Poly(amide) polymers for the delivery of oligonucleotides
View Patent ↗The present invention provides poly(amide) polymers, polyconjugates, compositions and methods for the delivery of oligonucleotides for therapeutic purposes.
1. A polymer comprising Formula Z:
wherein:
x is 2 to 1000;
y is 2 to 1000;
R 1 is a cationic component;
R 2 is an aliphatic component selected from the group consisting of ethyl, propyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, cholesterol, lipid chains, benzyl, benzyl propanoate, benzyl acetate, isopropyl, 2-methylpropane, 2-methylbutane, isobutyl, 2-n-butyl, benzyl, 4-methyl phenol, ethylbenzene, 1-fluoro-4-methylbenzene, 4-methylbiphenyl, 2-methylnaphthalene, 1-methylnaphthalene, 5-ethyl-1-H-imidazole, 4-methyl imidazole, and 2-methyl indole;
R a is independently selected from R 1 and R 2 ;
R b is independently selected from R 1 and R 2 ;
R c is independently selected from R 1 and R 2 ; and
R d is independently selected from R 1 and R 2 ;
or stereoisomer thereof.
2. A polymer according to claim 1 comprising Formula Z′:
wherein:
x is 2 to 1000;
y is 2 to 1000;
R is an initiator;
R′ is an end group;
R 1 is a cationic component;
R 2 is an aliphatic component selected from the group consisting of ethyl, propyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, cholesterol, lipid chains, benzyl, benzyl propanoate, benzyl acetate, isopropyl, 2-methylpropane, 2-methylbutane, isobutyl, 2-n-butyl, benzyl, 4-methyl phenol, ethylbenzene, 1-fluoro-4-methylbenzene, 4-methylbiphenyl, 2-methylnaphthalene, 1-methylnaphthalene, 5-ethyl-1-H-imidazole, 4-methyl imidazole, and 2-methyl indole;
R a is independently selected from R 1 and R 2 ;
R b is independently selected from R 1 and R 2 ;
R c is independently selected from R 1 and R 2 ; and
R d is independently selected from R 1 and R 2 ;
or stereoisomer thereof.
3. A polymer according to claim 2 comprising Formula Z″:
wherein:
x is 2 to 250;
y is 2 to 250;
R is an initiator;
R′ is an end group; and
R 2 is an aliphatic component selected from the group consisting of ethyl, propyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, cholesterol, lipid chains, benzyl, benzyl propanoate, benzyl acetate, isopropyl, 2-methylpropane, 2-methylbutane, isobutyl, 2-n-butyl, benzyl, 4-methyl phenol, ethylbenzene, 1-fluoro-4-methylbenzene, 4-methylbiphenyl, 2-methylnaphthalene, 1-methylnaphthalene, 5-ethyl-1-H-imidazole, 4-methyl imidazole, and 2-methyl indole;
or stereoisomer thereof.
4. A polymer conjugate composition comprising the polymer of Formula Z of claim 1 , a linker and an oligonucleotide.
5. The polymer conjugate composition of claim 4 further comprising a masking agent.
6. The polymer conjugate composion of claim 4 further comprising a targeting ligand.
7. A polymer conjugate composition of claim 4 further comprising a masking agent and a targeting ligand.
8. A polymer conjugate composition made by the 1) synthesis of an activated polymer comprising Formula Z of claim 1 ; 2 ) synthesis of an activated oligonucleotide; and 3) conjugation of the activated polymer with the activated oligonucleotide; optionally including the addition of a masking agent and/or a targeting ligand.
9. A polymer according to claim 1 , wherein R 1 is independently an amine or a nitrogen heterocycle.
10. A polymer according to claim 1 , wherein R 1 is selected from the group consisting of methyl amine, ethyl amine, propyl amine, butylamine, pentyl amine, hexyl amine, heptyl amine, octyl amine, nonyl amine, decyl amine, undecyl amine, dodecyl amine, tridecyl amine, tetradecyl amine, pentadecyl amine, hexadecyl amine, heptadecyl amine, octadecyl amine, 2-(2-aminoethoxy)ethyl, 2-(1H-imidazol-4-yl)ethyl, 2-[2-(2-aminoethoxy) ethoxy]ethyl, 3-amino-2-hydroxypropyl, 2-aminoethyl, 4-aminobutyl, 6-aminohexyl, 8-aminooctyl, 10-aminodecyl, and 1-methyl-2-imidazole modified ornithine.
11. A polymer according to claim 1 , wherein R 2 is selected from the group consisting of isopropyl, benzyl, 4-methyl phenol, 4-methyl imidazole, and 2-methyl indole.
12. A polymer according to claim 2 , wherein R 1 is an amine or a nitrogen heterocycle.
13. A polymer according to claim 2 , wherein R 1 is selected from the group consisting of methyl amine, ethyl amine, propyl amine, butylamine, pentyl amine, hexyl amine, heptyl amine, octyl amine, nonyl amine, decyl amine, undecyl amine, dodecyl amine, tridecyl amine, tetradecyl amine, pentadecyl amine, hexadecyl amine, heptadecyl amine, octadecyl amine, 2-(2-aminoethoxy)ethyl, 2-(1H-imidazol-4-yl)ethyl, 2-[2-(2-aminoethoxy)ethoxy]ethyl, 3-amino-2-hydroxypropyl, 2-aminoethyl, 4-aminobutyl, 6-aminohexyl, 8-aminooctyl, 10-aminodecyl, and 1-methyl-2-imidazole modified ornithine.
14. A polymer according to claim 2 , wherein R 2 is selected from the group consisting of isopropyl, benzyl, 4-methyl phenol, 4-methyl imidazole, and 2-methyl indole.
15. A polymer according to claim 2 , wherein R is an amine, alcohol, water, alkali halide, alkoxide, hydroxide, or a transition metal initiator.
16. A polymer according to claim 2 , wherein R′ is hydrogen or carboxylate.
17. A polymer according to claim 3 , wherein R is n-butylamine or mPEG-amine.
18. A polymer according to claim 3 , wherein R 2 is selected from the group consisting of: