] in:

[0270] A is -O- or -NR2-, where:

[0271] R2 is hydrogen or alkyl. (C≤6) or substituted alkyl (C≤6) ;

[0272] R1 is a group in the following formula:

[0273]

[0274] in:

[0275] R5, R6, and X1 are each independently hydrogen or alkyl. (C≤8) ,-alkyldiyl (C≤6) -NH2, -alkyldiyl (C≤6) -alkylamino (C≤8) ,-alkyldiyl (C≤6) -Dialkylamino (C≤12) ,-alkyldiyl (C≤6) -NR'R" or any of these groups in a substituted form, wherein:

[0276] R' and R” are each independently -(CH2) s CH(OH)R7、-(CH2) s C(O)OR7、-(CH2) s C(O)(NR a R7; where:

[0277] s is 1, 2, 3, or 4;

[0278] R a It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0279] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0280] R5, R6, and X1 are each independently -(CH2). t CH(OH)R8、-(CH2) t C(O)OR8、-(CH2) t C(O)(NR b R8; where:

[0281] t is 1, 2, 3, or 4;

[0282] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0283] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0284] q is 1, 2, or 3; and

[0285] r is 1, 2, 3, or 4;

[0286] R1 is a group in the following formula:

[0287]

[0288] in:

[0289] Y is an aryldimethyl group. (C≤12) heterocyclic alkyl dimethyl (C≤12) Mixed aromatic dimethyl (C≤12) Or a substituted form of any of these groups;

[0290] R9, R 10 and R 11 Each is independently selected from hydrogen and alkyl groups. (C≤8) Substituted alkyl groups (C≤8) -(CH2) u CH(OH)R 12 -(CH2) u C(O)OR 12 -(CH2) u C(O)(NR c )R 12 ;in:

[0291] u is 1, 2, 3 or 4;

[0292] R c It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0293] R 12 It is an alkyl group (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;

[0294] R3 and R4 are independently hydrogen and alkyl groups, respectively. (C≤6) or substituted alkyl (C≤6) ;and

[0295] m, n, and p are each an integer selected independently from 0, 1, 2, 3, 4, 5, or 6.

[0296] Aminolipid delivery compounds can be compounds of the following formula or their pharmaceutically acceptable salts:

[0297]

[0298] in:

[0299] R1 is a group in the following formula:

[0300]

[0301] in:

[0302] R5, R6, and R2 are each independently hydrogen or alkyl. (C≤8) ,-alkyldiyl (C≤6) -NH2, -alkyldiyl (C≤6) -alkylamino (C≤8) ,-alkyldiyl (C≤6) -Dialkylamino (C≤12) ,-alkyldiyl (C≤6) -NR'R" or any of these groups in a substituted form, wherein:

[0303] R' and R” are independently hydrogen and alkyl groups, respectively. (C≤8) Substituted alkyl groups (C≤8) Or -Z2A'R7; where:

[0304] Z2 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0305] A' is -CHR j -、-C(O)O- or -C(O)NR b -;

[0306] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0307] R j It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;

[0308] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0309] R5, R6, and R2 are each independently -Z3A"R8; where:

[0310] Z3 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0311] A” is -CHR k -、-C(O)O- or -C(O)NR1-;

[0312] R1 is hydrogen or alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0313] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0314] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;

[0315] q is 1, 2, or 3; and

[0316] r is 1, 2, 3, or 4;

[0317] R a R3 and R4 are each independently hydrogen and alkyl groups. (C≤6) or substituted alkyl (C≤6) ;and

[0318] m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6; or alternatively, compounds or their pharmaceutically acceptable salts of the following formula:

[0319]

[0320] in:

[0321] R1 is a group in the following formula:

[0322]

[0323] in:

[0324] R5, R6, and X1 are each independently hydrogen or alkyl. (C≤8) ,-alkyldiyl (C≤6) -NH2, -alkyldiyl (C≤6) -alkylamino (C≤8) ,-alkyldiyl (C≤6) -Dialkylamino (C≤12) ,-alkyldiyl (C≤6) -NR'R" or any of these groups in a substituted form, wherein:

[0325] R' and R” are each independently -(CH2) s CH(OH)R7、-(CH2) s C(O)OR7、-(CH2) s C(O)(NR a R7; where:

[0326] s is 1, 2, 3, or 4;

[0327] R a It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0328] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0329] R5, R6, and X1 are each independently -(CH2). t CH(OH)R8、-(CH2) tC(O)OR8、-(CH2) t C(O)(NR b R8; where:

[0330] t is 1, 2, 3, or 4;

[0331] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0332] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0333] q is 1, 2, or 3; and

[0334] r is 1, 2, 3, or 4;

[0335] R2, R3, and R4 are each independently hydrogen or alkyl. (C≤6) or substituted alkyl (C≤6) ;and

[0336] m, n, and p are each an integer selected independently from 0, 1, 2, 3, 4, 5, or 6.

[0337] In one embodiment, the aminolipid delivery compound is a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0338]

[0339] in:

[0340] R1 is a group in the following formula:

[0341]

[0342] in:

[0343] Y is an aryldimethyl group. (C≤12) heterocyclic alkyl dimethyl (C≤12) Mixed aromatic dimethyl (C≤12) Or a substituted form of any of these groups;

[0344] R9, R 10 and R 11 Each is independently selected from hydrogen and alkyl groups. (C≤8) Substituted alkyl groups (C≤8) -(CH2) u CH(OH)R 12 -(CH2) u C(O)OR 12-(CH2) u C(O)(NR c )R 12 ;in:

[0345] u is 1, 2, 3 or 4;

[0346] R c It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0347] R 12 It is an alkyl group (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;

[0348] R2, R3, and R4 are each independently hydrogen or alkyl. (C≤6) or substituted alkyl (C≤6) ;and

[0349] m, n, and p are each an integer selected independently from 0, 1, 2, 3, 4, 5, or 6.

[0350] In other embodiments, the aminolipid delivery compound comprises a sulfonamide group, a quaternary ammonium group, a protonated amino group 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:

[0351]

[0352] in:

[0353] R1 is a group in the following formula:

[0354]

[0355] in:

[0356] R7 and R8 are independently hydrogen and alkyl groups, respectively. (C≤6) Substituted alkyl groups (C≤6) Or the following groups:

[0357]

[0358] in:

[0359] R9 is hydrogen, halogen, hydroxyl, or alkoxy. (C≤24) acyloxy (C≤24) Or either of these two groups in a substituted form; and

[0360] R 10 It is an alkyl group (C≤24)alkenyl (C≤24) Or a substituted form of either of these two groups;

[0361] q is 1, 2, or 3; and

[0362] r is 0, 1, 2, 3 or 4;

[0363] R2, R3, R4, R5, and R6 are each independently hydrogen or alkyl. (C≤6) or substituted alkyl (C≤6) ;and

[0364] m and n are each independently 1, 2, 3, 4 or 5.

[0365] Aminolipid delivery compounds can be compounds of the following formula or their pharmaceutically acceptable salts:

[0366]

[0367] in:

[0368] R1, R2, and R3 are each independently hydrogen or alkyl. (C≤6) Substituted alkyl groups (C≤6) Or the following groups:

[0369]

[0370] in:

[0371] R7 and R8 are independently hydrogen and alkyl groups, respectively. (C≤6) Substituted alkyl groups (C≤6) Or the following groups:

[0372]

[0373] in:

[0374] R9 is hydrogen, halogen, hydroxyl, or alkoxy. (C≤24) acyloxy (C≤24) Or either of these two groups in a substituted form; and

[0375] R 10 It is an alkyl group (C≤24) alkenyl (C≤24) Or a substituted form of either of these two groups;

[0376] q is 1, 2, or 3; and

[0377] r is 0, 1, 2, 3 or 4;

[0378] R4, R5, and R6 are each independently hydrogen or alkyl. (C≤6) or substituted alkyl (C≤6) ;and

[0379] m and n are each independently 1, 2, 3, 4 or 5.

[0380] In other embodiments, the aminolipid comprises a polyester group, a thioether group, and an amine group protonated at physiological pH. In some embodiments, the aminolipid comprises a polyester group of the following formula or a pharmaceutically acceptable salt thereof:

[0381]

[0382] in:

[0383] X1 is an alkyl group. (C≤18) or substituted alkyl (C≤18) ;

[0384] X2 is hydrogen or alkyl. (C≤18) or substituted alkyl (C≤18) ;

[0385] R1 is -AZ;

[0386] in:

[0387] A is an alkyl dimethyl group. (C≤18) Or substituted alkyl diols (C≤18) ;

[0388] Z is -NR3R4;

[0389] in:

[0390] R3 and R4 are each independently selected from hydrogen and alkyl groups. (C≤18) Substituted alkyl groups (C≤18) Or R3 and R4 combined and forming an alkyldiyl group. (C≤18) Or substituted alkyl diols (C≤18) ;

[0391] R2 is an alkyl group. (C≤24) alkenyl (C≤24) Substituted alkyl groups (C≤24) Or substituted alkenyl (C≤24) ;

[0392] x and y are each independently 0, 1, 2, 3, 4 or 5;

[0393] m and n are each independent integers from 0 to 250, provided that at least one of m and n is greater than 1; and

[0394] The repeating units, defined by m and n, are randomly distributed throughout the polymer.

[0395] In some embodiments, A is -CH2CH2-. Z can be -NR3R4; wherein: R3 and R4 are each independently an alkyl group.(C≤18) or substituted alkyl (C≤18) In some embodiments, R3 is an alkyl group. (C≤18) For example, methyl, ethyl, propyl, or butyl. Similarly, R4 can be an alkyl group. (C≤18) For example, methyl, ethyl, propyl, or butyl. In other embodiments, Z is -NR3R4; wherein: R3 and R4 are combined and are alkyldiyl. (C≤18) Or substituted alkyl diols (C≤18) For example, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2CH2-. In some embodiments, X1 is an alkyl group. (C≤18) or substituted alkyl (C≤18) X1 can be an alkyl group. (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) Examples include butyl, hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl.

[0396] In one embodiment, x is 1. In one embodiment, y is 1. In some embodiments, m is an integer from 1 to 100. Alternatively, 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. Alternatively, 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 molar ratio of m repeating units to n repeating units of the polymer is from about 10:1 to about 1:10. The molar ratio of m repeating units to n repeating units can be from about 5:1 to about 1:5, for example, 3:1, 1:1, or 1:3.

[0397] In some embodiments, such as those measured by gel permeation chromatography, the average molecular weight of the polymer is about 1,000 to about 100,000, for example about 2,000 to about 10,000.

[0398] In some embodiments, the compound is further defined as the following or a pharmaceutically acceptable salt thereof:

[0399]

[0400] in:

[0401] R1, R2, and R3 are each independently hydrogen or alkyl.(C≤8) or substituted alkyl (C≤8) ;

[0402] R4 is hydrogen, halogen, hydroxyl, or alkyl. (C≤8) or substituted alkyl (C≤8) ;

[0403] R5 is an alkyl group. (C≤24) alkenyl (C≤24) Or a substituted form of either of these two groups;

[0404] R6 is Y1-R7;

[0405] in:

[0406] Y1 is an alkyldiyl group. (C≤8) Substituted alkyl diols (C≤8) -(CH2) r C(O)- or -(CH2) r C(O)NR a (CH2) s -;

[0407] in:

[0408] r and s are each independently 1, 2, or 3; and

[0409] R a It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;

[0410] R7 is an amino or heteroaryl group. (C≤12) heterocyclic alkyl (C≤12) alkylamino (C≤12) Dialkylamino (C≤12) arylalkylamino (C≤12) Or a substituted form of any of these groups;

[0411] a, b, m, d, e, and n are each 1, 2, 3, or 4 independently;

[0412] c and f are each independently 1 to 10; and

[0413] x and y are each independent integers from 0 to 250, provided that at least one of x and y is greater than 1.

[0414] In some implementations, a is 1 or 2. In one instance, a can be 1. In some implementations, b is 1 or 2. In one instance, b can be 1. In some implementations, m is 1 or 2. In one instance, m can be 1. In some implementations, d is 1 or 2. In one instance, d can be 1. In some implementations, e is 1 or 2. In one instance, e can be 1. In some implementations, n is 1 or 2. In one instance, n can be 1. In some implementations, c is 5 to 9, such as 6 or 8. In some implementations, f is 5 to 9, such as 6 or 8.

[0415] In some implementations, R1 is hydrogen. R2 may be an alkyl group. (C≤8) For example, ethyl. In some embodiments, R3 is an alkyl group. (C≤8) For example, ethyl. In some embodiments, R4 is a hydroxyl group. In other embodiments, R4 is a halogen. In some embodiments, R5 is an alkyl group. (C≤24) or substituted alkyl (C≤24) R5 can be an alkyl group. (C≤24) For example, hexyl, decyl, or dodecyl.

[0416] In some implementations, R6 is Y1-R7;

[0417] in:

[0418] Y1 is an alkyldiyl group. (C≤8) Or substituted alkyl diols (C≤8) ;and

[0419] R7 is an amino or heteroaryl group. (C≤12) heterocyclic alkyl (C≤12) alkylamino (C≤12) Dialkylamino (C≤12) arylalkylamino (C≤12) Or a substituted form of any of these groups.

[0420] Y1 can be -CH2CH2-. In some embodiments, R7 is an amino group. In other embodiments, R7 is an alkylamino group. (C≤12) Dialkylamino (C≤12) arylalkylamino (C≤12) Or a substituted form of any of these groups. R7 can be -NH2, -NHCH2CH2CH2CH3-, -N(CH3)2 or -N(CH2CH3)2.

[0421] In some other implementations, R6 is Y1-R7;

[0422] in:

[0423] Y1 is -(CH2)r C(O)- or -(CH2) r C(O)NR a (CH2) s -;

[0424] in:

[0425] r and s are each independently 1, 2, 3, or 4; and

[0426] R a It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0427] R7 is an amino or heteroaryl group. (C≤12) heterocyclic alkyl (C≤12) alkylamino (C≤12) Dialkylamino (C≤12) arylalkylamino (C≤12) Or a substituted form of any of these groups.

[0428] In some implementations, r is 2 or 3. In one instance, r can be 3. In some implementations, s is 2 or 3. In one instance, s can be 3. In some implementations, R a It is hydrogen. In some embodiments, R7 is a heteroaryl group. (C≤12) Or substituted heteroaryl (C≤12) For example, pyridyl or imidazole. In other embodiments, R7 is a heterocyclic alkyl group. (C≤12) or substituted heterocyclic alkyl (C≤12) For example, morpholino, pyrrolidinyl, piperidinyl, piperazinyl, 4-N-methylpiperazinyl, 4-N-(2-hydroxyethyl)piperazinyl, or 4-N-(2-dimethylaminoethyl)piperazinyl. In other embodiments, R7 is a dialkylamino group. (C≤12) Or substituted dialkylamino (C≤12) Examples include dimethylamino, diethylamino, dibutylamino, and di(2-hydroxyethyl)amino. In other embodiments, R7 is an arylalkylamino group. (C≤12) Or substituted arylalkylamino (C≤12) For example, (N-methyl,N-phenyl)amino.

[0429] In other embodiments, the dendritic polymer has the following formula or a pharmaceutically acceptable salt thereof:

[0430] Core - (Repeating Unit) n -Terminal group (I)

[0431] The core is connected to the repeating unit by removing one or more hydrogen atoms from the core and replacing them with repeating units, wherein:

[0432] The core is alkylamine (C≤18) dialkylamine (C≤36) Heterocyclic alkanes (C≤12) Or the substituted form of any of these groups; and

[0433] The repeating unit contains a biodegradable diacyl group and a linker;

[0434] Degradable diacyl groups have the following formula:

[0435]

[0436] in:

[0437] A1 and A2 are independently -O- or -NR. a -,in:

[0438] R a It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;

[0439] Y3 is an alkyldiyl group. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or a substituted form of any of these groups; or a group of the following formula:

[0440]

[0441] in:

[0442] X3 and X4 are alkyldiyl groups. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or a substituted form of any of these groups;

[0443] Y5 is a covalent bond, alkyl diol. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or the substituted form of any of these groups; and

[0444] R9 is an alkyl group. (C≤8) or substituted alkyl (C≤8) ;

[0445] The linker group has the following formula:

[0446]

[0447] in:

[0448] Y1 is an alkyldiyl group. (C≤12) alkenyl (C≤12) Arandibral(C≤12) Or the substituted form of any of these groups; and

[0449] When the repeating unit contains a linker group, the linker group is attached to both the nitrogen and sulfur atoms of the linker group, wherein the first group in the repeating unit is a degradable diacyl group, and for each linker group, the next group contains two degradable diacyl groups attached to the nitrogen atom of the linker group; and where n is the number of linker groups present in the repeating unit; and

[0450] End-capping groups, wherein the end-capping groups have the following formula:

[0451]

[0452] in:

[0453] Y4 is an alkyldiyl group. (C≤18) alkenyl (C≤18) Or a substituted form of either of these two groups;

[0454] R 10 It is hydrogen, carboxyl, hydroxyl, or

[0455] Aryl (C≤12) alkylamino (C≤12) Dialkylamino (C≤12) N-heterocyclic alkyl (C≤12) -C(O)N(R) 11 )-alkyldiyl (C≤6) - Heterocyclic alkyl (C≤12) -C(O)-alkylamino (C≤12) -C(O)-dialkylamino (C≤12) -C(O)-N-heterocyclic alkyl (C≤12) ,in:

[0456] R 11 It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;

[0457] In this chain, the last degradable diacyl group is connected to a capping group;

[0458] n is 0, 1, 2, 3, 4, 5, or 6.

[0459] In some implementations, the end-capping group is further defined by the following formula:

[0460]

[0461] in:

[0462] Y4 is an alkyldiyl group. (C≤18) alkenyl(C≤18) Or either of these two groups in a substituted form; and

[0463] R 10 It is hydrogen.

[0464] In other embodiments, the capping group is further defined by the following formula:

[0465]

[0466] in:

[0467] Y4 is an alkyldiyl group. (C≤18) ;and

[0468] R 10 It is hydrogen.

[0469] In some implementations, Y4 is an alkyldiyl group. (C4-18) In other embodiments, the end-capping group is further defined by the following formula:

[0470]

[0471] in:

[0472] Y4 is an alkyldiyl group. (C≤18) alkenyl (C≤18) Or either of these two groups in a substituted form; and

[0473] R 10 It is an alkylamino (C≤12) Dialkylamino (C≤12) N-heterocyclic alkyl (C≤12) .

[0474] In other embodiments, the capping group is further defined by the following formula:

[0475]

[0476] in:

[0477] Y4 is an alkyldiyl group. (C≤18) alkenyl (C≤18) Or either of these two groups in a substituted form; and

[0478] R 10 It is a hydroxyl group.

[0479] In some implementations, the core is further defined by the following formula:

[0480]

[0481] in:

[0482] X1 is an alkylamino group.(C≤12) Dialkylamino (C≤12) heterocyclic alkyl (C≤12) , heteroaryl (C≤12) or its substituted form;

[0483] R1 is an amino, hydroxyl, or mercapto group, or an alkylamino group. (C≤12) Dialkylamino (C≤12) Or either of these two groups in a substituted form; and

[0484] a is 1, 2, 3, 4, 5 or 6.

[0485] In some embodiments, X1 is an alkylamino group. (C≤12) or substituted alkylamino (C≤12) For example, ethylamino. In other embodiments, X1 is a dialkylamino. (C≤12) Or substituted dialkylamino (C≤12) For example, dimethylamino. In other embodiments, X1 is a heterocyclic alkyl group. (C≤12) or substituted heterocyclic alkyl (C≤12) For example, 4-piperidinyl, N-piperidinyl, N-morpholinyl, N-pyrrolidinyl, 2-pyrrolidinyl, N-piperazinyl, or N-4-methylpiperadizinyl. In other embodiments, X1 is a heteroaryl group. (C≤12) Or substituted heteroaryl (C≤12) For example, 2-pyridyl or N-imidazolyl.

[0486] R1 can be hydroxyl or amino. In other embodiments, R1 is an alkylamino group. (C≤12) or substituted alkylamino (C≤12) In some embodiments, R1 is an alkylamino group. (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 following formula:

[0487]

[0488] In other implementations, the core is further defined by the following formula:

[0489]

[0490] in:

[0491] X2 is N(R5) y ;

[0492] R5 is hydrogen or alkyl. (C≤8) or substituted alkyl (C≤18) ;and

[0493] y can be 0, 1, or 2, provided that the sum of y and z is 3;

[0494] R2 is an amino, hydroxyl, or mercapto group, or an alkylamino group. (C≤12) Dialkylamino (C≤12) Or a substituted form of either of these two groups;

[0495] b is 1, 2, 3, 4, 5, or 6; and

[0496] z is 1, 2, or 3; the premise is that the sum of z and y is 3.

[0497] 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.

[0498] R2 can be a hydroxyl group or an amino group. In other embodiments, R2 is an alkylamino group. (C≤12) or substituted alkylamino (C≤12) R2 can be an alkylamino group. (C≤12) For example, methylamino. In other embodiments, R2 is a dialkylamino. (C≤12) Or substituted dialkylamino (C≤12) R2 can be a dialkylamino group. (C≤12) For example, 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 still other embodiments, the core is further defined as:

[0499]

[0500] In other implementation schemes, the core is further defined as follows:

[0501]

[0502] in:

[0503] X3 is -NR6-, where R6 is hydrogen or alkyl. (C≤8) or substituted alkyl (C≤8) -O-, or alkylamine dimethyl (C≤8) Alkoxydiyl (C≤8) Arandibral (C≤8) Mixed aromatic dimethyl (C≤8)heterocyclic alkyl dimethyl (C≤8) Or a substituted form of any of these groups;

[0504] R3 and R4 are each independently an amino, hydroxyl, or mercapto group, or an alkylamino group. (C≤12) Dialkylamino (C≤12) Or a substituted form of either of these two groups; or a group of the following formula: -(CH2CH2N) e (R c )R d ;

[0505] in:

[0506] e is 1, 2, or 3;

[0507] R c and R d Each is independently hydrogen or alkyl (C≤6) or substituted alkyl (C≤6) ;

[0508] c and d are each independently 1, 2, 3, 4, 5 or 6.

