Site specific delivery of nucleic acids by combining targeting ligands with endosomolytic components

1. A method of inhibiting the expression of a Hepatitis B Virus gene in a cell, comprising contacting the cell with an effective amount of a modular composition, comprising a nucleic acid, at least one endosomolytic component, and at least one targeting ligand, the composition having the formula:

wherein

is the nucleic acid;

E is the endosomolytic component;

L is the targeting ligand;

x represents independently for each occurrence 0 or 1;

y represents independently for each occurrence 1, 2, 3, 4, 5, or 6;

z in formula (I) is 1, 2, 3, 4, 5, or 6 in one instance, and 0, 1, 2, 3, 4, 5, or 6 in the other instance; and z in formula (II) represents independently for each occurrence 1, 2, 3, 4, 5, or 6;

A is a linking moiety selected from the group consisting of:

wherein

Z 1 represents independently for each occurrence O or S;

Z 2 represents independently for each occurrence —OH, —OM, —Oalkyl, —Oaryl, —Oaralkyl, —SH, —SM, —Salkyl, —Saryl, -aralkyl, —N(R 3 )R 4 , —C(R 11 ) 2 ) m N(R 11 ) 2 , —N(R 11 )(C(R 11 ) 2 ) m N(R 11 ) 2 , or alkyl;

R 3 and R 4 represent independently H or alkyl; or R 3 and R 4 taken together form a 3-, 4-, 5-, 6-, or 7-membered ring;

R 11 represents independently for each occurrence hydrogen or alkyl;

M represents independently for each occurrence an alkali metal or a transition metal with an overall charge of +1;

R 8 represents independently for each occurrence hydrogen, alkyl, aryl, aralkyl, acyl, silyl, a bond to the nucleic acid, or, when combined with B 10 , a bond between linking moieties;

B 10 is a bond between A and the nucleic acid or, when combined with R 8 , is a bond between linking moieties;

A′ is a direct bond or a tether having the formula: —[(P-Q-R) q —X—(P′-Q′-R′) q′ ] q″ -T-,

wherein:

P, R, T, P′ and R′ are each independently absent, CO, NH, O, S, OC(O), NHC(O), CH 2 , CH 2 NH, CH 2 O; NHCH(R a )C(O), —C(O)—CH(R a )—NH—, C(O)-(optionally substituted alkyl)-NH—, CH═N—O,

cyclyl, heterocyclyl, aryl or heteroaryl;

R 50 and R 51 are independently alkyl, substituted alkyl, or R 50 and R 51 taken together form a cyclic ring;

Q and Q′ are each independently for each occurrence absent, —(CH 2 ) n —, —C(R 40 )(R 41 )(CH 2 ) n —, —(CH 2 ) n C(R 40 )(R 41 )—, —(CH 2 CH 2 O) m CH 2 CH 2 —, —(CH 2 CH 2 O) m CH 2 CH 2 NH—, aryl, heteroaryl, cyclyl, or heterocyclyl;

X is absent or a cleavable linking group;

R a is H or an amino acid side chain;

R 40 and R 41 are each independently H, CH 3 , OH, SH or N(R X ) 2 ;

R X is, for each occurrence, H, methyl, ethyl, propyl, isopropyl, butyl or benzyl;

q, q′ and q″ are each independently 0-30;

n is, for each occurrence, an integer from 1-20; and

m is, for each occurrence, an integer from 0-50;

provided that E and L are each present at least once,

wherein the nucleic acid inhibits the expression of the Hepatitis B Virus gene within the cell.

2. The method of claim 1 , wherein the composition has the formula:

3. The method of claim 1 , wherein the composition has the formula:

wherein each z is independently 1, 2, 3, 4, 5, or 6.

4. The method of claim 1 , wherein the nucleic acid is an iRNA agent.

5. The method of claim 1 , wherein the nucleic acid contains at least one sugar modification.

6. The method of claim 1 , which is performed in vitro, ex vivo or in vivo.

7. The method of claim 1 , wherein the cell is in a subject.

8. The method of claim 7 , wherein the subject is a mammal.

9. The method of claim 8 , wherein the mammal is a human.

10. The method of claim 9 , wherein the human has been diagnosed with a Hepatitis B Virus infection.