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

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
• Z1 represents independently for each occurrence O or S;
• Z2 represents independently for each occurrence —OH, —OM, —Oalkyl, —Oaryl, —Oaralkyl, —SH, —SM, —Salkyl, —Saryl, -aralkyl, —N(R3)R4, —C(R11)2)mN(R11)2, —N(R11)(C(R11)2)mN(R11)2, or alkyl;
• R3 and R4 represent independently H or alkyl;
• or R3 and R4 taken together form a 3-, 4-, 5-, 6-, or 7-membered ring;
• R11 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;
• R8 represents independently for each occurrence hydrogen, alkyl, aryl, aralkyl, acyl, silyl, a bond to the nucleic acid, or, when combined with B10, a bond between linking moieties;
• B10 is a bond between A and the nucleic acid or, when combined with R8, 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), CH2, CH2NH, CH2O;
• NHCH(Ra)C(O), —C(O)—CH(Ra)—NH—, C(O)-(optionally substituted alkyl)-NH—, CH═N—O,
• cyclyl, heterocyclyl, aryl or heteroaryl;
• R50 and R51 are independently alkyl, substituted alkyl, or R50 and R51 taken together form a cyclic ring;
• Q and Q′ are each independently for each occurrence absent, —(CH2)n—, —C(R40)(R41)(CH2)n—, —(CH2)nC(R40)(R41)—, —(CH2CH2O)mCH2CH2—, —(CH2CH2O)mCH2CH2NH—, aryl, heteroaryl, cyclyl, or heterocyclyl;
• X is absent or a cleavable linking group;
• Ra is H or an amino acid side chain;
• R40 and R41 are each independently H, CH3, OH, SH or N(RX)2;
• RX 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.