[0509] In some embodiments, X3 is -O-. In other embodiments, X3 is -NR6-, where R6 is hydrogen or an alkyl group. (C≤8) or substituted alkyl (C≤8) For example, -NH- or -NCH3-. In other embodiments, X3 is an alkylaminodiyl group. (C≤8) Or substituted alkylamine diol (C≤8) For example, -NHCH2CH2NH- or -NHCH2CH2NHCH2CH2NH-. In other embodiments, X3 is an alkoxydiyl group. (C≤8) Or substituted alkoxydiyl (C≤8) For example, -OCH2CH2O-. In other embodiments, X3 is an aryldiyl group. (C≤8) Or substituted aryl diol (C≤8) For example, phenylenediol. In other embodiments, X3 is a heterocyclic alkyl dimethyl group. (C≤8) Or substituted heterocyclic alkyl dimethyl (C≤8) For example, N,N'-piperazinediyl.

[0510] In some embodiments, R3 is an amino group. R3 may be a hydroxyl group. R3 may be an alkylamino group. (C≤12) or substituted alkylamino (C≤12) In some embodiments, R3 is an alkylamino group. (C≤12) For example, methylamino. R3 can be dialkylamino. (C≤12) Or substituted dialkylamino (C≤12) In some embodiments, R3 is a dialkylamino group.(C≤12) For example, dimethylamino. R4 can be an amino group. R4 can be a hydroxyl group. R4 can be an alkylamino group. (C≤12) or substituted alkylamino (C≤12) In some embodiments, R4 is an alkylamino group. (C≤12) For example, methylamino. R4 can be dialkylamino. (C≤12) Or substituted dialkylamino (C≤12) In some embodiments, R4 is a dialkylamino group. (C≤12) For example, dimethylamino. In some embodiments, R4 is -(CH2CH2N). e (R c )R d :

[0511] in:

[0512] e is 1, 2, or 3;

[0513] R c and R d Each is independently hydrogen or alkyl (C≤6) or substituted alkyl (C≤6) .

[0514] In some implementations, e is 1 or 2. In one instance, e can be 1. In some implementations, R c It is hydrogen. In some implementations, R d It is hydrogen. In some embodiments, c is 1, 2, 3, or 4. In one instance, 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 instance, 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:

[0515]

[0516] In other implementations, the core is an alkylamine. (C≤18) dialkylamine (C≤36) Heterocyclic alkanes (C≤12) Or a substituted form of any of these groups. In some embodiments, the core is an alkylamine. (C≤18) or substituted alkylamines (C≤18) Examples include octylamine, decylamine, dodecylamine, tetradecylamine, hexadecylamine, and octadecylamine. In other embodiments, the core is a dialkylamine. (C≤36) Or substituted dialkylamines (C≤36) Examples include N-methyl, N-dodecylamine, dioctylamine, or didecylamine. In other embodiments, the core is a heterocyclic alkane.(C≤12) Or substituted heterocyclic alkanes (C≤12) For example, 4-N-methylpiperazinyl.

[0517] In some implementations, Y1 is an alkyldiyl group. (C≤8) Or substituted alkyl diols (C≤8) Y1 can be an alkyl diene. (C≤8) For example, -CH2CH2-. In some embodiments, Y3 is an alkyldiyl group. (C≤8) Or substituted alkyl diols (C≤8) Y3 can be an alkyldiyl group. (C≤8) For example, -CH2CH2-. In other embodiments, Y3 is:

[0518]

[0519] in:

[0520] X3 and X4 are alkyldiyl groups. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or a substituted form of any of these groups;

[0521] Y5 is a covalent bond, alkyl diol. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or a substituted form of any of these groups.

[0522] In some implementations, X3 is an alkyldiyl group. (C≤12) Or substituted alkyl diols (C≤12) For example, -CH2CH2-. In some embodiments, X4 is an alkyldiyl group. (C≤12) Or substituted alkyl diols (C≤12) For example, -CH2CH2-. Y5 can be a covalent bond.

[0523] In other implementations, Y3 is:

[0524]

[0525] in:

[0526] X3 and X4 are alkyldiyl groups. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or a substituted form of any of these groups;

[0527] Y5 is a covalent bond, alkyl diol. (C≤12) alkenyl (C≤12) Arandibral (C≤12) Or a substituted form of any of these groups.

[0528] In some implementations, X3 is an alkyldiyl group. (C≤12) Or substituted alkyl diols (C≤12) For example, X3 is -CH2CH2-. In some embodiments, X4 is alkyldiyl. (C≤12) Or substituted alkyl diols (C≤12) For example, -CH2CH2-. Y5 can be covalent. In other embodiments, Y5 is -CH2- or -C(CH3)2-.

[0529] In some implementations, A1 is -O-. In other implementations, A1 is -NR. a -. R a It can be hydrogen. In some embodiments, A2 is -O-. In other embodiments, A2 is -NR. a -. R a It can be hydrogen. In some embodiments, R9 is an alkyl group. (C≤8) For example, 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.

[0530] In other embodiments, the compound is further defined as:

[0531]

[0532] in:

[0533] R1 is a group in the following formula:

[0534]

[0535] in:

[0536] R5, R6, and R2 are each independently hydrogen or alkyl. (C≤8) ,-alkyldiyl (C≤6) -NH2, -alkyldiyl (C≤6) -alkylamino (C≤8) ,-alkyldiyl (C≤6) -Dialkylamino (C≤12) ,-alkyldiyl (C≤6) -NR'R" or any of these groups in a substituted form, wherein:

[0537] R' and R” are independently hydrogen and alkyl groups, respectively. (C≤8) Substituted alkyl groups (C≤8) Or -Z2A'R7; where:

[0538] Z2 is an alkyldiyl group. (C≤4)Or substituted alkyl diols (C≤4) ;

[0539] A' is -CHR j -、-C(O)O- or -C(O)NR b -;

[0540] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0541] R j It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;

[0542] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0543] R5, R6, and R2 are each independently -Z3A"R8; where:

[0544] Z3 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0545] A” is -CHR k -、-C(O)O- or -C(O)NR l -;

[0546] R l It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0547] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0548] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;

[0549] q is 1, 2, or 3; and

[0550] r is 1, 2, 3, or 4; and

[0551] m, n, and p are each an integer selected independently from 0, 1, 2, 3, 4, 5, or 6;

[0552] Alternatively, compounds of the following formula or their pharmaceutically acceptable salts:

[0553]

[0554] in:

[0555] R1 is a group in the following formula:

[0556]

[0557] in:

[0558] R5, R6, and X1 are each independently hydrogen or alkyl. (C≤8) ,-alkyldiyl (C≤6) -NH2, -alkyldiyl (C≤6) -alkylamino (C≤8) ,-alkyldiyl (C≤6) -Dialkylamino (C≤12) ,-alkyldiyl (C≤6) -NR'R" or any of these groups in a substituted form, wherein:

[0559] R' and R” are independently hydrogen and alkyl groups, respectively. (C≤8) Substituted alkyl groups (C≤8) -(CH2) s CH(OH)R7、-(CH2) s C(O)OR7 or -(CH2) s C(O)(NR a R7; where:

[0560] s is 1, 2, 3, or 4;

[0561] R a It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0562] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0563] R5, R6, and X1 are each independently -(CH2). t CH(OH)R8、-(CH2) t C(O)OR8、-(CH2) t C(O)(NR b R8; where:

[0564] t is 1, 2, 3, or 4;

[0565] R bIt is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0566] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0567] q is 1, 2, or 3; and

[0568] r is 1, 2, 3, or 4; and

[0569] m, n, and p are each an integer selected independently from 0, 1, 2, 3, 4, 5, or 6.

[0570] In some embodiments, the compound is further defined as:

[0571]

[0572] in:

[0573] R1 is a group in the following formula:

[0574]

[0575] in:

[0576] R5, R6, and R2 are each independently hydrogen or alkyl. (C≤8) ,-alkyldiyl (C≤6) -NH2, -alkyldiyl (C≤6) -alkylamino (C≤8) ,-alkyldiyl (C≤6) -Dialkylamino (C≤12) ,-alkyldiyl (C≤6) -NR'R" or any of these groups in a substituted form, wherein:

[0577] R' and R” are independently hydrogen and alkyl groups, respectively. (C≤8) Substituted alkyl groups (C≤8) Or -Z2A'R7; where:

[0578] Z2 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0579] A' is -CHR j -、-C(O)O- or -C(O)NR b -;

[0580] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0581] R j It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;

[0582] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0583] R5, R6, and R2 are each independently -Z3A"R8; where:

[0584] Z3 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0585] A” is -CHR k -、-C(O)O- or -C(O)NR l -;

[0586] R l It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0587] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0588] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;

[0589] q is 1, 2, or 3; and

[0590] r is 1, 2, 3, or 4;

[0591] Alternatively, compounds of the following formula or their pharmaceutically acceptable salts:

[0592]

[0593] in:

[0594] R1 is a group in the following formula:

[0595]

[0596] in:

[0597] R5, R6, and X1 are each independently hydrogen or alkyl.(C≤8) ,-alkyldiyl (C≤6) -NH2, -alkyldiyl (C≤6) -alkylamino (C≤8) ,-alkyldiyl (C≤6) -Dialkylamino (C≤12) ,-alkyldiyl (C≤6) -NR'R" or any of these groups in a substituted form, wherein:

[0598] R' and R” are independently hydrogen and alkyl groups, respectively. (C≤8) Substituted alkyl groups (C≤8) -(CH2) s CH(OH)R7、-(CH2) s C(O)OR7 or -(CH2) s C(O)(NR a R7; where:

[0599] s is 1, 2, 3, or 4;

[0600] R a It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0601] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0602] R5, R6, and X1 are each independently -(CH2). t CH(OH)R8、-(CH2) t C(O)OR8、-(CH2) t C(O)(NR b R8; where:

[0603] t is 1, 2, 3, or 4;

[0604] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0605] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0606] q is 1, 2, or 3; and

[0607] r can be 1, 2, 3, or 4.

[0608] In some embodiments, the compound is further defined as:

[0609]

[0610] in:

[0611] R1 is a group in the following formula:

[0612]

[0613] in:

[0614] R5, R6, and R2 are each independently hydrogen or alkyl. (C≤8) ,-alkyldiyl (C≤6) -NH2, -alkyldiyl (C≤6) -alkylamino (C≤8) ,-alkyldiyl (C≤6) -Dialkylamino (C≤12) ,-alkyldiyl (C≤6) -NR'R" or any of these groups in a substituted form, wherein:

[0615] R' and R” are independently hydrogen and alkyl groups, respectively. (C≤8) Substituted alkyl groups (C≤8) Or -Z2A'R7; where:

[0616] Z2 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0617] A' is -CHR j -、-C(O)O- or -C(O)NR b -;

[0618] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0619] R j It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;

[0620] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0621] R5, R6, and R2 are each independently -Z3A"R8; where:

[0622] Z3 is an alkyldiyl group. (C≤4)Or substituted alkyl diols (C≤4) ;

[0623] A” is -CHR k -、-C(O)O- or -C(O)NR l -;

[0624] R l It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0625] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0626] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;

[0627] q is 1, 2, or 3; and

[0628] r is 1, 2, 3, or 4;

[0629] Alternatively, compounds of the following formula or their pharmaceutically acceptable salts:

[0630]

[0631] in:

[0632] R1 is a group in the following formula:

[0633]

[0634] in:

[0635] R5 is -(CH2) t CH(OH)R8、-(CH2) t C(O)OR8、-(CH2) t C(O)(NH)R8; where:

[0636] t is 1 or 2; and

[0637] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;

[0638] R6 is an alkyl group. (C≤8) or substituted alkyl (C≤8) ;and

[0639] X1 is an alkyldiyl group. (C≤6) -NR'R" or the substituted form of the group, wherein:

[0640] R' and R” are each independently -(CH2) s CH(OH)R7、-(CH2) s C(O)OR7 or -(CH2) s C(O)(NH)R7; where:

[0641] s is 1 or 2; and

[0642] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0643] q is 1 or 2; and

[0644] r is 1 or 2.

[0645] In other embodiments, the compound is further defined as:

[0646]

[0647] in:

[0648] R1 is a group in the following formula:

[0649]

[0650] in:

[0651] R5 is -Z3A"R8; where:

[0652] Z3 is an alkyldiyl group. (C≤2) Or substituted alkyl diols (C≤2) ;

[0653] A” is -CHR k -、-C(O)O- or -C(O)NR l -;

[0654] R l It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0655] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0656] R8 is an alkyl group. (C6-24)Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;

[0657] R6 is an alkyl group. (C≤8) or substituted alkyl (C≤8) ;and

[0658] R2 is an alkyldiyl group. (C≤6) -NR'R" or the substituted form of the group, wherein:

[0659] R' and R” are each independently -Z2A'R7; where:

[0660] Z2 is an alkyldiyl group. (C≤2) Or substituted alkyl diols (C≤2) ;

[0661] A' is -CHR j -、-C(O)O- or -C(O)NR b -;

[0662] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0663] R j It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;

[0664] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0665] q is 1 or 2; and

[0666] r is 1 or 2;

[0667] Alternatively, compounds of the following formula or their pharmaceutically acceptable salts:

[0668]

[0669] in:

[0670] R1 is a group in the following formula:

[0671]

[0672] in:

[0673] R5 is an alkyl group. (C≤8) or substituted alkyl (C≤8);

[0674] R6 is an alkyldiyl group. (C≤6) -NR'R" or the substituted form of the group, wherein:

[0675] R' and R” are each independently an alkyl group. (C≤8) Substituted alkyl groups (C≤8) -(CH2) s CH(OH)R7、-(CH2) s C(O)OR7 or -(CH2) s C(O)(NH)R7; where:

[0676] s is 1 or 2; and

[0677] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;and

[0678] X1 is an alkyldiyl group. (C≤6) -NR'R" or the substituted form of the group, wherein:

[0679] R' and R” are each independently an alkyl group. (C≤8) Substituted alkyl groups (C≤8) -(CH2) s CH(OH)R7、-(CH2) s C(O)OR7 or -(CH2) s C(O)(NH)R7; where:

[0680] s is 1 or 2; and

[0681] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups ( C6-24) ;

[0682] q is 1 or 2; and

[0683] r is 1 or 2.

[0684] In other embodiments, the compound is further defined as:

[0685]

[0686] in:

[0687] R1 is a group in the following formula:

[0688]

[0689] in:

[0690] R5 is an alkyl group. (C≤8) or substituted alkyl (C≤8) ;

[0691] R6 is an alkyldiyl group. (C≤6) -NR'R" or the substituted form of the group, wherein:

[0692] R' and R” are each independently an alkyl group. (C≤8) Substituted alkyl groups (C≤8) Or -Z2A'R7; where:

[0693] Z2 is an alkyldiyl group. (C≤2) Or substituted alkyl diols (C≤2) ;

[0694] A' is -CHR j -、-C(O)O- or -C(O)NR b -;

[0695] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0696] R j It is hydrogen, hydroxyl, acyloxy (C≤6) or substituted acyloxy group (C≤6) ;

[0697] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0698] R2 is an alkyldiyl group. (C≤6) -NR'R" or the substituted form of the group, wherein:

[0699] R' and R” are each independently an alkyl group. (C≤8) Substituted alkyl groups (C≤8) Or -Z2A'R7; where:

[0700] Z2 is an alkyldiyl group. (C≤2) Or substituted alkyl diols (C≤2) ;

[0701] A' is -CHR j -、-C(O)O- or -C(O)NR b -;

[0702] R b It is hydrogen, alkyl (C≤6)or substituted alkyl (C≤6) ;and

[0703] R j It is hydrogen, hydroxyl, acyloxy (C≤6) or substituted acyloxy group (C≤6) ;

[0704] q is 1 or 2; and

[0705] r is 1 or 2;

[0706] Alternatively, compounds of the following formula or their pharmaceutically acceptable salts:

[0707]

[0708] in:

[0709] R1 is a group in the following formula:

[0710]

[0711] in:

[0712] R5 is -(CH2) t CH(OH)R8、-(CH2) t C(O)OR8、-(CH2) t C(O)(NH)R8; where:

[0713] t is 1 or 2; and

[0714] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24)

[0715] R6 is an alkyldiyl group. (C≤6) -NR'R" or the substituted form of the group; wherein:

[0716] R' and R” are each independently -(CH2) s CH(OH)R7、-(CH2) s C(O)OR7, or -(CH2) s C(O)(NH)R7; where:

[0717] s is 1 or 2; and

[0718] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;and

[0719] X1 is an alkyldiyl group. (C≤6) -NR'R" or the substituted form of the group; wherein:

[0720] R' and R” are each independently -(CH2) s CH(OH)R7、-(CH2) s C(O)OR7 or -(CH2) s C(O)(NH)R7; where:

[0721] s is 1 or 2; and

[0722] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;

[0723] q is 1 or 2; and

[0724] r is 1 or 2.

[0725] In some embodiments, the compound is further defined as:

[0726]

[0727] in:

[0728] R1 is a group in the following formula:

[0729]

[0730] in:

[0731] R5 is -Z3A"R8; where:

[0732] Z3 is an alkyldiyl group. (C≤2) Or substituted alkyl diols (C≤2) ;

[0733] A” is -CHR k -、-C(O)O- or -C(O)NR l -;

[0734] R l It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0735] R k It is hydrogen, hydroxyl, acyloxy (C≤6) or substituted acyloxy group (C≤6) ;and

[0736] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24)alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;

[0737] R6 is an alkyldiyl group. (C≤6) -NR'R" or the substituted form of the group; wherein:

[0738] R' and R” are each independently -Z2A'R7; where:

[0739] Z2 is an alkyldiyl group. (C≤2) Or substituted alkyl diols (C≤2) ;

[0740] A' is -CHR j -、-C(O)O- or -C(O)NR b -;

[0741] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0742] R j It is hydrogen, hydroxyl, acyloxy (C≤6) or substituted acyloxy group (C≤6) ;

[0743] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;and

[0744] R2 is an alkyldiyl group. (C≤6) -NR'R" or the substituted form of the group; wherein:

[0745] R' and R” are each independently -Z2A'R7; where:

[0746] Z2 is an alkyldiyl group. (C≤2) Or substituted alkyl diols (C≤2) ;

[0747] A' is -CHR j -、-C(O)O- or -C(O)NR b -;

[0748] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0749] R j It is hydrogen, hydroxyl, acyloxy (C≤6) or substituted acyloxy group (C≤6) ;

[0750] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;

[0751] q is 1 or 2; and

[0752] r is 1 or 2;

[0753] Alternatively, compounds of the following formula or their pharmaceutically acceptable salts:

[0754]

[0755] in:

[0756] R1 is a group in the following formula:

[0757]

[0758] in:

[0759] Y is an aryldimethyl group. (C≤12) heterocyclic alkyl dimethyl (C≤12) Mixed aromatic dimethyl (C≤12) Or a substituted form of any of these groups;

[0760] R9, R 10 and R 11 Each is independently selected from hydrogen and alkyl groups. (C≤8) Substituted alkyl groups (C≤8) -(CH2) u CH(OH)R 12 -(CH2) u C(O)OR 12 -(CH2) u C(O)(NR c )R 12 ;in:

[0761] u is 1, 2, 3 or 4;

[0762] R c It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0763] R 12 It is an alkyl group (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;and

[0764] x and y are 1, 2, 3, or 4; and

[0765] m, n, and p are each an integer selected independently from 0, 1, 2, 3, 4, 5, or 6.

[0766] In other embodiments, the compound is further defined as:

[0767]

[0768] in:

[0769] R1 is a group in the following formula:

[0770]

[0771] in:

[0772] Y2 is an aryldimethyl group. (C≤12) heterocyclic alkyl dimethyl (C≤12) Mixed aromatic dimethyl (C≤12) Alkoxydiyl (C≤12) Or a substituted form of any of these groups;

[0773] R9, R 10 and R 11 Each is independently selected from hydrogen and alkyl groups. (C≤8) Substituted alkyl groups (C≤8) or -Z4A”'R 12 ;in:

[0774] Z4 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0775] A”' is -CHR k -、-C(O)O- or -C(O)NR l -;

[0776] R l It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0777] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0778] R 12 It is an alkyl group (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;and

[0779] x and y are 1, 2, 3 or 4;

[0780] Ra R3 and R4 are each independently hydrogen and alkyl groups. (C≤6) or substituted alkyl (C≤6) ;and

[0781] m, n, and p are each independently an integer selected from 0, 1, 2, 3, 4, 5, or 6; or alternatively, compounds or their pharmaceutically acceptable salts of the following formula:

[0782]

[0783] in:

[0784] R1 is a group in the following formula:

[0785]

[0786] in:

[0787] Y is an aryldimethyl group. (C≤12) heterocyclic alkyl dimethyl (C≤12) Mixed aromatic dimethyl (C≤12) Or a substituted form of any of these groups;

[0788] R9, R 10 and R 11 Each is independently selected from hydrogen and alkyl groups. (C≤8) Substituted alkyl groups (C≤8) 、-Z4A”'R 12 ;in:

[0789] Z4 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0790] A”' is -CHR k -、-C(O)O- or -C(O)NR l -;

[0791] R l It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0792] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0793] R 12 It is an alkyl group (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;and

[0794] x and y are 1, 2, 3 or 4.

[0795] In other embodiments, the compound is further defined as the following or a pharmaceutically acceptable salt thereof:

[0796]

[0797] in:

[0798] R1 is a group in the following formula:

[0799]

[0800] in:

[0801] Y is a heterocyclic alkyl dimethyl group. (C≤12) Or substituted heterocyclic alkyl dimethyl (C≤12) ;

[0802] R9, R 10 and R 11 Each is independently selected from hydrogen and alkyl groups. (C≤8) Substituted alkyl groups (C≤8) 、-Z4A”'R 12 ;in:

[0803] Z4 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0804] A”' is -CHR k -、-C(O)O- or -C(O)NR l -;

[0805] R l It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0806] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0807] R 12 It is an alkyl group (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;and

[0808] x and y are 1, 2, 3 or 4.

[0809] In other embodiments, the compound is further defined as the following or a pharmaceutically acceptable salt thereof:

[0810]

[0811] in:

[0812] R1 is a group in the following formula:

[0813]

[0814] in:

[0815] Y is a heterocyclic alkyl dimethyl group. (C≤12) Or substituted heterocyclic alkyl dimethyl (C≤12) ;

[0816] R9, R 10 and R 11 Each is independently selected from hydrogen, -Z4A”'R 12 ;

[0817] in:

[0818] Z4 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0819] A”' is -CHR k -、-C(O)O- or -C(O)NR l -;

[0820] R l It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0821] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0822] R 12 It is an alkyl group (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;and

[0823] x and y are 1, 2, 3 or 4.

