| 主权项 |
1. 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 represents independently for each occurrence 0, 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—,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. |
