Dual molecular delivery of oligonucleotides and peptide containing conjugates

1. A method for inhibiting expression of a gene of a subject comprising administering:

(1) a composition comprising R-(L) a -(G) b to the subject; wherein:

R is an oligonucleotide selected from the group consisting of DNA, RNA, siRNA, and microRNA;

L is a linker and each occurrence of L is independently selected from Table 3:

TABLE 3

G is a targeting ligand and each occurrence of G is independently selected from Table 4:

TABLE 4

wherein each X is independently —O—, —S—, —CH 2 — or

—NH—; and each n is independently 1, 2, 3, or 4

wherein each n is independently an integer from 1 to 20

wherein each n is independently an integer from 1 to 20

wherein n is an integer between 1 and 100

wherein n is an integer between 1 and 100

wherein n is an integer between 1 and 100

and each of a and b is independently 0, 1, 2, 3 or 4; and

(2) a composition comprising (P) c -(L) d -(G) e to the subject; wherein:

P is a peptide and each occurrence of P is independently selected from SEQ ID No. 1-1802;

L is a linker and each occurrence of L is independently selected from Table 3;

G is a targeting ligand and each occurrence of G is independently selected from Table 4;

d is 0, 1, 2, 3, 4, 5 or 6; and

each of c and e is independently 1, 2, 3, 4, 5 or 6.

2. The method of claim 1 , wherein R is a double stranded siRNA or single stranded siRNA.

3. The method of claim 1 , wherein each occurrence of P is independently selected from the group consisting of SEQ ID NOS: 1697, 1701-1713, 1715-1734, 1738, 1740, 1741, 1744-1749, 1751-1753, 1755, 1756, 1758-1786, 1788, and 1793-1802.

4. The method of claim 1 , wherein each occurrence of L is independently selected from Table 3a:

TABLE 3a

5. The method of claim 1 , wherein each occurrence of G is independently selected from Table 4a:

TABLE 4a

wherein each X is independently —O—, —S—, —CH 2 — or —NH—;

and each n is independently 1, 2, 3, or 4

6. The method of claim 5 , wherein G is a ligand of the following formula:

7. The method of claim 1 , wherein:

each of a and b is independently 0, 1 or 2;

c is 1 or 2; and

each of d and e is independently 1, 2 or 3.

8. The method of claim 1 , comprising

administering composition (1) comprising R-(L) a -(G) b to the subject; wherein: R is an siRNA;

L is a linker and each occurrence of L is independently selected from Table 3a

TABLE 3a

G is a targeting ligand and each occurrence of G is independently selected from Table 4a:

TABLE 4a

wherein each X is independently —O—, —S—, —CH 2 — or —NH—;

and each n is independently 1, 2, 3, or 4

and each of a and b is independently 0, 1 or 2;

and administering composition (2) comprising (P) c -(L) d -(G) e to the subject; wherein:

P is a peptide and each occurrence of P is independently selected from the group consisting of SEQ ID NOS: 1697, 1701-1713, 1715-1734, 1738, 1740, 1741, 1744-1749, 17581-1753, 1755, 1756, 1758-1786, 1788, and 1793-1802;

L is a linker and each occurrence of L is independently selected from Table 3a;

G is a targeting ligand and each occurrence of G is independently selected from Table 4a; and

each of c, d and e is independently 1, 2 or 3.

9. The method of claim 8 , wherein:

L of R-(L) a -(G) b is selected from

wherein m is an integer selected from 0 to 10;

G of R-(L) a -(G) b is:

and

(P) c -(L) d -(G) e of composition (2) is:

and wherein L of composition (2) is selected from:

wherein m is an integer selected from 0 to 10,

10. The method of claim 9 , wherein L of composition (1)

11. The method of claim 1 , wherein:

the composition comprising R-(L) a -(G) b and the composition comprising (P) c -(L) d -(G) e are co-administered at the same time.

12. The method of claim 1 , wherein:

the composition comprising R-(L) a -(G) b and the composition comprising (P) c -(L) d -(G) e are sequentially administered about 0.1 to 1 hour apart.

13. The method of claim 1 , wherein the oligonucleotide is administered at a dose of 0.1 to 5 mpk; and the peptide is administered at a dose of 1 to 100 mpk.

14. A composition for dual molecular delivery of an oligonucleotide and a peptide conjugate comprising:

(1) R-(L) a -(G) b ; and

(2) (P) c -(L) d -(G) e ; wherein:

R is an oligonucleotide selected from the group consisting of DNA, RNA, siRNA, and microRNA;

P is a peptide and each occurrence of P is independently selected from SEQ ID No. 1-1802;

L is a linker and each occurrence of L is independently selected from Table 3 as shown in claim 1 ;

G is a targeting ligand and each occurrence of G is independently selected from Table 4 as shown in claim 1 ;

each of a and b is independently 0, 1, 2, 3 or 4; and

each of c, d and e is independently 1, 2, 3, 4, 5 or 6.

15. The composition of claim 14 , wherein:

R is an siRNA;

each occurrence of P is independently selected from the group consisting of SEQ ID NOS: 1697, 1701-1713, 1715-1734, 1738, 1740, 1741, 1744-1749, 17581-1753, 1755, 1756, 1758-1786, 1788, and 1793-1802;

each occurrence of L is independently selected from Table 3a:

TABLE 3a

each occurrence of G is independently selected from Table 4a:

TABLE 4a

wherein each X is independently —O—, —S—, —CH 2 — or —NH—;

and each n is independently 1, 2, 3, or 4

each of a and b is independently 0, 1 or 2;

c is 1 or 2; and

each of d and e is independently 1, 2 or 3.

16. The composition of claim 14 , wherein Y comprises a ligand of the following formula:

17. The composition of claim 14 , wherein each of a and b is

independently 0 or 1;

c is 1; and

each of d and e is 1.

18. The composition of claim 14 , wherein:

(1) G of R-(L) a -(G) b is:

and

each of a and b is 1; and

(2) (P) c -(L) d -(G) e is:

wherein P is a peptide selected from the group consisting of SEQ ID NOS: 1697, 1701-1713, 1715-1734, 1738, 1740, 1741, 1744-1749, 17581-1753, 1755, 1756, 1758-1786, 1788, and 1793-1802; and

wherein each L of compositions (1) and (2) is independently selected from:

19. The composition of claim 14 , wherein R-(L) a -(G) b further comprises a lipid and/or a solubilizing agent.

20. The composition of claim 14 , wherein:

the oligonucleotide is a double stranded siRNA; and

G is attached to the guide strand or the passenger strand of the siRNA at different 2′-positions of the ribose rings and/or at different terminal 3′ and/or 5′-positions.