[0824] R2 can be hydrogen. In other embodiments, R2 is an alkyl group. (C≤8) or substituted alkyl (C≤8) R3 can be hydrogen. In other embodiments, R3 is an alkyl group. (C≤8) or substituted alkyl (C≤8) In some embodiments, R3 is an alkyl group. (C≤8) For example, methyl. In some embodiments, R3 is hydrogen. In other embodiments, R4 is an alkyl group. (C≤8)or substituted alkyl (C≤8) R4 can be an alkyl group. (C≤8) For example, methyl.

[0825] 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.

[0826] In some implementations, R1 is a group of the following formula:

[0827] R1 is a group in the following formula:

[0828]

[0829] in:

[0830] R5, R6, and R2 are each independently hydrogen or alkyl. (C≤8) ,-alkyldiyl (C≤6) -NH2, -alkyldiyl (C≤6) -alkylamino (C≤8) ,-alkyldiyl (C≤6) -Dialkylamino (C≤12) ,-alkyldiyl (C≤6) -NR'R" or any of these groups in a substituted form, wherein:

[0831] R' and R” are independently hydrogen and alkyl groups, respectively. (C≤8) Substituted alkyl groups (C≤8) -Z2A'R7; where:

[0832] Z2 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0833] A' is -CHR j -、-C(O)O- or -C(O)NR b -;

[0834] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0835] R j It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;

[0836] R7 is an alkyl group. (C6-24)Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0837] R5, R6, and X1 are each independently -Z3A"R8; where:

[0838] Z3 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0839] A” is -CHR k -、-C(O)O- or -C(O)NR l -;

[0840] R l It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0841] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0842] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;

[0843] q is 1, 2, or 3; and

[0844] r can be 1, 2, 3, or 4.

[0845] In some implementations, R1 is a group of the following formula:

[0846]

[0847] in:

[0848] R5, R6, and X1 are each independently hydrogen or alkyl. (C≤8) ,-alkyldiyl (C≤6) -NH2, -alkyldiyl (C≤6) -alkylamino (C≤8) ,-alkyldiyl (C≤6) -Dialkylamino (C≤12) ,-alkyldiyl (C≤6) -NR'R" or any of these groups in a substituted form, wherein:

[0849] R' and R” are independently hydrogen and alkyl groups, respectively. (C≤8) Substituted alkyl groups (C≤8) -(CH2) sCH(OH)R7、-(CH2) s C(O)OR7 or -(CH2) s C(O)(NR a R7; where:

[0850] s is 1, 2, 3, or 4;

[0851] R a It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0852] R7 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0853] R5, R6, and X1 are each independently -(CH2). t CH(OH)R8、-(CH2) t C(O)OR8、-(CH2) t C(O)(NR b R8; where:

[0854] t is 1, 2, 3, or 4;

[0855] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0856] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;or

[0857] q is 1, 2, or 3; and

[0858] r can be 1, 2, 3, or 4.

[0859] 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 an alkyl group. (C≤8) or substituted alkyl (C≤8) In some implementations, R5 is an alkyl group. (C≤8) For example, methyl or isopropyl.

[0860] In some implementations, R5 is further defined as "-Z3A"R8, where:

[0861] Z3 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0862] A” is -CHR k -、-C(O)O- or -C(O)NR l -;

[0863] R l It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0864] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0865] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) .

[0866] In some implementations, Z3 is an alkyldiyl group. (C1-2) In one instance, Z3 is -CH2-. In some embodiments, Z3 is a substituted alkyldiyl group. (C1-2) In one instance, Z3 is -CH2CH(OH). In some implementations, A” is -CHR. k -. In one instance, R k It is a hydroxyl group. In some embodiments, R k It is an acyl group (C≤24) or substituted acyloxy group (C≤24) In some implementations, R k It is an acyl group (C1-8) or substituted acyloxy group (C1-8) In some implementations, R k It is an acyl group (C≤12-24) or substituted acyloxy group (C≤12-24) In one instance, A” is -C(O)O-. In another instance, A” is -C(O)NH-.

[0867] In some other implementations, R5 is -(CH2). t CH(OH)R8、-(CH2) t C(O)OR8 or -(CH2) t C(O)(NR b R8; where:

[0868] t is 1, 2, 3, or 4;

[0869] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0870] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) .

[0871] In some implementations, R5 is -(CH2). t CH(OH)R8. In some other embodiments, R5 is -(CH2). t C(O)OR8. In some other implementations, R5 is -(CH2). t C(O)(NR b R8. t can be 1 or 2. In some implementations, t is 1. In other implementations, t is 2. In some implementations, R b It is hydrogen. In some other embodiments, R b It is an alkyl group (C≤6) or substituted alkyl (C≤6) , for example alkyl (C6-24) or substituted alkyl (C6-24) .

[0872] In some implementations, R8 is an alkyl group. (C6-24) For example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. In other embodiments, R8 is alkenyl. (C6-24) Or substituted alkenyl (C6-24) In some embodiments, R6 is hydrogen. In other embodiments, R6 is an alkyl group. (C≤8) or substituted alkyl (C≤8) R6 can be an alkyl group. (C≤8) For example, methyl or isopropyl.

[0873] In some implementations, R6 is -Z3A”R8; where:

[0874] Z3 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0875] A” is -CHR k -、-C(O)O- or -C(O)NR l -;

[0876] R l It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0877] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0878] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) .

[0879] In some implementations, Z3 is an alkyldiyl group. (C1-2) In one instance, Z3 is -CH2-. In some embodiments, Z3 is a substituted alkyldiyl group. (C1-2) In one instance, Z3 is -CH2CH(OH). In some implementations, A” is -CHR. k -. In one instance, R k It is a hydroxyl group. In some embodiments, R k It is an acyl group (C≤24) or substituted acyloxy group (C≤24) In some implementations, R k It is an acyl group (C1-8) or substituted acyloxy group (C1-8) In some implementations, R k It is an acyl group (C≤12-24) or substituted acyloxy group (C≤12-24) In one instance, A” is -C(O)O-. In another instance, A” is -C(O)NH-. In some embodiments, R8 is an alkyl group. (C6-24) or substituted alkyl (C6-24) R8 can be an alkyl group. (C6-24) For example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. In some embodiments, R8 is alkenyl. (C6-24) Or substituted alkenyl (C6-24) .

[0880] In other implementations, R6 is -(CH2). t CH(OH)R8、-(CH2) t C(O)OR8 or -(CH2) t C(O)(NR b R8; where:

[0881] t is 1, 2, 3, or 4;

[0882] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0883] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) .

[0884] In some implementations, R6 is -(CH2). t CH(OH)R8. In some other embodiments, R6 is -(CH2). t C(O)OR8. In some other implementations, R6 is -(CH2). t C(O)(NR b R8. In some implementations, t is 1 or 2. In some implementations, t is 1. In other implementations, t is 2. In some implementations, R b It is hydrogen. In some other embodiments, R b It is an alkyl group (C≤6) or substituted alkyl (C≤6) R8 can be an alkyl group. (C6-24) or substituted alkyl (C6-24) In some embodiments, R8 is an alkyl group. (C6-24) For example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. In other embodiments, R8 is alkenyl. (C6-24) Or substituted alkenyl (C6-24) .

[0885] In some implementations, R6 is an alkyldiyl group. (C≤6) -NH2, -alkyldiyl (C≤6) -alkylamino (C≤8) ,-alkyldiyl (C≤6) -Dialkylamino (C≤12) Or a substituted form of any of these groups. In some embodiments, R6 is an alkyldiyl group. (C≤6) -NH2 or a substituted form of the group, such as -CH2CH2NH2. In other embodiments, R6 is an alkyldiyl group. (C≤6) -alkylamino (C≤8) Or a substituted form of the group, such as -CH2CH2NHMe or -CH2CH2NHiPr. In other embodiments, R6 is an alkyldiyl group. (C≤6) -Dialkylamino (C≤8) Or the substituted form of the group.

[0886] In some embodiments, R2 is hydrogen. In other embodiments, R2 is an alkyl group. (C≤8) or substituted alkyl (C≤8) In some embodiments, R2 is an alkyl group. (C≤8)For example, methyl or isopropyl. In some embodiments, R2 is -Z3A”R8; wherein:

[0887] Z3 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0888] A” is -CHR k -、-C(O)O- or -C(O)NR l -;

[0889] R l It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0890] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0891] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) .

[0892] In some implementations, Z3 is an alkyldiyl group. (C1-2) In one instance, Z3 is -CH2-. In some embodiments, Z3 is a substituted alkyldiyl group. (C1-2) In one instance, Z3 is -CH2CH(OH). In some implementations, A” is -CHR. k -. In one instance, R k It is a hydroxyl group. In some embodiments, R k It is an acyl group (C≤24) or substituted acyloxy group (C≤24) In some implementations, R k It is an acyl group (C1-8) or substituted acyloxy group (C1-8) In some implementations, R k It is an acyl group (C≤12-24) or substituted acyloxy group (C≤12-24) In one instance, A” is -C(O)O-. In another instance, A” is -C(O)NH-. In some embodiments, R8 is an alkyl group. (C6-24) or substituted alkyl (C6-24) R8 can be an alkyl group. (C6-24) For example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. In some embodiments, R8 is alkenyl. (C6-24) Or substituted alkenyl (C6-24) .

[0893] In other implementations, R2 is -(CH2). t CH(OH)R8、-(CH2) t C(O)OR8 or -(CH2) t C(O)(NR b R8; where:

[0894] t is 1, 2, 3, or 4;

[0895] R b It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0896] R8 is an alkyl group. (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) .

[0897] In some implementations, R2 is -(CH2). t CH(OH)R8. In other embodiments, R2 is -(CH2). t C(O)OR8. In other implementations, R2 is -(CH2). t C(O)(NR b R8. t can be 1 or 2. In some implementations, t is 1. In other implementations, t is 2. In some implementations, R b It is hydrogen. In some other embodiments, R b It is an alkyl group (C≤6) or substituted alkyl (C≤6) R8 can be an alkyl group. (C6-24) or substituted alkyl (C6-24) In some embodiments, R8 is an alkyl group. (C6-24) For example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. In some embodiments, R8 is alkenyl. (C6-24) Or substituted alkenyl (C6-24) .

[0898] In other embodiments, R2 is an alkyldiyl group. (C≤6) -NH2, -alkyldiyl (C≤6) -alkylamino (C≤8) ,-alkyldiyl (C≤6) -Dialkylamino (C≤12) Or a substituted form of any of these groups. In some embodiments, R2 is an alkyldiyl group. (C≤6)-NH2 or a substituted form of the group, such as -CH2CH2NH2. In other embodiments, R2 is an alkyldiyl group. (C≤6) -alkylamino (C≤8) Or a substituted form of the group, such as -CH2CH2NHMe or -CH2CH2NHiPr. In other embodiments, R2 is an alkyldiyl group. (C≤6) -Dialkylamino (C≤8) Or the substituted form of the group.

[0899] In other respects, R1 is a group of the following formula:

[0900]

[0901] in:

[0902] Y is an aryldimethyl group. (C≤12) heterocyclic alkyl dimethyl (C≤12) Mixed aromatic dimethyl (C≤12) Or a substituted form of any of these groups;

[0903] R9, R 10 and R 11 Each is independently selected from hydrogen and alkyl groups. (C≤8) Substituted alkyl groups (C≤8) -(CH2) u CH(OH)R 12 -(CH2) u C(O)OR 12 -(CH2) u C(O)(NR c )R 12 ;

[0904] in:

[0905] u is 1, 2, 3 or 4;

[0906] R c It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0907] R 12 It is an alkyl group (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;and

[0908] x and y are 1, 2, 3 or 4.

[0909] In other respects, R1 is a group of the following formula:

[0910]

[0911] in:

[0912] Y2 is an aryldimethyl group. (C≤12) heterocyclic alkyl dimethyl (C≤12) Mixed aromatic dimethyl (C≤12) Alkoxydiyl (C≤12) Or a substituted form of any of these groups;

[0913] R9, R 10 and R 11 Each is independently selected from hydrogen and alkyl groups. (C≤8) Substituted alkyl groups (C≤8) or -Z4A”'R 12 ;in:

[0914] Z4 is an alkyldiyl group. (C≤4) Or substituted alkyl diols (C≤4) ;

[0915] A”' is -CHR k -、-C(O)O- or -C(O)NR l -;

[0916] R l It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0917] R k It is hydrogen, halogen, hydroxyl, acyloxy (C≤24) or substituted acyloxy group (C≤24) ;and

[0918] R 12 It is an alkyl group (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) ;and

[0919] x and y are 1, 2, 3 or 4.

[0920] In some implementations, Y is a heterocyclic alkyl dimethyl group. (C≤12) Or substituted heterocyclic alkyl dimethyl (C≤12) In some implementations, Y is a heterocyclic alkyl dimethyl group. (C≤12) For example, piperazine dimethyl. In other embodiments, Y is a heteroaryl dimethyl group. (C≤12) Or substituted heteroaryl (C≤12) In other embodiments, Y is an aryldiyl group. (C≤12) Or substituted aryl diol (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.

[0921] In one implementation, R9 is -(CH2). u CH(OH)R 12 -(CH2) u C(O)OR 12 -(CH2) u C(O)(NR c )R 12 ;in:

[0922] u is 1, 2, 3 or 4;

[0923] R c It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0924] R 12 It is an alkyl group (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) .

[0925] In some implementations, R9 is -(CH2). u CH(OH)R 12 In other implementations, R9 is -(CH2). u C(O)OR 12 In some implementations, R9 is -(CH2). u C(O)(NR c )R 12 u can be 1, 2, or 3. In some implementations, u is 1 or 2. In one implementation, u is 1. In another implementation, u is 2. In some implementations, R c It is hydrogen. In some other embodiments, R c It is an alkyl group (C≤6) or substituted alkyl (C≤6) R 12 It can be an alkyl group (C6-24) or substituted alkyl (C6-24) In some implementations, R 12 It is an alkyl group (C6-24) For example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. In other embodiments, R 12 It is an alkenyl group (C6-24) Or substituted alkenyl(C6-24) .

[0926] In some implementation schemes, R 10 It is -(CH2) u CH(OH)R 12 -(CH2) u C(O)OR 12 -(CH2) u C(O)(NR c )R 12 ;in:

[0927] u is 1, 2, 3 or 4;

[0928] R c It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0929] R 12 It is an alkyl group (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) .

[0930] In some implementation schemes, R 10 It is -(CH2) u CH(OH)R 12 In other implementations, R 10 It is -(CH2) u C(O)OR 12 In other implementations, R 10 It is -(CH2) u C(O)(NR c )R 12 u can be 1, 2, or 3. In some implementations, u is 1 or 2. In one implementation, u is 1. In another implementation, u is 2. In some implementations, R c It is hydrogen. In some other embodiments, R c It is an alkyl group (C≤6) or substituted alkyl (C≤6) R 12 It can be an alkyl group (C6-24) or substituted alkyl (C6-24) In some implementations, R 12 It is an alkyl group (C6-24) For example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. In other embodiments, R 12 It is an alkenyl group (C6-24) Or substituted alkenyl (C6-24) .

[0931] In some implementation schemes, R 11 It is -(CH2) u CH(OH)R 12 -(CH2) u C(O)OR 12 -(CH2) u C(O)(NR c )R 12 ;in:

[0932] u is 1, 2, 3 or 4;

[0933] R c It is hydrogen, alkyl (C≤6) or substituted alkyl (C≤6) ;and

[0934] R 12 It is an alkyl group (C6-24) Substituted alkyl groups (C6-24) alkenyl (C6-24) Substituted alkenyl groups (C6-24) .

[0935] In some implementation schemes, R 11 It is -(CH2) u CH(OH)R 12 In other implementations, -(CH2) u C(O)OR 12 In other implementations, R 11 It is -(CH2) u C(O)(NR c )R 12 u can be 1, 2, or 3. In some implementations, u is 1 or 2. In one implementation, u is 1. In another implementation, u is 2. In some implementations, R c It is hydrogen. In some other embodiments, R c It is an alkyl group (C≤6) or substituted alkyl (C≤6) R 12 It can be an alkyl group (C6-24) or substituted alkyl (C6-24) In some implementations, R 12 It is an alkyl group (C6-24) For example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. In other embodiments, R 12 It is an alkenyl group (C6-24) Or substituted alkenyl (C6-24) .

[0936] In other embodiments, the compound is further defined as the following or a pharmaceutically acceptable salt thereof:

[0937]

[0938] in:

[0939] R1, R2, and R3 are each independently hydrogen or alkyl. (C≤6) Substituted alkyl groups (C≤6) Or the following groups:

[0940]

[0941] in:

[0942] R7 and R8 are independently hydrogen and alkyl groups, respectively. (C≤6) Substituted alkyl groups (C≤6) Or the following groups:

[0943]

[0944] in:

[0945] R9 is hydrogen, halogen, hydroxyl, or alkoxy. (C≤8) acyloxy (C≤8) Or the substituted form of any of these groups; and

[0946] R 10 It is an alkyl group (C≤24) alkenyl (C≤24) Or a substituted form of either of these two groups;

[0947] q is 1, 2, or 3; and

[0948] r is 0, 1, 2, 3 or 4;

[0949] R5 and R6 are independently hydrogen and alkyl groups, respectively. (C≤6) or substituted alkyl (C≤6) ;and

[0950] m and n are each independently 1, 2, 3, 4 or 5.

[0951] In some embodiments, the compound is further defined as the following or a pharmaceutically acceptable salt thereof:

[0952]

[0953] in:

[0954] R1, R2, and R3 are each independently hydrogen or alkyl. (C≤6) Substituted alkyl groups (C≤6) Or the following groups:

[0955]

[0956] in:

[0957] R7 and R8 are independently hydrogen and alkyl groups, respectively. (C≤6) Substituted alkyl groups (C≤6) Or the following groups:

[0958]

[0959] in:

[0960] R9 is hydrogen, halogen, hydroxyl, or alkoxy. (C≤8) acyloxy (C≤8) Or the substituted form of any of these groups; and

[0961] R 10 It is an alkyl group (C≤24) alkenyl (C≤24) Or a substituted form of either of these two groups;

[0962] q is 1, 2, or 3; and

[0963] r is 0, 1, 2, 3 or 4;

[0964] R5 and R6 are independently hydrogen and alkyl groups, respectively. (C≤6) or substituted alkyl (C≤6) ;and

[0965] m can be 1, 2, 3, 4, or 5.

[0966] In some implementations, R2 is hydrogen. R2 may be an alkyl group. (C≤6) or substituted alkyl (C≤6) In some embodiments, R2 is an alkyl group. (C≤6) For example, methyl or ethyl. In other embodiments, R2 is a group of the following formula:

[0967]

[0968] in:

[0969] R7 and R8 are independently hydrogen and alkyl groups, respectively. (C≤6) Substituted alkyl groups (C≤6) Or the following groups:

[0970]

[0971] in:

[0972] R9 is hydrogen, halogen, hydroxyl, or alkoxy. (C≤8) acyloxy (C≤8) Or the substituted form of any of these groups; and

[0973] R 10 It is an alkyl group (C≤24) alkenyl (C≤24) Or a substituted form of either of these two groups;

[0974] q is 1, 2, or 3; and

[0975] r can be 0, 1, 2, 3, or 4.

[0976] In some embodiments, R7 is hydrogen. In other embodiments, R7 is an alkyl group. (C≤6) or substituted alkyl (C≤6) R7 can be an alkyl group. (C≤6) For example, methyl or ethyl. In other embodiments, R7 is...

[0977] in:

[0978] R9 is hydrogen, halogen, hydroxyl, or alkoxy. (C≤8) acyloxy (C≤8) Or the substituted form of any of these groups; and

[0979] R 10 It is an alkyl group (C≤24) alkenyl (C≤24) Or a substituted form of either of these two groups.

[0980] In some embodiments, R9 is a halogen, such as chlorine or bromine. In other embodiments, R9 is a hydroxyl group. In still other embodiments, R9 is an alkoxy group. (C≤8) or substituted alkoxy (C≤ 8 ) R9 can be an alkoxy group. (C≤8) For example, a methoxy group. In other embodiments, R9 is an acyloxy group. (C≤8) or substituted acyloxy group (C≤8) R9 can be an acyl group. (C≤8) For example, acetoxy or neopentanoyloxy. In other embodiments, R 10 It is an alkyl group (C≤24) or substituted alkyl (C≤24) For example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. In other embodiments, R 10 It is an alkenyl group (C≤24) Or substituted alkenyl (C≤24) .

[0981] In some embodiments, R8 is hydrogen. In other embodiments, R8 is an alkyl group. (C≤6) or substituted alkyl (C≤6) R8 can be an alkyl group. (C≤6)For example, methyl or ethyl. In other embodiments, R8 is...

[0982] in:

[0983] R9 is hydrogen, halogen, hydroxyl, or alkoxy. (C≤8) acyloxy (C≤8) Or the substituted form of any of these groups; and

[0984] R 10 It is an alkyl group (C≤24) alkenyl (C≤24) Or a substituted form of either of these two groups.

[0985] In some embodiments, R9 is a halogen, such as chlorine or bromine. In other embodiments, R9 is a hydroxyl group. In still other embodiments, R9 is an alkoxy group. (C≤8) or substituted alkoxy (C≤8) R9 can be an alkoxy group. (C≤8) For example, a methoxy group. In other embodiments, R9 is an acyloxy group. (C≤8) or substituted acyloxy group (C≤8) R9 can be an acyl group. (C≤8) For example, acetoxy or neopentanoyloxy. In other embodiments, R 10 It is an alkyl group (C≤24) or substituted alkyl (C≤24) For example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. In other embodiments, R 10 It is an alkenyl group (C≤24) Or substituted alkenyl (C≤24) .

[0986] 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 an alkyl group. (C≤6) or substituted alkyl (C≤6) R3 can be an alkyl group. (C≤6) For example, methyl or ethyl.

[0987] In some embodiments, R4 is hydrogen. In other embodiments, R4 is an alkyl group. (C≤6) or substituted alkyl (C≤6) In some embodiments, R5 is hydrogen. In other embodiments, R5 is an alkyl group. (C≤6) or substituted alkyl (C≤6) R5 can be an alkyl group.(C≤6) For example, methyl or ethyl. In some embodiments, R6 is hydrogen. In other embodiments, R6 is an alkyl group. (C≤6) or substituted alkyl (C≤6) R6 can be an alkyl group. (C≤6) For example, methyl or ethyl. In some embodiments, m is 2, 3, or 4. In some embodiments, m is 2. In some embodiments, n is 3.

