Tetragalnac containing conjugates and methods for delivery of oligonucleotides

1. A modular composition, comprising:

1) a single stranded oligonucleotide, containing n nucleotides, represented by:

[O 1 ][O 2 ][O 3 ] . . . [O n], or

a double stranded oligonucleotide, containing n and n′ nucleotides respectively, represented by:

[O 1 ][O 2 ][O 3 ] . . . [O n]

[O n′ ] . . . [O 3′ ][O 2′ ][O 1′ ],

wherein n and n′ are the same or different integers ranging from 8 to 50;

2) one or more tetraGalNAc ligands of Formula (I), (II) or (III), which may be the same or different, represented by G:

wherein:

X′ is —O—, —S—, —CR 1 R 2 — or —NR 1 —, wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

m is 1, 2, 3, or 4; and

the bond with “ ” indicates the point of attachment of the tetraGalNAc ligands to the oligonucleotide, either directly or through one or more linkers; and

optionally, 3) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents, represented by X; and

4) one or more linkers which may be the same or different, represented by L, that attach G or X to the oligonucleotide through the terminal 3′ and/or 5′ positions of the oligonucleotide, and/or an internal 2′ position of the oligonucleotide.

2. The modular composition of claim 1 , wherein:

1) n and n′ are the same or different integers ranging from 12 to 28;

2) the modular composition comprises 1-8 of the tetraGalNAc ligands of Formula (I), (II) or (III), wherein X′ is —O—, —S—, —CH 2 — or —NH—; and m is 1, 2, 3, or 4; and

3) the modular composition optionally comprises 1-8 of the targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents; and

4) the modular composition comprises 1-16 of the linkers.

3. The modular composition of claim 2 , wherein the two nucleotides [O n-1 ] and [O n ] or [O n′-1 ] and [O n′ ] are connected via phosphodiester or thio-phosphodiester bonds.

4. The modular composition of claim 2 , wherein at least one of the nucleotides is a modified nucleotide comprising a modification selected from the group consisting of 2′ sugar modification, a base modification, and a phosphate modification in a single strand overhang.

5. The modular composition of claim 4 , wherein at least one of the nucleotides has an inverted base modification.

6. The modular composition of claim 5 , wherein at least one of the nucleotides has an inverted abasic modification.

7. The modular composition of claim 2 , wherein the oligonucleotide contains at least one L attaching the G and/or X to an internal 2′ position of the oligonucleotide, wherein the attached nucleotide [O n ] or [O n′ ] has the structure of:

wherein:

each E is independently O or S;

each Base is independently A, U, G or C, which can be modified or unmodified;

each D is independently the connection point between the ribose ring of the nucleotide and G and/or X, selected from the group consisting of —O—, —S—, —S(O)—, —S(O) 2 —, —NR—, —CHR—, —P(O)R—, or —P(O)(OR)—; and

each R is independently alkyl or a L.

8. The modular composition of claim 2 , wherein the oligonucleotide contains at least one L attaching the G and/or X to the terminal 3′ and/or 5′ positions of the oligonucleotide.

9. The modular composition of claim 8 , wherein the modular composition has the structure of: G-L-[O 1 ][O 2 ][O 3 ] . . . [O n ].

10. The modular composition of claim 8 , wherein the modular composition has the structure of: G-L-[O 1 ][O 2 ][O 3 ] . . . [O n ] -X.

11. The modular composition of claim 8 , wherein the modular composition has the structure of:

12. The modular composition of claim 8 , wherein the modular composition has the structure of:

13. The modular composition of claim 8 , wherein the modular composition has the structure of:

14. The modular composition of claim 8 , wherein the modular composition has the structure of:

15. The modular composition of claim 8 , wherein the modular composition has the structure of:

16. The modular composition of claim 8 , wherein the modular composition has the structure of:

17. The modular composition of claim 8 , wherein the modular composition has the structure of:

18. The modular composition of claim 8 , wherein the modular composition has the structure of:

19. The modular composition of claim 8 , wherein the modular composition has the structure of:

20. The modular composition of claim 8 , wherein the modular composition has the structure of: