Membrane lytic poly(amido amine) polymers for the delivery of oligonucleotides

1. A polymer conjugate composition comprising

i) a polymer of Formula Z or Formula Z′ or stereoisomer thereof:

wherein:

n is 2 to 250,

R is a capped end group selected from the group consisting of a primary amine and secondary amine,

R′ is hydrogen or methylene,

R 1 is independently selected from the group consisting of a primary amine, secondary amine, tertiary amine, and quaternary amine, and

R 2 is independently selected from the group consisting of a primary amine, secondary amine, tertiary amine, quaternary amine, a heterocyclic amine, and a lipophilic group;

ii) an oligonucleotide covalently linked to R 1 or R 2 of the polymer via a linker; and

iii) a masking agent and/or a targeting ligand covalently linked to R 1 or R 2 of the polymer.

2. The polymer conjugate composition of claim 1 , wherein the polymer is a polymer of Formula Z′, and wherein:

R is C 4 H 10 N;

R′ is hydrogen;

R 1 is independently selected from the group consisting of aminoethoxy, 2-(2-aminoethoxy)ethyl, 2-[2-(2-aminoethoxy)ethoxy]ethyl, 2-[2-(2-aminoethoxy)ethoxy]ethyl, 3-amino-2-hydroxypropyl, 2-aminoethyl, 4-aminobutyl, 6-aminohexyl, 8-aminooctyl, and 10-aminodecyl; and

R 2 is independently selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, 2-(2-aminoethoxy)ethyl, 2-[2-(2-aminoethoxy)ethoxy]ethyl, 2-[2-(2-aminoethoxy)ethoxy]ethyl, 3-amino-2-hydroxypropyl, 2-aminoethyl, 4-aminobutyl, 6-aminohexyl, 8-aminooctyl, 10-aminodecyl, 2-(1H-imidazol-4-yl)ethyl, 2-(4-methyl-1H-imidazol-5-yl)ethyl, 2-(1-Ethyl-1H-imidazol-4-yl)-ethyl, 2-(5-Methyl-3H-imidazol-4-yl)-ethyl, 2-(2-isopropyl-1-methyl-1H-imidazol-4-yl)ethyl, 2-(1-butyl-1H-imidazol-4-yl)ethyl, 2-(1-hexyl-1H-imidazol-4-yl)ethyl, 2-(1-octyl-1H-imidazol-4-yl)ethyl, 2-(1-dodecyl-1H-imidazol-4-yl)ethyl, 2-pyridin-4-yl ethyl, 2-(2,6-dimethylpyridin-4-yl)ethyl, 2_pyridin-2-yl ethyl, 2-pyridin-3-yl ethyl, 2-piperazin-1-yl ethyl, [4-(2-ethyl)piperidin-1-yl]methanol, and 2-morpholin-4-ylethyl.

3. The polymer conjugate composition of claim 2 , wherein:

R 1 is aminoethoxy; and

R 2 is independently selected from the group consisting of dodecyl, 2-(1H-imidazol-4-yl)ethyl, and 2-(2-aminoethoxy)ethyl.

4. The polymer conjugate composition of claim 3 , wherein the polymer has the formula:

wherein the polymer is random or block, and wherein each n is independently 0 to 60, provided that the sum of the n variables is at least 2.

5. The polymer conjugate composition of claim 4 , wherein each n is independently 1 to 60.

6. The polymer conjugate composition of claim 1 , wherein the composition includes a masking agent, and the masking agent is a maleic anhydride derivative, or a disubstituted maleic anhydride derivative.

7. The polymer conjugate composition of claim 1 , wherein the composition includes a targeting ligand, and the targeting ligand is selected from the group consisting of carbohydrates, glycans, galactose and its derivatives, mannose and its derivatives, vitamins, folate, biotin, aptamers, RGD-containing peptides, insulin, EGF, and transferrin.

8. The polymer conjugate composition of claim 7 , wherein the targeting ligand is N-acetylgalactosamine (NAG), mannose, or glucose.

9. The polymer conjugate composition of claim 1 , wherein the masking agent and/or targeting ligand is carboxy dimethylmaleic anhydride of N-acetylgalactosamine (CDM-NAG) or carboxy dimethylmaleic anhydride of polyethylene glycol (CDM-PEG).

10. The polymer conjugate composition of claim 9 , wherein the polymer conjugate has the structure of:

wherein the polymer is random or block, and wherein each n is independently 0 to 60, provided that the sum of the n variables is at least 2.

11. The polymer conjugate composition of claim 10 , wherein each n is independently 1 to 60.

12. The polymer conjugate composition of claim 1 , wherein the oligonucleotide is an siRNA, miRNA, or antisense.

13. The polymer conjugate composition of claim 12 , wherein the oligonucleotide is an siRNA.

14. The polymer conjugate composition of claim 13 , wherein the siRNA comprises a passenger strand and a guide strand, and wherein the 5′ end of the passenger strand of the siRNA is covalently linked to the polymer.

15. The polymer conjugate composition of claim 1 , wherein the linker is a derivative of (4-succinimidyloxycarbonyl-α-methyl-α-[2-pyridyldithio]toluene) (SMPT) or a derivative of (N-succinimidyl-S-acetylthioacetate) (SATA).

16. The polymer conjugate composition of claim 2 , wherein the polymer conjugate has the structure of:

wherein the polymer is random or block, and wherein each n is independently 0 to 60, provided that the sum of the n variables is at least 2.

17. The polymer conjugate composition of claim 16 , wherein each n is independently 1 to 60.