[0988] In some embodiments, R1 is hydrogen. In other embodiments, R1 is an alkyl group. (C≤6) or substituted alkyl (C≤6) R1 can be an alkyl group. (C≤6) For example, methyl or ethyl. In other embodiments, R1 is a group of the following formula:

[0989]

[0990] in:

[0991] R7 and R8 are independently hydrogen and alkyl groups, respectively. (C≤6) Substituted alkyl groups (C≤6) Or the following groups:

[0992]

[0993] in:

[0994] R9 is hydrogen, halogen, hydroxyl, or alkoxy. (C≤8) acyloxy (C≤8) Or the substituted form of any of these groups; and

[0995] R 10 It is an alkyl group (C≤24) alkenyl (C≤24) Or a substituted form of either of these two groups;

[0996] q is 1, 2, or 3; and

[0997] r can be 0, 1, 2, 3, or 4.

[0998] In some embodiments, R7 is hydrogen. In other embodiments, R7 is an alkyl group. (C≤6) or substituted alkyl (C≤6) R7 can be an alkyl group. (C≤6) For example, methyl or ethyl. In other embodiments, R7 is...

[0999] in:

[1000] R9 is hydrogen, halogen, hydroxyl, or alkoxy. (C≤8) acyloxy(C≤8) Or the substituted form of any of these groups; and

[1001] R 10 It is an alkyl group (C≤24) alkenyl (C≤24) Or a substituted form of either of these two groups.

[1002] In some embodiments, R9 is a halogen, such as chlorine or bromine. In other embodiments, R9 is a hydroxyl group. In still other embodiments, R9 is an alkoxy group. (C≤8) or substituted alkoxy (C≤8) R9 can be an alkoxy group. (C≤8) For example, a methoxy group. In other embodiments, R9 is an acyloxy group. (C≤8) or substituted acyloxy group (C≤8) R9 can be an acyl group. (C≤8) For example, acetoxy or neopentanoyloxy. In other embodiments, R 10 It is an alkyl group (C≤24) or substituted alkyl (C≤24) For example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. In other embodiments, R 10 It is an alkenyl group (C≤24) Or substituted alkenyl (C≤24) .

[1003] In some embodiments, R8 is hydrogen. In other embodiments, R8 is an alkyl group. (C≤ 6 ) or substituted alkyl (C≤6) R8 can be an alkyl group. (C≤6) For example, methyl or ethyl. In other embodiments, R8 is...

[1004] in:

[1005] R9 is hydrogen, halogen, hydroxyl, or alkoxy. (C≤8) acyloxy (C≤8) Or the substituted form of any of these groups; and

[1006] R 10 It is an alkyl group (C≤24) alkenyl (C≤24) Or a substituted form of either of these two groups.

[1007] In some embodiments, R9 is a halogen, such as chlorine or bromine. In other embodiments, R9 is a hydroxyl group. In still other embodiments, R9 is an alkoxy group. (C≤8) or substituted alkoxy (C≤8) R9 can be an alkoxy group. (C≤8)For example, a methoxy group. In other embodiments, R9 is an acyloxy group. (C≤8) or substituted acyloxy group (C≤8) R9 can be an acyl group. (C≤8) For example, acetoxy or neopentanoyloxy. In other embodiments, R 10 It is an alkyl group (C≤24) or substituted alkyl (C≤24) For example, octyl, decyl, dodecyl, tetradecyl, hexadecyl, or octadecyl. In other embodiments, R 10 It is an alkenyl group (C≤24) Or substituted alkenyl (C≤24) .

[1008] In some implementations, q is 1 or 2. In some implementations, q is 1. In other implementations, q is 2. In some implementations, r is 1, 2, or 3. In some implementations, r is 1. In other implementations, r is 2. In other implementations, r is 3.

[1009] In some embodiments, the tRNA is unmodified tRNA. In other embodiments, the tRNA is modified tRNA. In some embodiments, the tRNA is a repressive tRNA. In some embodiments, the tRNA is a tRNA that delivers amino acids into a protein rather than terminating translation. In some embodiments, the tRNA is an amber suppressor. In other embodiments, the tRNA is an opal suppressor. In other embodiments, the tRNA is an ochre suppressor. In some embodiments, the tRNA is a frameshift suppressor. tRNA, such as tRNA arg / op It can be used to add arginine residues to growing peptides.

[1010] In some embodiments, the composition further comprises a steroid or a 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 phosphatidylcholine. In other embodiments, the phospholipid is distearylphosphatidylcholine. In some embodiments, the composition further comprises a PEG lipid. In some embodiments, the PEG lipid is a PEGylated diacylglycerol, such as a PEGylated dimyristoyl-sn-glycerol. In other embodiments, the PEG lipid is:

[1011]

[1012] in:

[1013] n1 is an integer from 1 to 250; and

[1014] 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.

[1015] In some implementations, n1 is 5 to 100. In some implementations, n1 is 45. In some implementations, n2 is 11, 12, 13, 14, 15, 16, or 17. In some implementations, n2 is 15. In some implementations, n3 is 11, 12, 13, 14, 15, 16, or 17. In some implementations, n3 is 15.

[1016] In some embodiments, the molar ratio of the compound to nucleic acid in the composition is from about 5:1 to about 1000:1. In some embodiments, the molar ratio of the compound to nucleic acid is from about 100:1 to about 1000:1. In some embodiments, the molar ratio is from about 166:1. In other embodiments, the molar ratio is from about 250:1 to about 750:1. In some embodiments, the ratio of the compound to steroid or steroid derivative in the composition is from about 1:1 to about 20:1, for example from about 1:1 to about 6:1. In some embodiments, the ratio of the compound to phospholipid in the composition is from about 1:1 to about 9:1, for example from about 2.5:1 to about 7.5:1. In some embodiments, the ratio of the compound to PEG-lipid in the composition is from about 2.5:1 to about 100:1, for example from about 7.5:1 to about 50:1.

[1017] In some embodiments, the tRNA is 5′-GGCCGCGTGGCCTAATGGAtAAGGCGTCTGACTTCAGATCAGAAGAtTGCAGGTTCGAGTCCTGCCGCGGTCGCCA-3′ (SEQ ID NO: 1). In other embodiments, the tRNA is:

[1018] 5′-GGCCGCGGGCCUAAUGGAUAAGGCGUCUGACUUCAGAUCAGAAGAUUGCAGGUUCGAGUCCUGCCGCGGUCGCCA-3′ (SEQ ID NO: 2);

[1019] 5′-GGCCUCGUGGCGCAACGGUAGCGCGUCUGACUUCAGAUCAGAAGGUUGCGUGUUCAAAUCACGUCGGGGUCACCA-3′(SEQ ID NO:3);

[1020] 5′-GCGUUGGUGGUAUAGUGGUUAGCAUAGCUGCCUUCAAAGCAGUUGACCCGGGUUCGAUUCCCGGCCAACGCACCA-3′(SEQ ID NO:4);

[1021] 5′-GCAGCGAUGGCCGAGUGGUUAAGGCGUUGGACUUCAAAUCCAAUGGGGUCUCCCCGCGCAGGUUCGAACCCUGCUCGCUGCGCCA-3′(SEQ ID NO:5);

[1022] 5′-GGUCCCAUGGUGUAAUGGUUAGCACUCUGGACUUUAAAUCCAGCGAUCCGAGUUCAAAUCUCGGUGGGACCUCCA-3′(SEQ ID NO:6);

[1023] 5′-GCCCGGAUAGCUCAGUCGGUAGAGCAUCAGACUUUAAAUCUGAGGGUCCAGGGUUCAAGUCCCUGUUCGGGCGCCA-3′(SEQ ID NO:7);

[1024] 5′-ACCAGGAUGGCCGAGUGGUUAAGGCGUUGGACUUUAGAUCCAAUGGACAUAUGUCCGCGUGGGUUCGAACCCCACUCCUGGUACCA-3′(SEQ ID NO:8);

[1025] 5′-GCCCGGCUAGCUCAGUCGGUAGAGCAUGGGACUCUAAAUCCCAGGGUCGUGGGUUCGAGCCCCACGUUGGGCGCCA-3′(SEQ ID NO:9);

[1026] 5′-UCCCUGGUGGUCUAGUGGUUAGGAUUCGGCGCUAUCACCGCCGCGGCCCGGGUUCGAUUCCCGGUCAGGGAACCA-3′(SEQ ID NO:10);

[1027] 5′-UCCCUGGUGGUCUAGUGGUUAGGAUUCGGCGCUAUCACCGCCGCGGCCCGGGUUCGAUUCCCGGUCAGGGAACCA-3′(SEQ ID NO:11);

[1028] 5′-GUCAGGAUGGCCGAGUGGUCUAAGGCGCCAGACUCUAGUUCUGGUCUCCGUAUGGAGGCGUGGGUUCGAAUCCCACUUCUGACACCA-3′(SEQ ID NO:12);

[1029] 5′-ACCAGGAUGGCCGAGUGGUUAAGGCGUUGGACUUCAGAUCCAAUGGACAUAUGUCCGCGUGGGUUCGAACCCCACUCCUGGUACCA-3′(SEQ ID NO:13);

[1030] 5′-CCUUCAAUAGUUCAGCUGGUAGAGCAGAGGACUCUAGGUCCUUAGGUUGCUGGUUCGAUUCCAGCUUGAAGGACCA-3′(SEQ ID NO:14);

[1031] 5′-CCUUCAAUAGUUCAGCUGGUAGAGCAGAGGACUUUAGGUCCUUAGGUUGCUGGUUCGAUUCCAGCUUGAAGGACCA-3′(SEQ ID NO:15);

[1032] 5′-GGCCUCGUGGCGCAACGGUAGCGCGUCUGACUCUAGAUCAGAAGGUUGCGUGUUCAAAUCACGUCGGGGUCACCA-3′(SEQ ID NO:16);

[1033] 5′-GCUGUGAUGGCCGAGUGGUUAAGGCGUUGGACUCGAAAUCCAAUGGGGUCUCCCCGCGCAGGUUCGAAUCCUGCUCACAGCGCCA-3′(SEQ ID NO:17);

[1034] 5′-GCAGCGAUGGCCGAGUGGUUAAGGCGUUGGACUUUAAAUCCAAUGGGGUCUCCCCGCGCAGGUUCGAACCCUGCUCGCUGCGCCA-3′(SEQ ID NO:18);

[1035] 5'-GCGUUGGUGGUAUAGUGGUGAGCAUAGCUGCCUUCAAAGCAGUUGACCCGGGUUCGAUUCCCGGCCAACGCACCA-3' (SEQ ID NO: 19); or

[1036] 5'-GCGUUGGUGGUAUAGUGGUAAGCAUAGCUGCCUUCAAAGCAGUUGACCCGGGUUCGAUUCCCGGCCAACGCACCA-3' (SEQ ID NO: 20).

[1037] In some implementations, tRNA corrects nonsense mutations in the cystic fibrosis transmembrane conductance regulator protein.

[1038] On the other hand, this disclosure provides pharmaceutical compositions comprising:

[1039] (A) The compositions described herein; and

[1040] (B) Excipients.

[1041] In some embodiments, the pharmaceutical composition is formulated for administration via: oral, intraadiposally, intraarticular, intra-articular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intracardiac, intraperitoneal, intrapleural, intraprostatic, intrarectal, intrasheath, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intracystic, intravitreal, via liposomes, locally, via mucosa, parenteral, rectal, subconjunctival, subcutaneous, sublingual, superficial, transbuccally, percutaneously, via vagina, via cream, in lipid composition, through catheter, via irrigation, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via local perfusion. In some embodiments, the pharmaceutical composition is formulated for administration by injection. In some embodiments, the pharmaceutical composition is formulated as a unit dose.

[1042] On the other hand, this disclosure provides a method of treating a disease or condition in a patient, comprising administering a therapeutically effective amount of the composition described herein to a patient in need. In some embodiments, the disease or condition is a hereditary disease or condition. In some embodiments, the hereditary disease or condition is cystic fibrosis. In some embodiments, the gene for the cystic fibrosis transmembrane conductance protein (CFTR) has a nonsense mutation. In some embodiments, the method causes a 25% increase in CFTR activity. In some embodiments, the method further includes administering a second cystic fibrosis treatment.

[1043] In other implementations, the hereditary disease or condition is Duchenemuscular dystrophy (DMD), congenital glycosylation disorder, Dravet syndrome, mucopolysaccharidosis I (MPS I), NGLY1 deficiency (N-glycanase deficiency), Rett syndrome, or cancer.

[1044] In some implementations, the disease or symptom is cancer. In some implementations, the cancer is carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma. In some implementations, the cancer is bladder cancer, leukemia, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genital cancer, genitourinary tract cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosal cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, stomach cancer, testicular cancer, or thyroid cancer. In some implementations, the cancer is lung cancer or colorectal cancer. In some implementations, lung cancer has a nonsense mutation in the p53 gene. In other implementations, colorectal cancer has a nonsense mutation in the APC gene. In some embodiments, the cancer comprises a gene mutation in one or more tumor suppressor proteins (e.g., p53, APC, LKB1, ERCC3, WRN, BRCA2, IDH1, or ARID1A). In some embodiments, the cancer is liver cancer, such as hepatocellular carcinoma (HCC) of hepatitis B origin.

[1045] In some embodiments, the method further includes administering a second cancer treatment, 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.

[1046] As used herein, a noun without a quantifier may mean one or more kinds. As used herein in the claims, a noun without a quantifier, when used in conjunction with the word "comprising," may mean one or more kinds.

[1047] The term “or” as used in the claims is intended to mean “and / or” unless explicitly stated otherwise, referring only to alternatives or the alternatives are mutually exclusive; however, this disclosure supports the definition of referring only to alternatives and “and / or”. As used herein, “another” may mean at least a second or more.

[1048] Throughout this application, the term “about / approximately” is used to indicate a value that includes inherent variations in the error of the method or apparatus used to determine the value, or variations that exist between the subjects under study.

[1049] Other objects, features, and advantages of this disclosure will become apparent from the following detailed description. However, it should be understood that while the detailed description and specific examples point to some preferred embodiments of this disclosure, they are given by way of example only, as numerous variations and modifications within the spirit and scope of this disclosure will be apparent to those skilled in the art from this detailed description. Attached Figure Description

[1050] The following figures form part of this specification and are included to further illustrate certain aspects of this disclosure. A better understanding of this disclosure can be achieved by referring to one or more of these figures in conjunction with the detailed description of the specific embodiments given herein.

[1051] Figure 1 A schematic diagram of the results of nonsense mutations is shown.

[1052] Figures 2A to 2C It shows ( Figure 2A Western blot analysis of CFTR mutations was performed in 293 cells 72 hours after transfection. G418 and PTC124 were added 24 hours after transfection. Figure 2B Western blot analysis of CFTR in IB3-1 cells after 48 hours of increasing concentrations of PTC124 and G418 is shown. Calu-3 cells were used as an antibody control. Figure 2CA schematic diagram illustrating the effect of a read-through agent on nonsense mutations is shown.

[1053] Figure 3A and 3B It shows ( Figure 3A Western blot analysis of CFTR mutants 48 hours after transfection in 293 cells. Figure 3B The results of transepithelial resistance measurements of a single layer of FRT across transient transfection are shown using a TECC 24 (EP Devices) after the addition of the specified compound.

[1054] Figure 4A and 4B It shows ( Figure 4A Representative single-channel recordings of wild-type (WT) and W1282L-CFTR cells from inside-out membrane patches excised from transiently transfected CHO cells. ATP (1 mM) and PKA (75 nM) were persistently present in the intracellular solution. Dotted lines represent closed channel states, with downward deflection corresponding to channel opening. The bar charts below show the single-channel current amplitude (i), single-channel slope conductance (γ), and opening probability (P) of WT and W1282L-CFTR cells. o Data are represented as mean ± SEM (n > 3); * > 0.05 relative to WT. Figure 4B Representative records demonstrating the effects of VX-770 (0.05, 0.2, and 1 μM) on the single-channel activity of W1282L-CFTR in inverted outer membrane flaps excised from CHO cells are shown. ATP (1 mM) and PKA (75 nM) were persistently present in the intracellular solution.

[1055] Figures 5A to 5C It shows ( Figure 5A Western blot analysis of CFTR mutants after 48 hours of transfection with the specified plasmid in 293 cells. Figure 5B This demonstrates the expression of Sup-tRNA using LiCOR Image Studio software. Arg Then, the full-length CFTR was quantified relative to the WT CFTR level normalized. Figure 5C Representative whole-cell current records from 293 cells transfected with the specified plasmid under basal and flow stimulation conditions are shown.

[1056] Figures 6A to 6C It shows ( Figure 6A This image shows a representative image of fluorescently labeled tRNA delivered by nanoparticles in HeLa cells 24 hours after exposure. Figure 6BWestern blot analysis of nmP53(R196X) rescued by the specified carrier after 48 hours of exposure in Calu6 cells is shown. Figure 6C A schematic diagram showing the result of nonsense mutations after delivery of modified tRNA is shown.

[1057] Figure 7 The fractions of tRNA binding for various nanoparticle compositions are shown.

[1058] Figure 8 The particle size and polydispersity index of various nanoparticle compositions are shown.

[1059] Figure 9 The amount of p53 rescued by various nanoparticle compositions was shown by Western blot analysis.

[1060] Figure 10 The results showed that composition RCT-Z100 induced p53 expression events at half dose. Compared with RCT-Z100, both G418 and PTC124 showed only extremely low p53 expression.

[1061] Figure 11 As observed by fluorescence microscopy, RCT-Z100 nanoparticles were readily taken up into Calu6 cells after incubation.

[1062] Figure 12 The results showed that zwitterionic aminolipids and cationic sulfonamide aminolipids could deliver repressive tRNA and thus restore p53 expression.

[1063] Figure 13 Results of luciferase response assays and viability of cells treated with nanoparticles containing tRNA are shown. The nanoparticles were prepared using artificial mixing or microfluidic mixing and dilution or expansion.

[1064] Figure 14 The components of ZAL used in these studies are shown.

[1065] Figure 15 The components of CSAL used in these studies are shown. Detailed Implementation

[1066] In some aspects, this disclosure provides compositions comprising tRNA, modified tRNA, or tRNA derivatives, and aminolipid delivery compounds that facilitate the delivery of tRNA to cells. These compositions can be administered to patients to correct nonsense mutations in their genome. Therefore, in some embodiments, said compositions can be administered to treat hereditary conditions, such as, but not limited to, cystic fibrosis, cancer, or Dechené muscular dystrophy.

[1067] I. Aminolipid delivery compounds

[1068] In some aspects, this disclosure provides compositions comprising aminolipid delivery compounds. An aminolipid delivery compound is a compound 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 compound may be a dendritic polymer (also known as a dendrite or dendritic lipid). In other embodiments, the aminolipid delivery compound is a polymer having a positively charged amine group and one or more hydrophobic components. In some embodiments, the polymer may be biodegradable. Some non-limiting examples of polymers that can be used in the composition include polyamides and polyesters. In other embodiments, the aminolipid delivery compound is a zwitterionic compound having a negatively charged group, a positively charged amine group, and one or more hydrophobic components. Some non-limiting examples of potentially negatively charged groups that may be included in the compositions of the present invention include sulfonic acids, phosphorous acids, or carboxylic acids. In some embodiments, the negatively charged group is a sulfonic acid. In another embodiment, the aminolipid delivery compound 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 ammonium functional group, and one or more lipid components.

[1069] In some embodiments, this disclosure relates to compounds, such as the polyesters in Table 1 and the dendritic polymers in Table 2. In the polyesters, the number of repeating units is measured based on the average molecular weight of the compound. More information about these compounds can be found in Yan et al., 2016. Further details regarding the aminolipid components can be found in WO 2016 / 094342, WO2017 / 048789 and International Application No. PCT / US2017 / 032950, ​​the entire contents of which are incorporated herein by reference. Additional structures include those using... Figure 14 and 15 The zwitterionic and cationic compositions prepared from the components described herein.

[1070]

[1071]

[1072]

[1073]

[1074]

[1075]

[1076]

[1077]

[1078]

[1079]

[1080]

[1081]

[1082]

[1083]

[1084]

[1085] The aminolipid delivery compounds provided in this disclosure are illustrated, for example, in the above Summary of the Invention section and the appended claims. They can be prepared using the methods outlined in the Examples section. These methods can be further improved and optimized using principles and techniques of organic chemistry applicable to those skilled in the art. Such principles and techniques are taught, for example, in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (2007), which is incorporated herein by reference.

[1086] The compounds described herein may contain one or more asymmetrically substituted carbon or nitrogen atoms and may be separable in optically active or racemic forms. Therefore, all chiral, diastereomeric, racemic, epimeric, and geometrical isomer forms of the chemical formula are contemplated unless a specific stereochemical or isomeric form is explicitly specified. The compounds may exist as racemates and mixtures of racemates, as single enantiomers, mixtures of diastereomers, and as single diastereomers. In some embodiments, a single diastereomer is obtained. The chiral center of the compounds of this disclosure may have an S or R configuration.

[1087] The chemical formulas used to represent aminolipid delivery compounds of this disclosure typically show only one of several possible tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and whichever is most prevalent, all tautomers of a given chemical formula are contemplated.

[1088] Whether used for the indications described herein or otherwise, the compounds of this disclosure may have the following advantages over compounds known in the prior art: they may be more effective, less toxic, have a longer duration of action, be more potent, produce fewer side effects, be more easily absorbed, and / or have better pharmacokinetic characteristics (e.g., higher oral bioavailability and / or lower clearance), and / or have other available pharmacological, physical or chemical properties.

[1089] Furthermore, the atoms constituting the compounds of this disclosure are intended to include all isotopic forms of these atoms. As used herein, an isotope includes those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include... 13 C and 14 C.

[1090] It should be recognized that the specific anion or cation forming part of any salt form of the compounds provided herein is not critical, provided that the salt as a whole is pharmacologically acceptable. Further examples of pharmaceutically usable salts and their preparation and use are shown in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.

