| 主权项 |
1. A method for delivery of a drug across biological membranes, the method comprising utilization of a Conjugate, having the structure as set forth in Formula (I): including pharmaceutically acceptable salts, hydrates, solvates and metal chelates of the compound represented by the structure as set forth in Formula (I), and solvates and hydrates of the salts, wherein: D is a drug to be delivered across biological membranes, selected from a group consisting of a small-molecule drug, a peptide, a protein, and a native or modified, single-stranded or double-stranded DNA or RNA, siRNA or ASO; y, z and w are each an integer, independently selected from 0, 1, 2, 3, 4, 5, 6; at least one of y, z or w is different from 0. E, E′, or E″ can be the same or different, each having the structure as set forth in general Formula (II):
(A)a-B-L1-Q1-L2-Q2-L3 Formula (II) wherein B is selected from the group consisting of: linear, cyclic or branched C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, alkyl or hetero-alkyl; linear, cyclic or branched C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 alkylene or heteroalkylene; C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 aryl or heteroaryl; one or more steroid moiety (such as, cholesterol, bile acid, estrogen, estradiol, estriol), nucleoside, nucleotide; and any combination thereof; and wherein one or more hydrogen atom(s) of B is optionally substituted by halogen, hydroxyl, methoxy, fluorocarbon, amine, or thiol; Q1 and Q2 are each an optionally cleavable group, independently selected from null, ester, thio-ester, amide [e.g., —C(═O)—NH— or —NH—C(═O)—], carbamate [e.g., —O—C(═O)—NH— or —NH—C(═O)—O—], urea [—NH—C(═O)—NH—], disulfide [—(S—S)—], ether [—O—], imidazole, triazole, a pH-sensitive moiety, a redox-sensitive moiety; a metal chelator, including its chelated metal ion; and any combinations thereof; L1, L2 and L3 are each independently selected from null and the group consisting of: linear, cyclic or branched C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14, alkyl or hetero-alkyl; linear, cyclic or branched C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14 alkylene or heteroalkylene; C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14 aryl or heteroaryl; —(O—CH2—CH2)u—, wherein u is an integer of 1, 2, 3, 4 or 5; nucleoside, nucleotide; imidazole, azide, acetylene; and any combinations thereof; wherein each group is optionally substituted by one or more of halogen, hydroxyl, methoxy, fluorocarbon, amine, or thiol; wherein each of Q1, Q2, L1, L2 and L3 optionally comprises a T moiety; wherein T is an initiator group, selected from C4, C5, C6—1,2-dithiocycloalkyl (1,2-dithiocyclo-butane; 1,2-dithiocyclo-pentane; 1,2-dithiocyclohexane; 1,2-dithiocycloheptane); γ-Lactam (5 atoms amide ring), δ-Lactam (6 atoms amide ring) or ∈-Lactam (7 atoms amide ring); γ-butyrolactone (5 atoms ester ring), δ-valerolactone (6 atoms ester ring) or ε-caprolactone (7 atoms ester ring); and wherein one or more hydrogen atom(s) of T is optionally substituted by halogen, hydroxyl, methoxy, fluorocarbon, amine, or thiol. Each A moiety is independently selected from the structures as set forth in Formulae (III), (IV), (V) and (VI): M is selected from —O— or —CH2—; and g, h and k are each individually an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16; * is —H, or a point of linkage to B; a is an integer, selected from 1, 2, 3 or 4. |
