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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): or 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 the 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 or 6, wherein whenever the integer is 0, it means that the respective E moiety is null; 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 each A moiety is independently selected from the structures as set forth in Formulae (III), (IV), (V) and (VI): M is selected from null, —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, or to another A group; a is an integer, selected from 1, 2, 3 or 4; Q is oxygen or amine. wherein B is selected from one or more groups consisting of : a linear, cyclic or branched C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, alkyl or hetero-alkyl, wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine or thiol; or optionally linked to an ether, an ester, or an amide group; linear, cyclic or branched C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 alkylene or heteroalkylene, wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine or thiol; or optionally linked to an ether, an ester, or an amide group; C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 aryl or heteroaryl, wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine thiol; or optionally linked to an ether, an ester, or an amide group; one or more steroid moiety, wherein the steroid moiety ischolesterol, bile acid, estrogen, estradiol, estriol, lithocholic acid or any analog thereof or a nucleoside or nucleotide; or any combination thereof, wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine or thiol; or each is optionally linked to an ether, an ester, an amine, or an amide group; and any combination thereof; Q1 and Q2 are each a 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—], amine, imidazole, triazole, dilactone; a metal chelator selected from BAPTA and EGTA, 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, wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine, or thiol; or linked to an ether group; linear, cyclic or branched C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14 alkylene or heteroalkylene, wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine, thiol; or linked to an ether group; C5, C6, C7, C8, C9, C10, C11, C12, C13 or C14 aryl or heteroaryl, wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine, thiol; or linked to an ether group; —(O—CH2—CH2)u—, wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine, or thiol; nucleoside, nucleotide; imidazole, azide, acetylene; and any combinations thereof, wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine, thiol; or linked to an ether group; and wherein u is an integer of 1, 2, 3, 4 or 5; and any combinations thereof; wherein at least one of Q1, Q2, L1, L2 and L3 is not null, and 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 ε-Lactam (7 atoms amide ring); γ-butyrolactone (5 atoms ester ring), δ-valerolactone (6 atoms ester ring) or ε-caprolactone (7 atoms ester ring); wherein each is optionally substituted by one or more halogen, hydroxyl, methoxy, fluorocarbon, amine, or thiol; wherein at least one of B, Q1, Q2, L1, L2 and L3 is conjugated to a drug as defined in Formula (I). |