[1091] II. tRNA

[1092] In some aspects, the compositions of the present invention comprise transfer RNA (referred to as tRNA). As used herein, unless explicitly stated otherwise, the terms transfer RNA or tRNA refer to both conventional tRNA molecules and tRNA molecules having one or more modifications. Transfer RNA is an RNA polymer of about 70 to 100 nucleotides in length. During protein synthesis, tRNA delivers amino acids to ribosomes for addition to the growing peptide chain. Active tRNA has a 3'CCA tail, which can be transcribed into tRNA during tRNA synthesis or added later during post-transcriptional processing. The amino acid is covalently linked to the 2' or 3' hydroxyl group of the 3' ribose to form aminoacyl-tRNA (aa-tRNA); the amino acid can spontaneously migrate from the 2'-OH to the 3'-OH and vice versa, but it is incorporated from the 3'-OH position into the growing protein chain at the ribosome. The loop at the other end of the folded aa-tRNA molecule contains a sequence of three bases called the anticodon. When the anticodon sequence pairs with a three-base codon sequence in ribosome-bound messenger RNA (mRNA), the aa-tRNA binds to the ribosome and its amino acid is incorporated into the nascent protein chain. Since all tRNAs that pair with a specific codon base are aminoacylated via a single specific amino acid, the translation of the genetic code is influenced by tRNA: each of the 61 non-stop codons in mRNA directs the binding of its homologous aa-tRNA and the addition of a single specific amino acid to the growing protein polymer. In some embodiments, the tRNA may contain a mutation in the anticodon region of the tRNA, causing the aa-tRNA to pair with a different codon base on the mRNA. In some embodiments, the mutated tRNA introduces an amino acid different from the amino acid encoded by the mRNA into the growing protein chain. In other embodiments, the mutated tRNA pairs with a stop codon base and introduces an amino acid instead of terminating protein synthesis, thereby allowing the nascent peptide to continue growing. In some embodiments, wild-type or mutated tRNA may read through a stop codon and introduce an amino acid instead of terminating protein synthesis. In some embodiments, the tRNA may comprise a full-length tRNA containing a 3'-CCA nucleotide. In other embodiments, tRNA lacking a 3'-A, -CA, or -CCA nucleotide is prepared in vivo as a full-length tRNA via a CCA-adding enzyme.

[1093] In other aspects, the compositions of the present invention may also comprise one or more modified tRNA molecules, including: acylated tRNA; alkylated tRNA; tRNA comprising one or more bases other than adenine, cytosine, guanine, or uracil; tRNA covalently modified by linking with a specific ligand or an antigenic, fluorescent, affinity, reactive, spectral, or other probe moiety; tRNA comprising one or more methylated or otherwise modified ribose moieties; aa-tRNA aminoacylated with amino acids other than 20 natural amino acids (including non-natural amino acids used as carriers of reagents, specific ligands, or as antigenic, fluorescent, reactive, affinity, spectral, or other probes); or any combination of these compositions. Some examples of modified tRNA molecules are taught by the following: et al., 1995; El Yacoubi, et al., 2012; Grosjean and Benne, et al., 1998; Hendrickson, et al., 2004; Ibba and 2000; Johnson, et al., 1995; Johnson, et al., 1982; Crowley, et al., 1994; Beier and Grimm, 2001; Torres, et al., 2014; and [References:] et al., 1987, all of which are incorporated herein by reference.

[1094] III. Hereditary diseases

[1095] In some respects, this disclosure provides compositions that can be used to treat one or more inherited conditions. One example of an inherited condition is cystic fibrosis. While some cases of cystic fibrosis result from mutations that lead to the deletion of phenylalanine at position 508, approximately 10% of cases are caused by mutations in the stop codon that produce a replacement amino acid in the next amino acid sequence of a protein. This type of mutation, called a nonsense mutation, results in a truncated and nonfunctional cystic fibrosis transmembrane conduction regulation (CFTR) protein.

[1096] Mutations in the CFTR protein impair chloride ion transport, and consequently, patients with cystic fibrosis experience salty skin, poor growth, poor weight gain, mucus buildup (particularly in the lungs), frequent chest infections, and persistent cough. Because cystic fibrosis is a hereditary condition, treatment options typically involve addressing the symptoms rather than the underlying pathology. Such treatments include treating infections, removing mucus buildup, and organ transplantation, such as a lung transplant. Therefore, efforts to address the underlying pathological condition are crucial.

[1097] On the other hand, this disclosure considers the treatment of cancers, particularly those 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 cancers, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genital cancer, genitourinary cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, muscle tissue cancer, neck cancer, oral or nasal mucosal cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, stomach cancer, testicular cancer, or thyroid cancer, or epithelial cancer, 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 may be treated with one or more other anticancer therapies, including chemotherapy, surgery, immunotherapy, or radiation therapy.

[1098] IV. Treatment

[1099] A. Drug formulation and administration route

[1100] When considering clinical applications, it is necessary to prepare pharmaceutical compositions in a form suitable for the intended use. In some embodiments, formulations having the compounds disclosed herein are considered. Generally, this would require preparing compositions substantially free of pyrogens and other impurities that could be harmful to humans or animals.

[1101] It is generally desirable to use suitable salts and buffers to stabilize the delivery carrier and allow it to be taken up by the target cells. Buffers are also used when recombinant cells are introduced into a patient. The aqueous compositions of this disclosure comprise an effective amount of the cell-target carrier dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. Such compositions are also referred to as inoculums. The phrase “pharmaceutically acceptable or pharmacologically acceptable” means a molecular entity and composition that does not produce adverse reactions, allergic reactions, or other adverse effects when administered to animals or humans. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonics, and absorption delay agents. The use of such media and reagents for pharmaceutically active substances is well known in the art. The use of any conventional media or reagent in therapeutic compositions is considered unless any conventional media or reagent is incompatible with the carrier or cells of this disclosure. Complementary active ingredients may also be incorporated into the composition.

[1102] The active compositions of this disclosure may include classic pharmaceutical formulations. These compositions according to this disclosure may be administered via any common route, as long as the target tissue is accessible by that route. Such routes include oral, nasal, sublingual, rectal, vaginal, or topical administration. Alternatively, administration may be by orthotopic, intradermal, subcutaneous, intramuscular, intratumoral, intraperitoneal, or intravenous injection. Such compositions are typically administered as pharmaceutically acceptable compositions as described above.

[1103] The active compounds can also be administered parenterally or intraperitoneally. Solutions of the active compounds, as free bases or pharmacologically acceptable salts, can be prepared in water appropriately mixed with a surfactant (e.g., hydroxypropyl cellulose). Dispersions can also be prepared in glycerol, liquid polyethylene glycol, mixtures thereof, and in oils. Under normal storage and use conditions, these formulations contain preservatives to prevent microbial growth.

[1104] Suitable injectable drug forms include sterile aqueous solutions or dispersions and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid, to the extent that it is injectable. It must be stable under manufacturing and storage conditions and must be preserved against contamination by microorganisms (e.g., bacteria and fungi). The carrier can be a solvent or dispersion medium, including, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Suitable flowability can be maintained, for example, by using coatings (e.g., lecithin), in the case of dispersions by maintaining the desired particle size, and by using surfactants. Protection against microbial action can be achieved by a variety of antibacterial and antifungal agents, such as parabens, chlorobutanol, phenols, sorbic acid, thimerosal, etc. In many cases, isotonic agents, such as sugars or sodium chloride, are preferably included. Extended absorption of the injectable composition can be achieved by using agents that delay absorption (e.g., aluminum monostearate and gelatin) in the composition.

[1105] Sterile injectable solutions are prepared as follows: The desired amount of the active compound is incorporated into a suitable solvent containing the various other components listed above, and then aseptically filtered. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile carrier comprising a base dispersion medium and the desired other components from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, preferred methods of preparation include vacuum drying and freeze-drying techniques, which produce powders of the active ingredient plus any other desired components after pre-sterile filtration of the solution.

[1106] As used herein, "pharmaceutical-grade carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonics, and absorption delay agents. The use of such media and reagents for pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is considered unless any conventional media or reagent is incompatible with the active ingredient. Complementary active ingredients may also be incorporated into the composition.

[1107] For oral application, the compositions described herein can be incorporated with excipients and used in the form of non-ingestible mouthwashes and dental flosses. Mouthwashes can be prepared by incorporating the desired amount of the active ingredient into a suitable solvent (e.g., a sodium borate solution (Dobell's solution)). Alternatively, the active ingredient can be incorporated into an antiseptic wash containing sodium borate, glycerin, and potassium bicarbonate. The active ingredient can also be dispersed in dental flosses, including gels, pastes, powders, and slurries. The active ingredient can be added in a therapeutically effective amount to a paste-like dental floss, which may contain water, binders, abrasives, flavoring agents, foaming agents, and wetting agents.

[1108] The compositions disclosed herein can be formulated in neutral or salt form. Pharmaceutically acceptable salts include acid addition salts (forming with the free amino group of a protein) and those formed with inorganic acids (e.g., hydrochloric acid or phosphoric acid) or organic acids (e.g., acetic acid, oxalic acid, tartaric acid, mandelic acid, etc.). Salts formed with free carboxyl groups can also 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.

[1109] After preparation, the solution will be administered in a manner compatible with the dosage form and in, for example, a therapeutically effective amount. The formulation is readily administered in various dosage forms, such as injectable solutions, drug-release capsules, etc. For parenteral administration in aqueous solutions, the solution should be appropriately buffered, if necessary, and the liquid diluent should first be made isotonic with sufficient saline or glucose. These specific aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. In this regard, sterile aqueous media that can be used are known to those skilled in the art based on this disclosure. For example, a dose can be dissolved in 1 ml of isotonic NaCl solution and added to 1000 ml of hypodermolysis fluid, or injected at the recommended infusion site (see, for example, "Remington's Pharmaceutical Sciences," 15th edition, pp. 1035-1038 and 1570-1580). Some dosage variation is inevitable depending on the condition of the person being treated. In any case, the person responsible for administration will determine the appropriate dosage for the individual subject. In addition, for human use, the formulation should meet the sterility, pyrogenicity, general safety and purity standards required by the FDA Office of Biologics Standards.

[1110] I. Steroids and steroid derivatives

[1111] In some aspects of this disclosure, aminolipids are mixed with one or more types of steroids or steroid derivatives to produce nanoparticle compositions. In some embodiments, the steroid or steroid derivative comprises any steroid or steroid derivative. As used herein, in some embodiments, the term "steroid" is a class of compounds having a tetracyclic 17-carbon ring structure, which may also contain one or more substitutions, including alkyl, alkoxy, hydroxyl, oxo, acyl groups, or double bonds between two or more carbon atoms. In one aspect, the cyclic structure of the steroid comprises three fused cyclohexyl rings and one fused cyclopentyl ring, as shown in the following formula:

[1112]

[1113] In some embodiments, the steroid derivative comprises the aforementioned ring structure having one or more non-alkyl substituted ions. In some embodiments, the steroid or steroid derivative is a sterol, wherein the formula is further defined as:

[1114]

[1115] In some embodiments of this disclosure, the steroid or steroid derivative is a cholesterane or a cholesterane derivative. In cholesteranes, the ring structure is further defined by the following formula:

[1116]

[1117] As described above, the cholesterane derivative comprises one or more non-alkyl substitutions in the aforementioned ring system. In some embodiments, cholesterane or cholesterane derivatives are cholesterene or cholesterene derivatives, or sterols or sterol derivatives. In other embodiments, cholesterane or cholesterane derivatives are both cholesterene and sterols, or derivatives thereof.

[1118] In some embodiments, the ratio of the compound or aminolipid in the composition of the present invention to the steroid or steroid derivative is from about 1:3 to about 30:1 or from about 1:1 to about 20:1. This ratio can be from about 1:1 to 6:1, for example, about 1.3:1. In some embodiments, this ratio is from 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 thereof from sources therein.

[1119] II. PEGylated lipids or PEGylated lipids

[1120] In some aspects of this disclosure, amino lipids (or compounds) are mixed with one or more PEGylated lipids (or PEG lipids) to produce nanoparticle compositions. In some embodiments, this disclosure includes the use of any lipid already linked with a PEG group. In some embodiments, the PEG lipid is a diglyceride that also contains a PEG chain linked to a glycerol group. In other embodiments, the PEG lipid is a compound containing one or more C6 to C24 long-chain alkyl or alkenyl or C6 to C24 fatty acid groups linked to a linker group having a PEG chain. Some non-limiting examples of PEG lipids include PEG-modified phosphatidylethanolamine and phosphatidic acid, PEG-ceramide-conjugated, PEG-modified dialkylamines and PEG-modified 1,2-diacyloxypropyl-3-amine, PEG-modified diacylglycerols and dialkylglycerols. In some embodiments, PEG-modified distearylphosphatidylethanolamine 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 molecular weight of the PEG modification is from 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 may be used in this disclosure are taught by U.S. Patent 5,820,873, WO 2010 / 141069 or U.S. Patent 8,450,298, which are incorporated herein by reference.

[1121] On the other hand, PEG lipids have the following formula:

[1122]

[1123] Wherein: n1 is an integer from 1 to 100, and n2 and n3 are each independently selected from integers from 1 to 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 derived therefrom. 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.

[1124] In some embodiments, the ratio of the compound or amino lipid to the PEG lipid in the composition of the present invention is from about 1:1 to about 150:1 or from about 2.5:1 to about 100:1. This ratio can be from about 7.5:1 to 50:1, for example, about 33.3:1. In some embodiments, this ratio is from 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 that may be derived from such sources.

[1125] III. Phospholipids

[1126] In some aspects of this disclosure, amino lipids are mixed with one or more phospholipids to produce nanoparticle compositions. In some embodiments, any lipid also contains a phosphate group. In some embodiments, the phospholipid is a structure containing one or two long-chain C6 to 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 phosphatidylcholine. In some embodiments, the phospholipid is distearylphosphatidylcholine.

[1127] In some embodiments, the ratio of the compound or amino lipid to the phospholipid in the composition of the present invention is from about 1:1 to about 15:1 or from about 1:1 to about 9:1. This ratio can be from about 2.5:1 to 7.5:1, for example, about 5:1. In some embodiments, this ratio is from 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 thereof from sources therein.

[1128] B. Treatment methods

[1129] In particular, compositions for treating hereditary diseases and cancers in subjects (e.g., human subjects) are disclosed herein. These compositions are preferably administered in an effective amount (i.e., an amount capable of producing the desired results in the treated subject) to mammals (e.g., rodents, humans, non-human primates, dogs, cattle, sheep, horses, cats, etc.). The toxicity and therapeutic efficacy of the compositions used in the methods of this disclosure can be determined by standard pharmaceutical practices. As is known in the medical and veterinary fields, the dosage for any 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 status, clinical symptoms of the hereditary disease or cancer, and other drugs administered concurrently. In some embodiments, these dosages may be reduced or increased based on specific patient biological factors, such as increased or decreased drug metabolism or (if administered orally) decreased gastrointestinal uptake. Additionally, the active composition may be more effective, and therefore a smaller dosage is required to achieve a similar effect. Such dosages are typically administered once daily for several weeks or until sufficient reduction of cancer cells has been achieved.

[1130] The treatments described in this disclosure (including preventative treatments) generally involve administering a therapeutically effective amount of the composition described herein to a subject (including mammals, particularly humans) in need. Such treatment would be suitable for subjects (particularly humans) who suffer from, have, are susceptible to, have a disease, condition or its symptoms, or are at risk of such disease. The determination of those subjects “at risk” can be made by diagnostic testing or by the opinion of the subject or a healthcare provider (e.g., genetic testing, enzyme or protein markers, biomarkers (as defined herein), family history, etc.) based on any objective or subjective determination.

[1131] C. Combination therapy

[1132] It is anticipated that the active compositions described herein can be used in combination with one or more treatments. In some embodiments, combining treatment modalities is common in the field of cancer treatment. The following is a general discussion of treatments that can be used in conjunction with the treatments described herein.

[1133] For example, to treat cancer using the methods and compositions of this disclosure, tumor cells or a subject are typically contacted with a compound and at least one other treatment. These treatments are provided in combined amounts that effectively reduce one or more disease parameters. The process may involve contacting the cells / subject simultaneously with both agents / treatments, for example, using a single composition or pharmacological formulation containing both agents, or by contacting the cells / subject simultaneously with two different compositions or formulations, one containing the compound and the other containing another agent.

[1134] Alternatively, the active compositions described herein may be administered minutes to weeks before or after another treatment. Generally, it should be ensured that there is no significant time interval between each delivery so that the treatment still produces a beneficial combined effect on the cells / subject. In some such cases, it is considered to expose cells to both modes of administration within approximately 12 to 24 hours of each other, within approximately 6 to 12 hours of each other, or with a delay of only approximately 1 to 2 hours. In some cases, significantly prolonged treatment time may be expected; however, this may involve intervals of several days (2, 3, 4, 5, 6, or 7 days) to several weeks (1, 2, 3, 4, 5, 6, 7, or 8 weeks) between each administration.

[1135] It is also conceivable to expect the compound or another treatment to be administered more than once. Various combinations can be used, wherein the compound of this disclosure is "A" and the other treatment is "B," as follows:

[1136]

[1137] Other combinations are also considered. The following is a general discussion of cancer treatments that can be used in combination with the compounds disclosed herein.

[1138] 1. Chemotherapy

[1139] The term "chemotherapy" refers to the use of drugs to treat cancer. "Chemotherapy agents" are used to refer to compounds or compositions administered in cancer treatment. These agents or drugs are classified by their mode of activity within cells (e.g., whether they affect the cell cycle and at what stage). Alternatively, agents can be characterized based on their ability to directly cross-link DNA, embed themselves in DNA, or induce chromosomal and mitotic aberrations by affecting nucleic acid synthesis. Most chemotherapy agents fall into the following categories: alkylating agents, antimetabolites, antitumor antibiotics, mitotic inhibitors, and nitrosoureas.

[1140] Some examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, inprossurfan, and piperazine; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bullatacin and buprofen). Bullatacinone; camptothecins (including synthetic analogs such as topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs such as KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards. Mustards include chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, and uracil mustard.Nitrosures, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ1 and calicheamicin ω1); dynemicins, including dynemicin A; uncialamycin and its derivatives; bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophores and related chromogens, enediyne antibiotic chromophores, aclarubicin... inomysin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin C, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin D, daunorubicin, detorubicin, 6-diaza-5-oxo-L-leucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrole-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin (e.g., mitomycin C), mycophenolic acid (acid), nogalarnycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, or zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU);Folic acid analogs, such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thioimidazoline, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azouridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, and enoxabin. e) Floxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenergics, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as folinic acid; aceglatone; and aldophosphamide. glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate); epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;Podophyllinic acid; 2-ethylhydrazine; procarbazine; PSK polysaccharide complex; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2'-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A) A) and anguidine; polyurethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; 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 compounds; etoposide (VP-16); isophosphamide; mitoxantrone; vincristine; vinorelbine Nogantrone; Teniposide; Idatroxa; Daunorubicin; Aminopterin; Xeloda; Ibandronate; Irinotecan (e.g., CPT-11); Topoisomerase inhibitor RFS2000; Difluoromethylornithine (DMFO); Retinoids, such as retinoic acid; Capecitabine; Cisplatin (CDDP), Carboplatin, Procarbazine, Dichloromethyldiethylamine, Cyclophosphamide, Camptothecin, Ifosfamide, Melphalan Chlorobenzamide, busulfan, nitrosamine, actinomycin D, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, raloxifene, estrogen receptor binders, taxol, paclitaxel, docetaxel, gemcitabine, novibenten, farnesyltransferase inhibitors, antiplatinum, 5-fluorouracil, vincristine, vinblastine, and methotrexate, as well as any pharmaceutically acceptable salts, acids, or derivatives of the above.

[1141] 2. Radiation therapy

[1142] Radiation therapy, also known as radiotherapy, uses ionizing radiation to treat cancer and other diseases. Ionizing radiation deposits energy, which damages or destroys cells in the area being treated by damaging their genetic material, making those cells unable to continue growing. Although radiation damages both cancer cells and normal cells, the latter are able to repair themselves and function normally.

[1143] Radiation therapy used according to this disclosure may include, but is not limited to, the use of gamma rays, X-rays, and / or targeted delivery of radioisotopes to tumor cells. Other forms of DNA damage, such as microwave and UV irradiation, are also considered. Most likely, all of these factors will cause extensive damage to DNA, DNA precursors, DNA replication and repair, and chromosome assembly and maintenance. X-ray doses range from daily doses of 50 to 200 roentgens for extended periods (3 to 4 weeks) to single doses of 2000 to 6000 roentgens. The dose range for radioisotopes varies considerably and depends on the isotope's half-life, the intensity and type of emitted radiation, and the uptake by the proliferating cells.

[1144] Radiation therapy can include delivering radiation doses directly to the cancer site using radiolabeled antibodies (radioimmunotherapy). Antibodies are highly specific proteins produced 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 prepared in the laboratory and bound to radioactive materials (a process called radiolabeling). Once injected into the body, the antibodies actively seek out cancer cells, which are destroyed by the cytotoxic effects of radiation. This method minimizes the risk of radiation damage to healthy cells.

[1145] Conformal radiotherapy uses the same radiotherapy machine and linear accelerator as conventional radiotherapy, but a metal block is placed in the path of the X-ray beam to alter its shape and match the shape of the cancer. This ensures a higher radiation dose is delivered to the tumor. Healthy surrounding cells and nearby structures receive a lower dose of radiation, 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 multiple metal plates fixed to the linear accelerator. The layers can be adjusted so that the radiotherapy beam can be shaped to the treatment area without the need for the metal block. Precise positioning of the radiotherapy machine is crucial for conformal radiotherapy, and the location of internal organs can be checked using a special scanner at the start of each treatment.

[1146] High-resolution intensity-modulated radiotherapy also uses multi-leaf collimators. During this treatment, the layers of the multi-leaf collimator are moved simultaneously with the treatment. This method is likely to achieve even more precise shaping of the treatment beam and to keep the radiotherapy dose constant throughout the treatment area.

[1147] Although studies have shown that conformal radiotherapy and intensity-modulated radiotherapy can reduce the side effects of radiotherapy, such precise shaping of the treatment area can prevent the destruction of microscopic cancer cells that happen to be outside the treatment area. This means that using these specialized radiotherapy techniques may increase the risk of future cancer recurrence.

[1148] Scientists are also searching for ways to improve the effectiveness of radiotherapy. The effects of two types of investigational drugs on irradiated cells are being studied. Radiosensitizers make tumor cells more likely to be destroyed, while radioprotective agents protect normal tissue from radiation. The effectiveness of using hyperthermia (heat) in sensitizing tissues to radiation is also being investigated.

[1149] 3. Immunotherapy

[1150] In cancer treatment, immunotherapy agents typically rely on using immune effector cells and molecules to target and destroy cancer cells. Trastuzumab (Herceptin) TM This is one such example. An immune effector can be, for example, an antibody specific to certain markers on the surface of tumor cells. An antibody alone can act as a therapeutic effector, or it can recruit other cells to actually influence cell killing. Antibodies can also be conjugated to drugs or toxins (chemotherapeutic agents, radionuclides, ricin A chains, cholera toxin, pertussis toxin, etc.) and act solely as a target. Alternatively, an effector can be a lymphocyte carrying surface molecules that interact directly or indirectly with tumor cell targets. Various effector cells include cytotoxic T cells and NK cells. A combination of therapeutic modalities (i.e., direct cytotoxic activity and inhibition or reduction of ErbB2) will provide therapeutic benefit in treating ErbB2-overexpressing cancers.

