Dual molecular delivery of oligonucleotides and peptide containing conjugates
Disclosed herein is a method for inhibiting expression of a gene of a subject comprising administering (1) a composition comprising R-(L) a -(G) b ; 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; G is a targeting ligand and each occurrence of G is independently selected from Table 4; each of a and b is independently 0, 1, 2, 3 or 4; and (2) a composition comprising (P) c -(L) d -(G) e ; wherein P is a peptide and each occurrence of P is independently selected from Table 2; 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. Compositions in (1) and (2) can be co-administered or sequentially administered.
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:
G is a targeting ligand and each occurrence of G is independently selected from Table 4:
each of a and b is independently 0, 1, 2, or 3; 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 NOS: 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, or 4; and
each of c and e is independently 1, 2, 3, or 4.
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 L is independently selected from Table 3a:
4. The method of claim 1 , wherein each occurrence of G is independently selected from Table 4a:
5. The method of claim 4 , wherein G is a ligand of the following formula:
6. 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 or 2.
7. The method of claim 1 , comprising administering:
(1) a composition 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:
G is a targeting ligand and each occurrence of G is independently selected from Table 4a:
each of a and b is independently 0, 1 or 2; 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 NOS: 1697, 1701-1713, 1715-1734, 1738, 1740, 1741, 1744-1749, 1751-1753, 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 or 2.
8. The method of claim 7 , 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:
wherein P is a peptide selected from SEQ ID NOS: 1697, 1701-1713, 1715-1734, 1738, 1740, 1741, 1744-1749, 1751-1753, 1755, 1756, 1758-1786, 1788, and 1793-1802; and
wherein L of composition (2) is selected from:
wherein m is an integer selected from 0 to 10,
9. The method of claim 8 , wherein each L of compositions (1) and (2) is independently
10. 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.
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 sequentially administered about 0.1 to 1 hour apart.
12. 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.
13. 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 NOS: 1697, 1701-1713, 1715-1734, 1738, 1740, 1741, 1744-1749, 1751-1753, 1755, 1756, 1758-1786, 1788, and 1793-1802;
L is a linker and each occurrence of L is independently selected from Table 3 of claim 1 ;
G is a targeting ligand and each occurrence of G is independently selected from Table 4 of claim 1 ;
each of a and b is independently 0, 1, 2, or 3; and
each of c, d and e is independently 1, 2, 3, 4, or 5.
14. The composition of claim 13 , wherein Y comprises a ligand of the following formula:
15. The composition of claim 13 , wherein each of a and b is independently 0 or 1;
c is 1; and
each of d and e is an 1.
16. The composition of claim 13 , 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:
and
wherein each L of compositions (1) and (2) is independently selected from:
17. The composition of claim 13 , wherein R-(L) a -(G) b further comprises a lipid and/or solubilizing agent.
18. The composition of claim 13 , 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.