[1151] In one aspect of immunotherapy, tumor cells must carry certain biomarkers suitable for targeting—that is, biomarkers not present on most other cells. Many tumor biomarkers exist, and any one of these biomarkers may be suitable for targeting in the context of this disclosure. Common tumor biomarkers include carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), urinary tumor-associated antigen (URTA), fetal antigen (FAA), tyrosinase (p97), gp68, TAG-72, HMFG, sialic acid Lewis antigen (SALE), MucA, MucB, PLAP, estrogen receptor, laminin receptor, erb B, and p155. An alternative aspect of immunotherapy is the combination of anticancer effects with immunostimulatory effects. Immunostimulatory molecules also exist, including cytokines (e.g., IL-2, IL-4, IL-12, GM-CSF, γ-IFN), chemokines (e.g., MIP-1, MCP-1, IL-8), and growth factors (e.g., FLT3 ligand). Combinations of immunostimulatory molecules (whether used as proteins or in combination with tumor inhibitors for gene delivery) have been shown to enhance antitumor activity (Ju et al., 2000). Furthermore, antibodies against any of these compounds can be used to target the anticancer agents discussed herein.

[1152] Some examples of immunotherapies currently under investigation or in use are immune adjuvants, such as those against Mycobacterium bovis and Plasmodium falciparum. falciparum, dinitrochlorobenzene and aromatic compounds (US Patents 5,801,005 and 5,739,169; Hui and Hashimoto, 1998; Christodoulides et al., 1998); cytokine therapy, 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, such as TNF, IL-1, IL-2, p53 (Qin et al., 1998; Austin-Ward and Villaseca, 1998; US Patents 5,830,880 and 5,846,945); and monoclonal antibodies, such as antiganglioside GM2, antiHER-2, antip185 (Pietras et al., 1998; Hanibuchi et al., 1998; US Patent 5,824,311). Consider using one or more anticancer therapies in conjunction with the gene silencing therapies described in this article.

[1153] In active immunotherapy, antigenic peptides, polypeptides or proteins, or compositions of autologous or allogeneic tumor cells or “vaccines” are usually administered together with different bacterial adjuvants (Ravindranath and Morton, 1991; Morton et al., 1992; Mitchell et al., 1990; Mitchell et al., 1993).

[1154] In adoptive immunotherapy, the patient’s circulating lymphocytes or tumor-infiltrating lymphocytes are isolated in vitro, activated by lymphokines (e.g., IL-2) or transduced with tumor necrosis genes and re-administered (Rosenberg et al., 1988; 1989).

[1155] 4. Surgical procedures

[1156] Approximately 60% of cancer patients will undergo some type of surgery, including preventative, diagnostic or staging, curative, and palliative surgeries. Curative surgeries are cancer treatments that can be used in combination with other treatments, such as the treatments described in this disclosure, chemotherapy, radiation therapy, hormone therapy, gene therapy, immunotherapy, and / or replacement therapy.

[1157] Curative surgical procedures include 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 a portion of a tumor. In addition to tumor resection, surgical treatment includes laser surgery, cryosurgery, electrosurgery, and microsurgical procedures (Mohs's surgery). Further consideration is that this disclosure can be used in conjunction with the removal of superficial carcinoma, precancerous lesions, or accompanying amounts of normal tissue.

[1158] After partial or complete removal of cancerous cells, tissue, or tumors, a cavity may be formed in the body. Treatment can be accomplished by perfusion, direct injection, or local application of additional anticancer therapy to this area. Such treatments 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. These treatments can also be administered at different doses.

[1159] In some specific embodiments, adjuvant therapy with the compounds of this disclosure after tumor removal has been considered particularly effective in reducing tumor recurrence. Additionally, the compounds of this disclosure can also be used in neoadjuvant situations.

[1160] 5. Treatment of cystic fibrosis

[1161] Cystic fibrosis is incurable, and therefore many treatments focus on addressing the underlying pathological condition rather than the symptoms. Some treatments involve methods to reduce mucus buildup in the airways. Treatment can include physical therapy, exercise, artificial expectoration, or medication. These medications include the use of saline, DNases (such as dornase alfa), mucolytics (such as acetylcysteine), bronchodilators (such as salbutamol or salmeterol), or anticholinergics. In other respects, cystic fibrosis treatment is antibiotics, such as, but not limited to: gentamicin, piperacillin, tazobactam, azteonam, ciprofloxacin, tobramycin, ceftazidime, amikacin, meropenem, or azithromycin. In yet another respect, cystic fibrosis treatment can be anti-inflammatory agents (such as NSAIDs), membrane stabilizers (such as cromoglycine), or corticosteroids (such as fluticasone or prednisone). In still other respects, cystic fibrosis treatment is other treatments (such as ivacaftor).

[1162] V. Definition

[1163] When used in the context of chemical groups: "hydrogen" refers to -H; "hydroxyl" refers to -OH; "oxo" refers to =O; "carbonyl" refers to -C(=O)-; "carboxyl" refers to -C(=O)OH (also written as -COOH or -CO2H); "halogen" independently refers to -F, -Cl, -Br, or -I; "amino" refers to -NH2; "hydroxyamino" refers to -NHOH; "nitro" refers to -NO2; "imino" refers to =NH; "cyano" refers to -CN; "isocyanate" refers to -N= C = O; "azido" means -N3; ​​in the monovalent case, "phosphate" means -OP(O)(OH)2 or its deprotonated form; in the divalent case, "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; "sulfonamide" means -S(O)2NH2; and "sulfinyl" means -S(O)-.

[1164] In chemical formulas, the symbol "-" indicates a single bond, "=" indicates a double bond, and "≡" indicates a triple bond. The symbol "----" represents an optional bond, which, if present, is either a single or double bond. This indicates a single or double bond. Therefore, for example, the formula... include Furthermore, it should be understood that no single ring atom forms part of more than one double bond. Additionally, note that when connecting one or two stereoisogenic atoms, the covalent bond symbol "-" does not indicate any preferred stereochemistry. Rather, it encompasses all stereoisomers and mixtures thereof. When drawn perpendicularly to the bond (e.g., for methyl groups), the symbol "-" indicates a different type of stereoisomer. ),symbol This indicates the junction point of the group. Note that junction points are typically indicated in this way only for larger groups to help the reader clearly identify them. (Symbol) This refers to the following single bond, where the group attached to the thicker end of the wedge "leaves the page". (Symbol) This refers to the following single bond, where the group attached to the thicker end of the wedge "enters the page". (Symbol) This refers to single bonds where the geometry surrounding the double bond (e.g., E or Z) is undefined. Therefore, both options and combinations thereof are indicated. Any undefined valence on an atom in the structure shown in this application implicitly represents a hydrogen atom bonded to that atom. Bold dots on carbon atoms indicate that the hydrogen atoms bonded to that carbon are oriented outwards from the plane of the paper.

[1165] When the group "R" in a ring system is described as a "floating group", for example, in the following formula:

[1166]

[1167] R can substitute for any hydrogen atom bonded to any ring atom, including depicted, implicit, or explicitly defined hydrogens, as long as a stable structure is formed. When the group "R" in a fused ring system is described as a "floating group," for example in the following formula:

[1168]

[1169] Unless otherwise specified, R can substitute for any hydrogen atom bonded to any ring atom of one of the fused rings. Substituted hydrogens include the hydrogens depicted (e.g., the hydrogen bonded to nitrogen in the above formula), implicit hydrogens (e.g., hydrogens not shown in the above formula but understood to be present), explicitly defined hydrogens, and optional hydrogens whose presence depends on the identity of the ring atom (e.g., the hydrogen bonded to group X when X equals -CH-), provided a stable structure is formed. In the examples shown, R can be located on a 5-membered or 6-membered ring of the fused ring system. In the above formula, the subscript letter "y" immediately following the group "R" in parentheses indicates 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 substituted hydrogen atoms in the ring or ring system.

[1170] For chemical groups and compound categories, the number of carbon atoms in the group or category is as follows: "Cn" specifies the exact number (n) of carbon atoms in that group / category. "C≤n" specifies the maximum number (n) of carbon atoms that can be in the group / category, where the minimum number is as small as possible for the group / category in question. For example, it should be understood that in the group "alkenyl", the minimum number is much smaller. (C≤8) "or category "olefins" (C≤8) The minimum number of carbon atoms in "" is two. In contrast, "alkoxy" (C≤10) "" indicates an alkoxy group having 1 to 10 carbon atoms. "Cn-n'" defines the minimum number (n) and maximum number (n') of carbon atoms in the group. Therefore, "alkyl" (C2-10) The parentheses indicate alkyl groups having 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical group or class they modify, and may or may not be included in parentheses without indicating any change in meaning. Therefore, the terms "C5 olefin," "C5-olefin," and "olefin" are used interchangeably. (C5) "and "olefins" C5 "" are all synonyms. When any chemical group or class of compounds defined herein is modified by the term "substituted," any carbon atom in the portion replacing the hydrogen atom is not counted. Therefore, methoxyhexyl is a substituted alkyl group. (C1-6) One example.

[1171] When used to modify compounds or chemical groups, the term "saturated" means that the compound or chemical group does not have carbon-carbon double bonds or carbon-carbon triple bonds, unless otherwise stated below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted forms of saturated groups, one or more carbon-oxygen double bonds or carbon-nitrogen double bonds may be present. And when such bonds are present, carbon-carbon double bonds that may appear as part of keto-enol tautomerism or imine / enamine tautomerism are not excluded. When the term "saturated" is used to modify a solution of a substance, it means that more of the substance cannot dissolve in the solution.

[1172] When used without the modifier "substituted," the term "aliphatic" indicates that the modified compound or chemical group is an acyclic or cyclic but non-aromatic hydrocarbon compound or group. In aliphatic compounds / groups, carbon atoms can be linked together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds / groups can be saturated, linked by carbon-carbon single bonds (alkane / alkyl); or unsaturated, having one or more carbon-carbon double bonds (alkene / alkenyl) or one or more carbon-carbon triple bonds (alkynyl / alkynyl).

[1173] When used to modify compounds or chemical groups, the term "aromatic" refers to a planar unsaturated atomic ring with 4n+2 electrons in a fully conjugated cyclic π system.

[1174] When used without the modifier "substituted," the term "alkyl" refers to a monovalent saturated aliphatic group having a single carbon atom as a linker, a straight or branched acyclic structure, and containing no atoms other than carbon and hydrogen. Examples of alkyl groups include -CH3(Me), -CH2CH3(Et), -CH2CH2CH3(n-Pr or propyl), and -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), tert-butyl, t-Bu or tBu) and -CH2C(CH3)3 (neopentyl) are some non-limiting examples of alkyl groups. When used without the modifier "substituted," the term "alkyl dieryl" refers to a divalent saturated aliphatic group having one or two saturated carbon atoms as connecting points, having a straight or branched acyclic structure, containing no carbon-carbon double or triple bonds, and containing no atoms other than carbon and hydrogen. The groups -CH2- (methylene), -CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2CH2- are some non-limiting examples of alkyl dieryl groups. When used without the modifier "substituted," the term "alkylene" refers to a divalent group =CRR', where R and R' are independently hydrogen or alkyl. Some non-limiting examples of alkylene include: =CH2, =CH(CH2CH3), and =C(CH3)2. "Alkane" refers to a class of compounds having the formula HR, where R is an alkyl group, as defined above. When any of these terms is used with the modifier “substituted”, one or more hydrogen atoms have been independently substituted by: -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH or -S(O)2NH2. The following groups are some non-limiting examples of substituted alkyl groups: -CH2OH, -CH2Cl, -CF3, -CH2CN, -CH2C(O)OH, -CH2C(O)OCH3, -CH2C(O)NH2, -CH2C(O)CH3, -CH2OCH3, -CH2OC(O)CH3, -CH2NH2, -CH2N(CH3)2, and -CH2CH2Cl. The term "haloalkyl" is a subset of substituted alkyl groups in which hydrogen atom substitution is restricted to halogens (i.e., -F, -Cl, -Br, or -I), such that no other atoms exist besides carbon, hydrogen, and the halogen. The group -CH2Cl is a non-limiting example of a haloalkyl group. The term "fluoroalkyl" is a subset of substituted alkyl groups in which hydrogen atom substitution is restricted to fluorine, such that no other atoms exist besides carbon, hydrogen, and fluorine. The groups -CH2F, -CF3, and -CH2CF3 are some non-limiting examples of fluoroalkyl groups.

[1175] When used without the modifier "substituted," the term "cycloalkyl" refers to a monovalent saturated aliphatic group having a carbon atom as a connecting point (which forms part of one or more non-aromatic ring structures), containing no carbon-carbon double or triple bonds, and containing no atoms other than carbon and hydrogen. Some non-limiting examples include: -CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). When used without the modifier "substituted," the term "cycloalkyldiyl" refers to a divalent saturated aliphatic group having two carbon atoms as connecting points, containing no carbon-carbon double or triple bonds, and containing no atoms other than carbon and hydrogen. This is a non-limiting example of a cycloalkanediyl group. "Cycloalkane" refers to a class of compounds having the formula HR, where R is a cycloalkyl group, as defined above. When any of these terms is used with the modifier "substituted," one or more hydrogen atoms have been independently substituted by: -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[1176] When used without the modifier "substituted," the term "alkenyl" refers to a monovalent unsaturated aliphatic group having one carbon atom as a linking point, a straight-chain or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Some non-limiting examples include: -CH=CH2 (vinyl), -CH=CHCH3, -CH=CHCH2CH3, -CH2CH=CH2 (allyl), -CH2CH=CHCH3, and -CH=CHCH=CH2. When used without the modifier "substituted," the term "alkenidyl" refers to a divalent unsaturated aliphatic group having two carbon atoms as linking points, a straight-chain or branched, linear or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups -CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2-, and -CH2CH=CHCH2- are some non-limiting examples of alkenadiyl groups. Note that although alkenadiyl groups are aliphatic, once attached 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 a class of compounds having the formula HR, where R is an alkenyl group, as defined above. Similarly, the terms "terminal alkene" and "α-alkene" are synonymous and refer to an alkene having only one carbon-carbon double bond, where the bond is part of a vinyl group at one end of the molecule. When any of these terms is used with the modifier “substituted,” one or more hydrogen atoms have been independently substituted by: -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. The groups -CH=CHF, -CH=CHCl, and -CH=CHBr are some non-limiting examples of substituted alkenyl groups.

[1177] When used without the modifier "substituted," the term "alkynyl" refers to a monovalent unsaturated aliphatic group having a single carbon atom as a linker, a straight-chain or branched acyclic structure, at least one carbon-carbon triple bond, and containing no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not exclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups -C≡CH, -C≡CCH3, and -CH2C≡CCH3 are some non-limiting examples of alkynyl groups. "Alkyne" refers to a class of compounds having the formula HR, where R is an alkynyl group. When any of these terms is used with the modifier “substituted”, one or more hydrogen atoms have been independently substituted by: -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH or -S(O)2NH2.

[1178] When used without the modifier "substituted," the term "aryl" refers to a monovalent unsaturated aromatic group having an aromatic carbon atom as a connecting point, said carbon atom forming part of one or more six-membered aromatic ring structures, wherein all ring atoms are carbon, and wherein the group does not contain atoms other than carbon and hydrogen. If more than one ring is present, these rings may be fused or unfused. As used herein, the term does not exclude the presence of one or more alkyl or aralkyl groups (if the carbon number limitation allows) connected to the first aromatic ring or any other aromatic ring present. Some non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C6H4CH2CH3 (ethylphenyl), naphthyl, and monovalent groups derived from biphenyl. When used without the modifier "substituted," the term "arandibular" refers to a divalent aromatic group having two aromatic carbon atoms as connecting points, said carbon atoms forming part of one or more six-membered aromatic ring structures, wherein all ring atoms are carbon, and wherein the monovalent group does not contain atoms other than carbon and hydrogen. As used herein, the term does not exclude the presence of one or more alkyl, aryl, or aralkyl groups (if carbon number restrictions permit) connected to the first aromatic ring or any other present aromatic ring. If more than one ring is present, these rings can be fused or unfused. Unfused rings can be connected by one or more of the following: covalent bonds, alkyldiyl, or alkylenediyl (if carbon number restrictions permit). Some non-limiting examples of arandibular groups include:

[1179]

[1180] "Aromatic hydrocarbons" refers to a class of compounds having the formula HR, where R is an aryl group, as defined above. Benzene and toluene are some non-limiting examples of aromatic hydrocarbons. When any of these terms is used with the modifier "substituted," one or more hydrogen atoms have been independently substituted by: -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[1181] When used without the modifier "substituted," the term "aralkyl" refers to the monovalent group -alkyldiyl-aryl, wherein the terms alkyldiyl and aryl are each used in a manner consistent with the definitions provided above. Some non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl. When the term aralkyl is used with the modifier "substituted," one or more hydrogen atoms derived from the alkyldiyl and / or aryl group have been independently substituted with: -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. Some non-limiting examples of substituted aralkyl groups are: (3-chlorophenyl)-methyl and 2-chloro-2-phenyl-ethyl-1-yl.

[1182] When used without the modifier "substituted," the term "heteroaryl" refers to a monovalent aromatic group having one aromatic carbon or nitrogen atom as a connecting point, said carbon or nitrogen atom forming part of one or more aromatic ring structures, wherein at least one ring atom is nitrogen, oxygen, or sulfur, and wherein the heteroaryl does not contain atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. If more than one ring is present, these 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 the carbon number limit allows) connected to the aromatic ring or aromatic ring system. Some non-limiting examples of heteroaryl include furanyl, imidazolyl, indoleyl, indazole (Im), isoaryl, etc. azole group, methylpyridinyl group, Azolyl, phenylpyridyl, pyridyl (nitrophenyl), pyrroleyl, pyrimidinyl, pyrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thiopheneyl, and triazolyl. When used without the modifier "substituted," the term "heteroaromatic dimethyl" 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 connecting points, said atoms forming part of one or more aromatic ring structures, wherein at least one ring atom is nitrogen, oxygen, or sulfur, and wherein the divalent group does not contain atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. If more than one ring is present, these rings can be fused or unfused. Unfused rings can be connected by one or more of the following: covalent bonds, alkyl dienes, or alkene dienes (if the carbon number restriction allows). As used herein, the term does not exclude the presence of one or more alkyl, aryl, and / or aralkyl groups (where carbon number restrictions permit) attached to an aromatic ring or aromatic ring system. Some non-limiting examples of heteroaryl dimethyl groups include:

[1183]

[1184] The term "N-heteroaryl" refers to a heteroaryl group having a nitrogen atom as a connecting point. "Heteroary hydrocarbon" refers to a class of compounds having the formula HR, where R is a heteroaryl group. Pyridine and quinoline are some non-limiting examples of heteroary hydrocarbons. When these terms are used with the modifier "substituted," one or more hydrogen atoms have been independently substituted by: -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[1185] When used without the modifier "substituted," the term "heterocyclic alkyl" refers to a monovalent non-aromatic group having a carbon or nitrogen atom as a connecting point, said carbon or nitrogen atom forming part of one or more non-aromatic ring structures, wherein at least one ring atom is nitrogen, oxygen, or sulfur, and wherein the heterocyclic alkyl group does not contain atoms other than carbon, hydrogen, nitrogen, oxygen, and sulfur. If more than one ring is present, these rings may be fused or unfused. As used herein, the term does not exclude the presence of one or more alkyl groups (if the carbon number limit allows) connected to the ring or ring system. Furthermore, 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. Some non-limiting examples of heterocyclic alkyl groups include aziridinyl, acridineyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, pyranyl, oxetanepropyl, and oxetanebutyl. When used without the modifier "substituted," the term "heterocyclic alkyl dieryl" refers to a divalent cyclic group having two carbon atoms, two nitrogen atoms, or one carbon atom and one nitrogen atom as two connecting points, said atoms forming part of one or more ring structures, wherein at least one ring atom is nitrogen, oxygen, or sulfur, and wherein the divalent group does not contain atoms other than carbon, hydrogen, nitrogen, oxygen, and sulfur. If more than one ring is present, these rings can be fused or unfused. Unfused rings can be connected by one or more of the following: covalent bonds, alkyl dieryl, or alkenyl dieryl (if the carbon number restriction allows). As used herein, the term does not exclude the presence of one or more alkyl groups (if the carbon number restriction allows) connected to the ring or ring system. Furthermore, 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. Some non-limiting examples of heterocyclic alkyl dieryl include:

[1186]

[1187] The term "N-heterocyclic alkyl" refers to a heterocyclic alkyl group having a nitrogen atom as a connecting point. N-pyrrolidinyl is an example of such a group. When these terms are used with the modifier "substituted", one or more hydrogen atoms have been independently substituted by: -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH or -S(O)2NH2.

[1188] When used without the modifier "substituted," the term "acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heteroaryl, as these terms are defined above. The groups -CHO, -C(O)CH3 (acetyl, Ac), -C(O)CH2CH3, -C(O)CH2CH2CH3, -C(O)CH(CH3)2, -C(O)CH(CH2)2, -C(O)C6H5, -C(O)C6H4CH3, -C(O)CH2C6H5, and -C(O) (imidazolyl) are some non-limiting examples of acyl groups. "Thioacyl" is defined in a similar manner, except that the oxygen atom in the group -C(O)R has been replaced with a sulfur atom, i.e., -C(S)R. The term "aldehyde" corresponds to an alkane as defined above, where at least one hydrogen atom has been replaced with a -CHO group. When any of these terms is used with the modifier “substituted”, one or more hydrogen atoms (including hydrogen atoms directly bonded to carbon atoms of the carbonyl or thiocarbonyl groups, if any) have been independently substituted by: -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH or -S(O)2NH2. The groups -C(O)CH2CF3, -CO2H (carboxyl), -CO2CH3 (methylcarboxyl), -CO2CH2CH3, -C(O)NH2 (carbamoyl), and -CON(CH3)2 are some non-limiting examples of substituted acyl groups.

[1189] When used without the modifier "substituted," the term "alkoxy" refers to the group -OR, where R is an alkyl group as defined above. Some non-limiting examples include: -OCH3 (methoxy), -OCH2CH3 (ethoxy), -OCH2CH2CH3, -OCH(CH3)2 (isopropoxy), -OC(CH3)3 (tert-butoxy), -OCH(CH2)2, -O-cyclopentyl, and -O-cyclohexyl. When used without the modifier "substituted," the terms "cycloalkoxy," "alkenoxy," "alkynoxy," "aryloxy," "araneoxy," "heteroaryloxy," "heterocyclic alkoxy," and "acyloxy" refer to groups defined as -OR, where R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclic alkyl, and acyl, respectively. The term "alkoxydiyl" refers to the divalent group -O-alkadiyl-, -O-alkadiyl-O-, or -alkadiyl-O-alkadiyl-. When used without the modifier "substituted," the terms "alkathio" and "acylthio" refer to the group -SR, where R is alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane as defined above, wherein at least one hydrogen atom has been replaced with a hydroxyl group. The term "ether" corresponds to an alkane as defined above, wherein at least one hydrogen atom has been replaced with an alkoxy group. When any of these terms is used with the modifier “substituted”, one or more hydrogen atoms have been independently substituted by: -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH or -S(O)2NH2.

[1190] When used without the modifier "substituted," the term "alkylamino" refers to the group -NHR, where R is an alkyl group as defined above. Some non-limiting examples include -NHCH3 and -NHCH2CH3. When used without the modifier "substituted," the term "dialkylamino" refers to the group -NRR', where R and R' can be the same or different alkyl groups, or R and R' can be combined to represent an alkyldiyl group. Some non-limiting examples of dialkylamino include -N(CH3)2 and -N(CH3)(CH2CH3). When used without the modifier "substituted," the terms "cycloalkylamino," "alkenylamino," "alkynylamino," "arylamino," "aralkylamino," "heteroarylamino," "heterocyclic alkylamino," "alkoxyamino," and "alkylsulfonylamino" refer to groups defined as -NHR, where R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclic alkyl, alkoxy, and alkylsulfonyl, respectively. A non-limiting example of an arylamino group is -NHC6H5. When used without the modifier "substituted," the term "acylamino" (acylamino) refers to the group -NHR, where R is an acyl group, as defined above. A non-limiting example of an acylamino group is -NHC(O)CH3. When used without the modifier "substituted," the term "alkylimino" refers to the divalent group =NR, where R is an alkyl group, as defined above. The term "alkylaminodiyl" refers to the divalent group -NH-alkyldiyl-, -NH-alkyldiyl-NH-, or -alkyldiyl-NH-alkyldiyl-. When any of these terms is used with the modifier “substituted,” one or more hydrogen atoms attached to a carbon atom have been independently substituted with the following: -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. The groups -NHC(O)OCH3 and -NHC(O)NHCH3 are some non-limiting examples of substituted amide groups.

[1191] When used in conjunction with the term "comprising / including" in the claims and / or description, the use of a word without a quantifier may mean "one / type", but it also means "one / type or more / types", "at least one / type" and "one / type or more than one / type".

[1192] Throughout this application, the term “about / approximately” is used to indicate a value that includes inherent variations in the error of the method or apparatus used to determine the value, or variations that exist between the subjects under study.

[1193] The terms “comprises,” “has,” and “includes” are open-ended conjunctions. 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 of “comprises,” “has,” or “includes” one or more steps is not limited to having only that one or more steps and also covers other steps not listed.

[1194] The term "effective," as used in the specification and / or claims, means sufficient to achieve the desired, anticipated, or desired result. When used in the context of treating a patient or subject with a compound, "effective amount," "therapeutic effective amount," or "pharmaceutical effective amount" means an amount of compound sufficient to achieve such treatment of the disease when administered to a subject or patient to treat the disease.

[1195] As used in this article, the term "IC" 50 "Inhibitor" refers to the amount of inhibitor that achieves 50% of the maximum response. This quantitative measure indicates how much of a specific drug or other substance (inhibitor) is needed to inhibit half of a given biological, biochemical, or chemical process (or a component of the process, i.e., an enzyme, cell, cell receptor, or microorganism).

[1196] An "isomer" of the first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but these atoms have different configurations in three dimensions.

[1197] As used herein, the terms "patient" or "object" refer to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or a transgenic species thereof. In some embodiments, the patient or object is a primate. Some non-limiting examples of human objects are adults, adolescents, infants, and fetuses.

[1198] As is commonly used in this article, “medicinal” means those compounds, materials, compositions, and / or dosage forms that, in accordance with reasonable medical judgment, are suitable for contact with the tissues, organs, and / or bodily fluids of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[1199] "Pharmacologically acceptable salt" means a salt of the compounds disclosed herein that is pharmaceutically acceptable as defined above and has the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-en-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-en-1-carboxylic acid, acetic acid, aliphatic monocarboxylic acids and dicarboxylic acids, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, etc. Benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfate, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkyl acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid, trimethylacetic acid, etc. Pharmaceutically acceptable salts also include base addition salts that can be formed when the present acidic protons can react 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-methylglucosamine, etc. It should be recognized that the specific anion or cation forming part of any salt that constitutes part of this disclosure is not critical, provided that the salt as a whole is pharmacologically acceptable. Further examples of pharmaceutically usable salts and their preparation and use are shown in Handbook of Pharmaceutical Salts: Properties, and Use (edited by PHStahl and CGWermuth, Verlag Helvetica Chimica Acta, 2002).

[1200] As used herein, the term "pharmaceutical carrier" means a pharmaceutically acceptable material, composition, or carrier that participates in the transport or delivery of a chemical agent, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.

[1201] "Prevention" or "avoidance" includes: (1) suppressing the occurrence of disease in any or all pathological conditions or symptoms of a subject or patient who may be at risk of disease and / or susceptible to disease but has not yet experienced or shown the disease, and / or (2) slowing the occurrence of any or all pathological conditions or symptoms of a disease in any or all subject or patient who may be at risk of disease and / or susceptible to disease but has not yet experienced or shown the disease.

[1202] "Stereoisomers" or "optical isomers" are isomers of a given compound in which the same atoms are bonded to the same other atoms, but in different configurations in three dimensions. "Enantiomers" are stereoisomers of a given compound that are mirror images of each other, like left-hand and right-hand sides. "Diabeta-isomeric" are stereoisomers of a given compound that are not diastereomers. Chiral molecules contain a chiral center, also called a stereocenter or stereoisomer source center, which is any point in the molecule carrying a group such that the interchange of any two groups results in a stereoisomer, but is not necessarily an atom. In organic compounds, the chiral center is typically a carbon, phosphorus, or sulfur atom, but other atoms can also be stereocenters in both organic and inorganic compounds. A molecule can have multiple stereocenters, resulting in many stereoisomers. In compounds where stereoisomerism is due to a tetrahedral stereoisomer source center (e.g., tetrahedral carbon), it is assumed that the total number of possible stereoisomers will not exceed 2^n, where n is the number of tetrahedral stereocenters. Molecules with symmetry typically have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers may be enantiomer-enriched, such that one enantiomer is present in an amount greater than 50%. Generally, enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. Consider any stereochemical center or chiral axis that is not yet determined, which may exist in its R-type, S-type, or as a mixture of R-type and S-type, said mixtures 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 other stereoisomers.

[1203] "Treatment" includes: (1) suppressing the disease in a subject or patient experiencing or displaying a pathological condition or symptoms of the disease (e.g., preventing further development of the pathological condition and / or symptoms), (2) improving the disease in a subject or patient experiencing or displaying a pathological condition or symptoms of the disease (e.g., reversing the pathological condition and / or symptoms), and / or (3) achieving any measurable reduction of the disease in a subject or patient experiencing or displaying a pathological condition or symptoms of the disease.

[1204] The above definitions supersede any conflicting definitions cited in any references incorporated herein by reference. However, the fact that certain terms are defined should not be construed as indicating that any undefined term is ambiguous. Rather, all terms used are intended to describe this disclosure in such a manner that those skilled in the art can understand the scope and practice of this disclosure.

[1205] V. Example

[1206] The following embodiments are included to illustrate some preferred embodiments of this disclosure. Those skilled in the art will understand that the techniques disclosed in embodiments following representative techniques discovered by the inventors work well in the practice of this disclosure and can therefore be considered as constituting a preferred mode of practice. However, based on this disclosure, those skilled in the art will understand that many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of this disclosure, and the same or similar results can still be obtained.

[1207] Example 1 - Methods and Materials

[1208] A. Cell Culture

[1209] Calu-6 and Calu-3 cells were obtained from the American Type Culture Collection and cultured in RMP1 1640 (Corning) medium supplemented with 5% FBS (Gemini Bio-Products) containing L-glutamine and 25 mM HEPES. 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).

[1210] B. Antibodies and reagents

[1211] 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 UNCA Antibody Distribution Program. As described in Johnson et al., 1982, chromatographically purified tRNA was chemically modified with a fluorescein dye reagent. Phe To prepare unacylated E. coli tRNA Phe -F 8(P-05). For other tRNAs, DNA fragments encoding a specific tRNA sequence following the T7 RNA polymerase promoter sequence were chemically synthesized. The T7 promoter-tRNA DNA sequence was amplified by PCR using standard techniques, such as those described by Green and Sambrook, 2012; Rio et al., 2011; Flanagan et al., 2003; and Janiak et al., 1992, followed by in vitro transcription using 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 precipitate was resuspended and dialyzed into water. RNAiMax and Lipofectamine 2000 were purchased from Invitrogen and used according to the supplier's recommended protocol. 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 below.

[1212]

[1213]

[1214]

[1215]

[1216]

[1217]

[1218]

[1219] plasmids and site-directed mutagenesis of C. CFTR

[1220] The expression plasmid of full-length wild-type CFTR (pBI-CFTR) was purchased from Clontech, and mutagenesis was performed using a standard protocol for site-directed mutagenesis (Sambrook et al., 1989). Site-directed mutagenesis was performed using Pfu high-fidelity DNA polymerase (Stratagene, Santa Clara, CA) via PCR. All mutations were confirmed by DNA sequencing. Sup-tRNA Arg Courtesy of Carla Oliveira (Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal).

[1221] D. Quantitative methods for mature CFTR

[1222] Seed HEK293 cells (9×10⁻⁶) 5 (2 μg CFTR plasmid and 500 ng Sup-tRNA) were transfected with the CFTR plasmid. Arg Co-transfected cells using 4 μl Lipofectamine 2000 in a 6-well configuration. 24 hours post-transfection, G418 (200 μg) or PTC124 (40 μM) was added to the culture medium and incubated for 48 hours. IB3-1 cells were seeded, and after 24 hours, G418 (0–400 μg) or PTC124 (0–20 μM) was added. After 48 hours, cells were directly lysed in 2× 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% stepwise (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 the 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). Imaging / quantification was performed using Li-CorOdyssey CLx (Li-Cor). Data were plotted using Prism 6 (Graphpad).

[1223] E. CFTR-dependent whole-cell currents in HEK293 cells

[1224] HEK293 cells were transfected with a plasmid intended for CFTR maturation assay. 2 μg of CFTR plasmid and 500 ng of Sup-tRNA were added. Arg Co-transfection was performed using 4 μl Lipofectamine 2000 in a 6-well configuration. 24 hours post-transfection, whole-cell configurations using patch-clamp technique were used to measure Cl- currents. The pipette solution contained 145 mM NMDG+-Cl-, 1 mM MgCl2, 2 mM EGTA, 5 mM ATP, and 10 mM HEPES (pH 7.3, containing 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, containing Tris). Currents were recorded using an Axopatch 200B patch-clamp amplifier and digitized at 2 kHz. Membrane conductance was probed by stepping the membrane potential from a hold potential of 0 mV to membrane potentials of -40 and +40 mV in 200 ms increments. Whole-cell current response was measured using 10 μM forscolin plus 100 μM IBMX and 10 μM CFTRInh-172 (Inh-172). The pipette resistance was 3 to 5 MΩ when filled with pipette solution, and the sealing resistance exceeded 8 GU. Current recording and analysis were performed using pClamp 9.2 software, and further analysis was conducted using Origin 8 software.

[1225] F. Intake Studies

[1226] Cell uptake studies were performed using the best-performing material selected from the screening. Calu6 cells were seeded at a density of 40,000 cells per well in 8-chamber coverslips (Nunc) and allowed to adhere for 24 hours. NP formulations were prepared artificially using a protocol similar to that described above for in vitro transfection assays using fluorescein-labeled tRNA. The formulation was prepared in 10 mM citrate buffer at pH 4.3 with a final molar ratio of carrier:siRNA of 25:1, and the carrier mixture consisted of a molar ratio of carrier:cholesterol:DSPC:PEG-lipid of 50:38:10:2. Nanoparticles were added to the cells at a final tRNA dose of 0.9 μg / well. After 6 hours of incubation, the culture medium was aspirated, washed with PBS, and cell membrane staining (Cell Mask Red, Molecular Probes) was performed using the manufacturer's protocol. Cell nuclei were stained with DAPI (Sigma-Aldrich). Confocal microscopy imaging was performed using a Nikon Eclipse TE2000-E, and the images were analyzed using ImageJ (NIH).

[1227] G. Screening of nanoparticle carriers in Calu6 cells

[1228] 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 according to the manufacturer's recommended protocol. For tRNA... Arg / Op - RNAiMax, using the manufacturer's recommended protocol, 3 μl RNAiMax was used to transfect 4 μg of cells. The particles were diluted in Opti-MEM (Invitrogen). G418 (50 μg) and PTC124 (10 μl M) were added directly to the culture medium. The nanoparticles were prepared as follows: all delivery components were mixed in ethanol and then rapidly mixed with tRNA in 10 mM citrate buffer at pH 4.3 to achieve a final molar ratio of 25:1 carrier:siRNA, and the carrier mixture of the formulation consisted of a molar ratio of 50:38:10:2 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, the cells were directly lysed in 2× 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 fluoride Immobilon membrane (EMDMillipore). Western blot analysis was performed using a primary p53 antibody (Santa Cruz Biotechnology, Inc.), an actin antibody (EMDMillipore), and a secondary antibody IRdye-680RD (Li-Cor), and imaging / quantification was performed using Li-Cor OdysseyCLx (Li-Cor).

[1229] H.NP Dimensional Analysis

[1230] Particle size was measured using a Malvern Zetasizer Nano ZS (He-Ne laser, λ = 632 nm) via dynamic light scattering (DLS).

[1231] Example 2 - tRNA Delivery

[1232] like Figure 1 As shown, nonsense mutations terminate synthesis at mutation sites in mRNA that produce premature stop codons, resulting in nonfunctional proteins. Efforts to correct these mutations in the protein using reading comprehensions have not restored the activity of transmembrane regulatory proteins of cystic fibrosis, such as... Figures 2A to 2C It can be shown. For example... Figure 3A and 3B As shown, correcting mutations with any amino acid does not yield a functional protein. Similarly, even if a mutation results in folding, the resulting protein may still be functionally defective. Figure 4A and 4B Therefore, readthrough methods used to correct gene mutations may be insufficient to restore protein activity. On the other hand, the introduction of modified tRNA leads to the restoration of CFTR folding and function, such as... Figures 5A to 5C As can be seen, similarly, the introduction of modified tRNA into nanoparticle formulations induces the delivery of tRNA into cells. Figure 6A And functional p53 is produced by introducing specific amino acids into the growing peptide chain. Figure 6B and 6C ).

[1233] A variety of different aminolipid delivery compositions were tested to determine the amount of tRNA bound to the nanoparticles. Figure 7 The results showed that most of the tested materials bound to tRNA with a fraction greater than 0.8. Similarly, Figure 8 The characteristics of these tRNA compositions are shown, including particle size and polydispersity index. Exogenous tRNA is used. Arg / Op The ability of these compositions to restore p53 expression in Calu6 cells was tested. Western blot analysis of these compositions showed that... Figure 9 In this study, one of the compositions that showed restoration of p53 expression was tested at several different concentrations, and two other reagents that showed only a critical restoration of p53 expression relative to that composition were also tested. Figure 10 To determine whether the tRNA composition was taken up by cells, fluorescence microscopy was performed using labeled tRNA. (e.g.) Figure 11 It is evident that tRNA was taken up by Calu6 cells after 6 hours of incubation. Furthermore, Figure 12 Updates to tRNAs using zwitterionic and cationic sulfonamide aminolipids are shown. Finally, Figure 13 The data in the paper, based on the response and viability in the luciferase assay, illustrate different methods for preparing nanoparticles.

[1234] ***

[1235] According to this disclosure, all methods disclosed and claimed herein can be operated and implemented without excessive experimentation. Although the compositions and methods of this disclosure have been described according to some preferred embodiments, it will be apparent to those skilled in the art that changes can be made to the methods and steps or order of steps described herein without departing from the concept, spirit, and scope of this disclosure. More specifically, it will be apparent that certain chemically and physiologically relevant reagents can be substituted for those described herein while obtaining the same or similar results. All such similar substitutions and modifications that will be apparent to those skilled in the art are considered to be within the spirit, scope, and concept of this disclosure as defined by the appended claims.

[1236] References

[1237] The following references are incorporated herein by reference in particular for providing exemplary practices or other details that supplement the content set forth herein.

[1238] WO 2016 / 094342

[1239] WO 2017 / 048789

[1240] International Application No. PCT / US2017 / 032950

[1241] et al., tRNA: Structure, Biosynthesis, and Function (ASM Press), 1995.

[1242] El Yacoubi, et al., Annu. Rev. Genet., 46: 69-95, 2012.

[1243] Grosjean and Benne, Modification and Editing of RNA (ASM Press), 1998.

[1244] Hendrickson, et al., Annu. Rev. Biochem., 73: 147-176, 2004.

[1245] Ibba and Annu. Rev. Biochem., 69: 617-650, 2000.

[1246] Johnson et al., Cold Spring Harbor Symp. Quant. Biol., 60: 71-82, 1995.

[1247] Johnson et al.,J.Mol.Biol.,156:113-140,1982.

[1248] Crowley et al.,Cell,78:61-71,1994.

[1249] Beier and Grimm,Nucleic Acids Res.,29:4767-4782,2001.

[1250] Torres,et al.,Trends Mol.Med.,20:306-314,2014.

[1251] et al.,Annu.Rev.Biochem.,56:263-287,1987.

[1252] Green and Sambrook,Molecular Cloning:A Laboratory Manual(CHSL Press),2012.

[1253] Rio et al.,RNA:A Laboratory Manual(CHSL Press),2011.

[1254] Flanagan et al.,J.Biol.Chem.,278:18628-18637,2003.

[1255] Janiak,et al.,Biochemistry,31:5830-5840,1992.

[1256] Yan et al.,Proc.Natl.Acad.Sci.,USA,113(39):E5702-E5710,2016.

Claims

1. A composition comprising: a. Transfer ribonucleic acid (tRNA); and b. Aminolipid delivery compounds; The aminolipid delivery compound forms nanoparticles, wherein the aminolipid delivery compound is a compound having the formula (AI) or a pharmaceutically acceptable salt thereof: Core - (Repeating Unit) n -Terminal capping group (AI) The core is connected to the one or more repeating units by removing one or more hydrogen atoms from the core and replacing the hydrogen atoms with one or more repeating units, wherein: The core has the following formula: In equation (A-II): X1 is an amino group, a C≤12 alkylamino group, a C≤12 dialkylamino group, a C≤12 heterocyclic alkyl group, a C≤12 heteroaryl group, or a substituted form of any of these groups; R1 is an amino, hydroxyl, mercapto group, or a substituted form of a C≤12 alkylamino, C≤12 dialkylamino, or any of these groups; and a is 1, 2, 3, 4, 5, or 6; or The core has the following formula: In equation (A-III): X2 is N(R5) y ; R5 is hydrogen, C≤18 alkyl, or substituted C≤18 alkyl; and y can be 0, 1, or 2, provided that the sum of y and z is 3; R2 is an amino, hydroxyl, mercapto, C≤12 alkylamino, C≤12 dialkylamino or any of these groups in a substituted form; b is 1, 2, 3, 4, 5, or 6; and z is 1, 2, or 3; provided that the sum of z and y is 3; or The core has the following formula: In equation (A-IV): X3 is a substituted form of -NR6-, -O-, C≤8 alkylaminodiyl, C≤8 alkoxydiyl, C≤8 aryldiyl, C≤8 heteroaryldiyl, C≤8 heterocycloalkyldiyl or any of these groups, wherein R6 is hydrogen, C≤8 alkyl or substituted C≤8 alkyl. R3 and R4 are each independently an amino, hydroxyl, mercapto, C≤12 alkylamino, C≤12 dialkylamino, or any of these groups in a substituted form; The core is a C≤18 alkylamine, C≤36 dialkylamine, C≤12 heterocyclic alkane, or a substituted form of any of these groups; The one or more repeating units comprise a degradable diacyl group and an optional linker; in The degradable diacyl group has the following formula: In equation (A-VII): A1 and A2 are independently -O-, -S-, or -NR. a -,in: R a It is hydrogen, C≤6 alkyl, or substituted C≤6 alkyl; Y3 is a substituted form of C≤12 alkyldiyl, C≤12 olefinicdiyl, C≤12 aryldiyl, or any of these groups; or a group of the following formula: in: X3 and X4 are substituted forms of C≤12 alkyldiyl, C≤12 olefinicdiyl, C≤12 aryldiyl, or any of these groups; Y5 is a covalent bond, a C≤12 alkyldiyl group, a C≤12 olefinic group, a C≤12 aryldiyl group, or a substituted form of any of these groups; and R9 is a C≤8 alkyl or a substituted C≤8 alkyl; The connector group has the following formula: In equation (A-VI): Y1 is a substituted form of C≤12 alkyldiyl, C≤12 olefinicdiyl, C≤12 aryldiyl, or any of these groups; and When one or more repeating units include the linker group, the linker group is attached to both the nitrogen and sulfur atoms of the linker group with the degradable diacyl group, wherein the first group in the one or more repeating units is a degradable diacyl group, and for each linker group, the next group contains two degradable diacyl groups attached to the nitrogen atom of the linker group; and where n is the number of linker groups present in the repeating unit; and The terminating group has the following formula: In equation (A-VIII): Y4 is a substituted form of C≤18 alkyldiyl, C≤18 olefinicdiyl, or either of these two groups; R 10 It consists of hydrogen, carboxyl, and hydroxyl groups. C≤12 aryl, C≤12 alkylamino, C≤12 dialkylamino, C≤12 N-heterocyclic alkyl, -C(O)N(R) 11 -C≤6 alkyldiyl-C≤12 heterocyclic alkyl, -C(O)-C≤12 alkylamino, -C(O)-C≤12 dialkylamino, or -C(O)-C≤12 N-heterocyclic alkyl, wherein: R 11 It is hydrogen, C≤6 alkyl, or substituted C≤6 alkyl; In this repeating unit, the last degradable diacyl group is connected to a capping group; and n is 0, 1, 2, 3, 4, 5, or 6; or The aminolipid delivery compound described herein is a compound having the structural formula (BI) or a pharmaceutically acceptable salt thereof: In formula (BI): X1 is -S(O)2O - -OP(O)OR e O - -(CHR) f ) z C(O)O - or -NR g R h R i + ;in: R e R g R h and R i Each is independently hydrogen, C≤6 alkyl, or substituted C≤6 alkyl; R f It is a substituted form of hydrogen, amino, hydroxyl, C≤12 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, or any of the last ten groups; and z is 1, 2, 3, or 4; Y1 is a substituted form of any of the following groups: C≤12 alkyldiyl, C≤12 alkylenediyl, C≤12 aryldiyl, C≤12 heteroaryldiyl, C≤12 heterocyclic alkyldiyl, -C≤8 alkyldiyl-C≤12 heterocyclic alkyldiyl, -C≤8 alkyldiyl-C≤12 heterocyclic alkyldiyl-C≤8 alkyldiyl, -C≤8 alkyldiyl-C≤12 heteroaryldiyl, -C≤8 alkyldiyl-C≤12 heteroaryldiyl-C≤8 alkyldiyl; Z1 is -N + R3R4-or-OP(O)O - O-; A is -NR a -, -S-, or -O-; where: R a It is hydrogen, C≤6 alkyl or substituted C≤6 alkyl, or alternatively, R a And one of R3 or R4 is combined with the attached atom to form a substituted form of C≤8 alkyldiyl, C≤8 olefinicdiyl, C≤8 alkoxydiyl, C≤8 alkylaminodiyl or any of these groups; R1 is a group in the following formula: in: R5, R6, and R2 are each independently hydrogen, C≤8 alkyl, -C≤6 alkyldiyl-NH2, -C≤6 alkyldiyl-C≤8 alkylamino, -C≤6 alkyldiyl-C≤12 dialkylamino, -C≤6 alkyldiyl-NR'R”, or a substituted form of any of these groups, or -Z3A”R8; wherein: R' and R" are each independently hydrogen, C≤8 alkyl, substituted C≤8 alkyl, or -Z2A'R7; wherein: Z2 is a C≤6 alkyldiyl group, a substituted C≤6 alkyldiyl group, or a group of the following formula: in: Z5 and Z6 are each independently C≤6 alkyldiyl or substituted C≤6 alkyldiyl; X2 and X3 are independently -O-, -S-, or -NR. m -;in: R m It is hydrogen, C≤6 alkyl, or substituted C≤6 alkyl; and a is 0, 1, 2, 3, 4, 5, or 6; A' is -CHR j -、-C(O)O- or -C(O)NR b -;in: R b It is hydrogen, C≤6 alkyl, or substituted C≤6 alkyl; and R j It is hydrogen, halogen, hydroxyl, C≤24 acyloxy or substituted C≤24 acyloxy; R7 is a C6-24 alkyl, a substituted C6-24 alkyl, a C6-24 alkenyl, or a substituted C6-24 alkenyl; Z3 is a C≤6 alkyldiyl group, a substituted C≤6 alkyldiyl group, or a group of the following formula: ， in: Z7 and Z8 are each independently C≤6 alkyldiyl or substituted C≤6 alkyldiyl; X4 and X5 are independently -O-, -S-, or -NR. n -;in: R n It is hydrogen, C≤6 alkyl, or substituted C≤6 alkyl; and b is 0, 1, 2, 3, 4, 5, or 6; A” is -CHR k -、-S-、-C(O)O- or -C(O)NR l -;in: R l It is hydrogen, C≤6 alkyl, or substituted C≤6 alkyl; and R k It is hydrogen, halogen, hydroxyl, C≤24 acyloxy group, or a substituted C≤24 acyloxy group; and R8 is a C6-24 alkyl, a substituted C6-24 alkyl, a C6-24 alkenyl, or a substituted C6-24 alkenyl; q is 1, 2, or 3; and r is 1, 2, 3, or 4; or Alternatively, R1 is a group of the following formula: ， in: Y2 is a substituted form of C≤12 aryldiyl, C≤12 heterocyclic alkyldiyl, C≤12 heteroaryldiyl, C≤12 alkoxydiyl or any of these groups; R9, R 10 and R 11 Each is independently hydrogen, C≤8 alkyl, substituted C≤8 alkyl, or -Z4A”'R 12 ;in: Z4 is a C≤6 alkyldiyl group, a substituted C≤6 alkyldiyl group, or a group of the following formula: ， in: Z9 and Z 10 Each is independently a C≤6 alkyldiyl or a substituted C≤6 alkyldiyl; X6 and X7 are independently -O-, -S-, or -NR. o -;in: R o It is hydrogen, C≤6 alkyl, or substituted C≤6 alkyl; and c is 0, 1, 2, 3, 4, 5, or 6; A”' is -CHR k -、-S-、-C(O)O- or -C(O)NR l -;in: R l It is hydrogen, C≤6 alkyl, or substituted C≤6 alkyl; and R k It is hydrogen, halogen, hydroxyl, C≤24 acyloxy group, or a substituted C≤24 acyloxy group; and R 12 It is a C6-24 alkyl, a substituted C6-24 alkyl, a C6-24 alkenyl, or a substituted C6-24 alkenyl; and x and y are each an independent integer selected from 0, 1, 2, 3 or 4; R3 and R4 are each independently hydrogen, C≤6 alkyl, or substituted C≤6 alkyl, or alternatively, R3 or R4 and R a Combined with the attached atoms to form a substituted form of C≤8 alkyldiyl, C≤8 olefinicdiyl, C≤8 alkoxydiyl, C≤8 alkylaminodiyl, or any of these groups; and m and p are each an integer selected independently from 0, 1, 2, 3, 4, 5 or 6; The premise is that if X1 carries a positive charge, then Z1 carries a negative charge, and if X1 carries a negative charge, then Z1 carries a positive charge; or The aminolipid delivery compound described herein is a compound having the structural formula (C–III) or a pharmaceutically acceptable salt thereof: In equation (C-III): R1, R2, and R3 are each independently hydrogen, C≤6 alkyl, substituted C≤6 alkyl, or groups of the following formula: ， in: R7 and R8 are each independently hydrogen, C≤6 alkyl, substituted C≤6 alkyl, or groups of the following formula: ， in: R9 is hydrogen, halogen, or hydroxyl, or a substituted form of C≤24 alkoxy, C≤24 acoxy, or either of these groups; and R 10 It is a substituted form of C≤24 alkyl, C≤24 alkenyl, or either of these two groups; q is 1, 2, or 3; and r is 0, 1, 2, 3 or 4; R4, R5, and R6 are each independently hydrogen, C≤6 alkyl, or substituted C≤6 alkyl; and m and n are each independently 1, 2, 3, 4, or 5; or The aminolipid delivery compound described herein is a compound having the structural formula (D-IV) or a pharmaceutically acceptable salt thereof: In equation (D-IV): X1 is a C≤18 alkyl or a substituted C≤18 alkyl; X2 is hydrogen, C≤18 alkyl, or substituted C≤18 alkyl; R1 is -AZ; in: A is a C≤18 alkyldiyl or a substituted C≤18 alkyldiyl; Z is -NR3R4; in: R3 and R4 are each independently selected from hydrogen, C≤18 alkyl, substituted C≤18 alkyl; or alternatively, R3 and R4 are combined with the attached atom to form C≤18 alkyldiyl or substituted C≤18 alkyldiyl. R2 is a C≤24 alkyl, C≤24 alkenyl, substituted C≤24 alkyl, or substituted C≤24 alkenyl; x and y are each independently 0, 1, 2, 3, 4 or 5; m and n are each independent integers from 0 to 250, provided that at least one of m and n is greater than 1; and The repeating units, defined by m and n, are randomly distributed throughout the polymer; or The aminolipid delivery compound is a compound having the structural formula (E-III) or a pharmaceutically acceptable salt thereof: In equation (E-III): R1, R2 and R3 are each independently hydrogen, C≤8 alkyl or substituted C≤8 alkyl; R4 is hydrogen, halogen, hydroxyl, C≤8 alkyl, or substituted C≤8 alkyl; R5 is a substituted form of C≤24 alkyl, C≤24 alkenyl, or either of these two groups; R6 is Y1-R7; in: Y1 is a C≤8 alkyldiyl, a substituted C≤8 alkyldiyl, -(CH2) r C(O)- or -(CH2) r C(O)NR a (CH2) s -; in: r and s are each independently 1, 2, or 3; and R a It is hydrogen, C≤6 alkyl, or substituted C≤6 alkyl; R7 is an amino group or a substituted form of a heteroaryl group, a heterocyclic alkyl group, an alkylamino group, a dialkylamino group, an arylalkylamino group, or any of these groups, with a C≤12 group. a, b, m, d, e, and n are each 1, 2, 3, or 4 independently; c and f are each independently 1 to 10; and x and y are each independent integers from 0 to 250, provided that at least one of x and y is greater than 1; When any of these terms is used with the modifier "substituted", one or more hydrogen atoms have been independently substituted by: -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH or -S(O)2NH2.

2. The composition according to claim 1, wherein the aminolipid delivery compound is a compound having the formula (AI), wherein: The core has the following formula: Wherein, in the degradable diacyl group having formula (A-VII): A1 and A2 are independently -O- or -NR. a - 3. The composition according to claim 1, wherein the aminolipid delivery compound is a compound having the formula (AI), wherein: The core has the following formula: Wherein, in the degradable diacyl group having formula (A-VII): A1 and A2 are independently -O- or -NR. a - 4. The composition according to claim 3, wherein X2 is NR5, and wherein R5 is hydrogen or C≤8 alkyl.

5. The composition according to claim 4, wherein R5 is methyl.

6. The composition according to claim 3, wherein z is 3.

7. The composition according to claim 3, wherein R2 is an amino group.

8. The composition according to claim 3, wherein R2 is a C≤12 alkylamino or a substituted C≤12 alkylamino.

9. The composition according to claim 3, wherein R2 is a C≤12 alkylamino or a substituted C≤12 alkylamino.

10. The composition according to claim 3, wherein b is 2 or 3.

11. The composition according to claim 1, wherein the aminolipid delivery compound is a compound having the formula (AI), wherein: The core has the following formula: Wherein, in the degradable diacyl group having formula (A-VII): A1 and A2 are independently -O- or -NR. a - 12. The composition according to claim 11, wherein X3 is a C≤8 alkylaminodiyl or a substituted C≤8 alkylaminodiyl.

13. The composition of claim 12, wherein X3 is -NHCH2CH2NH-, substituted -NHCH2CH2NH-, -NHCH2CH2NHCH2CH2NH-, or substituted -NHCH2CH2NHCH2CH2NH-.

14. The composition of claim 11, wherein X3 is a C≤8 heterocyclic alkyl diester or a substituted C≤8 heterocyclic alkyl diester.

15. The composition of claim 14, wherein X3 is N,N'-piperazinyl.

16. The composition according to claim 11, wherein R3 is an amino group.

17. The composition according to claim 11, wherein R3 is a C≤12 alkylamino or a substituted C≤12 alkylamino.

18. The composition of claim 17, wherein R3 is a substituted C≤12 alkylamino group, wherein one or more hydrogen atoms of the substituted C≤12 alkylamino group attached to a carbon atom have been independently replaced by -NH2, -NHCH3, -NHCH2CH3 or -N(CH3)2.

19. The composition according to claim 11, wherein R4 is an amino group.

20. The composition according to claim 11, wherein R4 is a C≤12 alkylamino or a substituted C≤12 alkylamino.

21. The composition of claim 20, wherein R4 is a substituted C≤12 alkylamino group, wherein one or more hydrogen atoms of the substituted C≤12 alkylamino group attached to a carbon atom have been independently replaced by -NH2, -NHCH3, -NHCH2CH3 or -N(CH3)2.

22. The composition according to claim 1, wherein the aminolipid delivery compound is a compound having the formula (AI), wherein: The core is a C≤18 alkylamine, C≤36 dialkylamine, C≤12 heterocyclic alkane, or a substituted form of any of these groups; and Wherein, in the degradable diacyl group having formula (A-VII): A1 and A2 are independently -O- or -NR. a - 23. The composition of claim 1, wherein the aminolipid delivery compound is a compound having the formula (AI), wherein the core is further defined as:

24. The composition of claim 1, wherein the aminolipid delivery compound is a compound having the formula (AI), wherein the core is further defined as:

25. The composition according to claim 11, wherein Y3 is a C≤8 alkyldiyl or a substituted C≤8 alkyldiyl.

26. The composition according to claim 11, wherein A1 is -NR a - 27. The composition according to claim 11, wherein A2 is -NR a - 28. The composition according to claim 11, wherein R9 is a C≤8 alkyl group.

29. The composition according to claim 11, wherein n is 0 or 1.

30. The composition according to claim 11, wherein Y4 is a substituted form of C≤18 alkyldiyl, C≤18 olefinic, or either of these two groups, and R 10 It is hydrogen.

31. The composition according to claim 30, wherein Y4 is a C4-18 alkyldiyl group.

32. The composition according to claim 30, wherein Y4 is a C≤18 alkyldiyl group, which is independently substituted by one or more substituents selected from the following: -OH, -F, -Cl, -Br, -I, -SH, -OCH3, -OCH2CH3, -SCH3 and -OC(O)CH3.

33. The composition of claim 1, wherein the aminolipid delivery compound is a compound having structural formula (B1) or a pharmaceutically acceptable salt thereof, and wherein the aminolipid delivery compound is further defined as having structural formula (B-II): in, In equation (B-II): Z2 is a C≤4 alkyldiyl or a substituted C≤4 alkyldiyl; Z3 is a C≤4 alkyldiyl or a substituted C≤4 alkyldiyl; and Z4 is a C≤4 alkyldiyl or a substituted C≤4 alkyldiyl.

34. The composition according to claim 33, wherein: Y1 is a substituted form of C≤12 alkyldiyl, C≤12 heterocyclic alkyldiyl, -C≤8 alkyldiyl-C≤12 heterocyclic alkyldiyl, -C≤8 alkyldiyl-C≤12 heterocyclic alkyldiyl-C≤8 alkyldiyl or any of these groups.

35. The composition according to claim 34, wherein Y1 is -CH2CH2-.

36. The composition of claim 33, wherein the aminolipid delivery compound is a compound having structural formula (B-II) or a pharmaceutically acceptable salt thereof, and wherein the aminolipid delivery compound is further defined as having structural formula (B-IIa): in, In equation (B-IIa): R1 is a group in the following formula: in: R a R3 and R4 are each independently hydrogen, C≤6 alkyl, or substituted C≤6 alkyl; and n is an integer selected from 0, 1, 2, 3, 4, 5, or 6.

37. The composition of claim 36, wherein R3 is a C≤8 alkyl or a substituted C≤8 alkyl.

38. The composition of claim 36, wherein R4 is a C≤8 alkyl or a substituted C≤8 alkyl.

39. The composition of claim 36, wherein the aminolipid delivery compound is a compound having structural formula (B-IIa) or a pharmaceutically acceptable salt thereof, and wherein the aminolipid delivery compound is further defined as having structural formula (B-IIb):

40. The composition according to claim 39, wherein n is 2 or 3.

41. The composition according to claim 39, wherein m is 1 or 2.

42. The composition according to claim 39, wherein p is 1, 2 or 3.

43. The composition according to claim 39, wherein q is 1 or 2.

44. The composition of claim 39, wherein the aminolipid delivery compound is a compound having structural formula (B-IIb) or a pharmaceutically acceptable salt thereof, and wherein the aminolipid delivery compound is further defined as having structural formula (B-III):

45. The composition according to claim 44, wherein R5 is -Z3A”R8.

46. ​​The composition according to claim 44, wherein R6 is -Z3A”R8.

47. The composition according to claim 44, wherein R2 is -Z3A”R8.

48. The composition according to claim 45, wherein R8 is a C6-24 alkyl or a substituted C6-24 alkyl.

49. The composition according to claim 46, wherein R8 is a C6-24 alkyl or a substituted C6-24 alkyl.

50. The composition of claim 47, wherein R8 is a C6-24 alkyl or a substituted C6-24 alkyl.

51. The composition according to claim 44, wherein: R5 is -Z3A”R8; in: Z3 is a C≤2 alkyldiyl or a substituted C≤2 alkyldiyl; R6 is a C≤8 alkyl or a substituted C≤8 alkyl; R2 is -C≤6 alkyldiyl-NR'R" or a substituted form of the group; wherein: R' and R” are each independently -Z2A'R7; where: Z2 is a C≤2 alkyldiyl or a substituted C≤2 alkyldiyl; q is 1 or 2; and r is 1 or 2.

52. The composition according to claim 44, wherein: R5 is a C≤8 alkyl or a substituted C≤8 alkyl; R6 is -C≤6 alkyldiyl-NR'R" or a substituted form of that group. R2 is -C≤6 alkyldiyl-NR'R" or a substituted form of the group, wherein: R' and R” are each independently C≤8 alkyl, substituted C≤8 alkyl, or -Z2A'R7; Z2 is a C≤2 alkyldiyl or a substituted C≤2 alkyldiyl; q is 1 or 2; and r is 1 or 2.

53. The composition according to claim 44, in: R5 is -Z3A”R8; in: Z3 is a C≤2 alkyldiyl or a substituted C≤2 alkyldiyl; R6 is -C≤6 alkyldiyl-NR'R" or a substituted form of the group; wherein: R2 is -C≤6 alkyldiyl-NR'R" or a substituted form of the group; wherein: R' and R” are each independently -Z2A'R7; where: Z2 is a C≤2 alkyldiyl or a substituted C≤2 alkyldiyl; q is 1 or 2; and r is 1 or 2.

54. The composition of claim 33, wherein the aminolipid delivery compound is a compound having structural formula (B-II) or a pharmaceutically acceptable salt thereof, and wherein the aminolipid delivery compound is further defined as having structural formula (B-IIb): in, In equation (B-IIb): R1 is a group in the following formula:

55. The composition according to claim 1, wherein the aminolipid delivery compound is a compound having the structural formula (C-III). in, In equation (C-III): R4 is hydrogen.

56. The composition according to claim 55, wherein R2 is a group of the following formula: 。 57. The composition according to claim 55, wherein R2 is a C≤6 alkyl or a substituted C≤6 alkyl.

58. The composition according to claim 55, wherein R3 is a C≤6 alkyl or a substituted C≤6 alkyl.

59. The composition according to claim 55, wherein R2 and R3 are each methyl.

60. The composition of claim 55, wherein the aminolipid delivery compound is a compound having structural formula (C-III) or a pharmaceutically acceptable salt thereof, and wherein the aminolipid delivery compound is further defined as having structural formula (CV):

61. The composition of claim 60, wherein the aminolipid delivery compound is a compound having a structural formula (CV) or a pharmaceutically acceptable salt thereof, and wherein the aminolipid delivery compound is further defined as having a structural formula (C-VI):

62. The composition according to claim 55, wherein R1 is a group of the following formula:

63. The composition according to claim 62, wherein R7 is 64. The composition according to claim 62, wherein R8 is 65. The composition according to claim 63, wherein R9 is a hydroxyl group.

66. The composition according to claim 64, wherein R9 is a hydroxyl group.

67. The composition according to claim 63, wherein R9 is a C≤8 acyloxy group or a substituted C≤8 acyloxy group.

68. The composition according to claim 64, wherein R9 is a C≤8 acyloxy group or a substituted C≤8 acyloxy group.

69. The composition according to claim 63, wherein R 10 It is an alkyl group with C≤24 or a substituted alkyl group with C≤24.

70. The composition according to claim 64, wherein R 10 It is an alkyl group with C≤24 or a substituted alkyl group with C≤24.

71. The composition according to claim 55, wherein R5 is a C≤6 alkyl or a substituted C≤6 alkyl.

72. The composition according to claim 55, wherein R6 is a C≤6 alkyl or a substituted C≤6 alkyl.

73. The composition according to claim 55, wherein m is 2, 3 or 4.

74. The composition according to claim 55, wherein n is 2, 3 or 4.

75. The composition according to claim 55, wherein q is 1 or 2.

76. The composition according to claim 55, wherein r is 1, 2 or 3.

77. The composition according to any one of claims 1 to 76, wherein the tRNA is an unmodified tRNA.

78. The composition according to any one of claims 1 to 76, wherein the tRNA is a modified tRNA.

79. The composition according to any one of claims 1 to 76, wherein the tRNA is a repressive tRNA.

80. The composition of claim 79, wherein the tRNA is a tRNA that delivers amino acids into a protein rather than terminating translation.

81. The composition according to claim 79, wherein the tRNA is amber repressor, milky repressor, ochre repressor, or frameshift repressor.

82. The composition of claim 80, wherein the tRNA adds arginine residues to the growing polypeptide.

83. The composition according to claim 82, wherein the tRNA is tRNA. arg / op .

84. The composition of claim 80, wherein the tRNA adds glycine residues to the growing polypeptide.

85. The composition according to claim 84, wherein the tRNA is tRNA. gly / op .

86. The composition of claim 80, wherein the tRNA adds tryptophan residues to the growing polypeptide.

87. The composition according to claim 86, wherein the tRNA is tRNA. trp / op .

88. The composition of claim 79, wherein the tRNA corrects nonsense mutations in the transmembrane regulatory protein of cystic fibrosis.

89. The composition according to any one of claims 1 to 76, wherein the composition further comprises a steroid.

90. The composition according to any one of claims 1 to 76, wherein the composition further comprises phospholipids.

91. The composition according to any one of claims 1 to 76, wherein the composition further comprises polyethylene glycol (PEG) conjugated lipids.

92. The composition according to claim 91, wherein the PEG-conjugated lipid is further defined as: in: n1 is an integer from 1 to 250; and n2 and n3 are each an independent integer from 5 to 23.

93. The composition according to claim 89, wherein the molar ratio of the compound to the steroid in the composition is from 1:1 to 20:

1.

94. The composition according to claim 90, wherein the molar ratio of the compound to the phospholipid in the composition is from 1:1 to 9:

1.

95. The composition according to claim 91, wherein the molar ratio of the compound to the PEG-conjugated lipid in the composition is from 2.5:1 to 100:

1.

96. The composition according to any one of claims 1 to 76, wherein the molar ratio of the compound to the nucleic acid in the composition is from 5:1 to 1000:

1.

97. The composition according to any one of claims 1 to 76, wherein the composition is a pharmaceutical composition and the pharmaceutical composition further comprises an excipient.

98. The composition of claim 97, wherein the pharmaceutical composition is formulated for administration by injection.

99. The composition according to claim 97, wherein the pharmaceutical composition is formulated into a unit dose.

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