| 摘要 |
Described herein are block copolymers, and methods of making and utilizing such copolymers. The described block copolymers are disruptive of a cellular membrane, including an extracellular membrane, an intracellular membrane, a vesicle, an organelle, an endosome, a liposome, or a red blood cell. Preferably, in certain instances, the block copolymer disrupts the membrane and enters the intracellular environment. In specific examples, the block copolymer is endosomolytic and capable of delivering an oligonucleotide (e.g., an mRNA) to a cell. Compositions comprising a block copolymer and an oligonucleotide (e.g., an mRNA) are also disclosed. |
| 主权项 |
1. A block copolymer having the formula VII
T1-L1-[A]x′-b-[B1-B2-B3-B4]y′Z VII wherein T1 is absent or a first targeting moiety; L1 is absent or a linking moiety; A is a first block that is a polymer formed from monomers comprising formula A2 or a random copolymer formed from monomers comprising formulae A2 and A3; A2, A4 and A5; A2 and A5; or A4 and A5; wherein n is 1-120, R3 is H or C1-C6 alkyl, R4 is S, O, NH or N(C1-C6 alkyl), R5 is O or S and R6 is H, C1-C6 alkyl, C1-C6 alkyl-NH2, C1-C6 alkyl-NH(C1-C6 alkyl), C1-C6 alkyl-N(C1-C6 alkyl)2; wherein R7 and R10 independently H or C1-C6 alkyl, R8 is S, O, NH or N(C1-C6 alkyl), and R9 is O or S and R11 is an amine protecting group; wherein n is 1-230, R17 is H or C1-C6 alkyl, R18 is O, S, NH or N(C1-C6 alkyl), R19 is O or S, and R20 is OH, NH, H, T2, or C1-C6 alkyl, where T2 is a second targeting moiety; wherein R21 is H or C1-C6 alkyl, R22 is O, NH or N(C1-C6 alkyl), R23 is H, aryl, arylhalide, alkyl, alkyl alcohol; B is a second block that is a random copolymer formed from monomers comprising formulae B1, B2, B3 and B4 or B1, B2 and B3wherein R12, R13, R14, R15, R16 and R17 are independently H or C1-C6 alkyl, R18 is O, S, NH, N(C1-C6 alkyl), or (OCH2CH2)1-120, and Q is selected from the group consisting of (i) S—S-G, (ii) (OCH2CH2)1-120—S—S-G, (iii) V-L3-G wherein V is an amide, ester, imine, oxime, thioester, product of a [3+2] cycloaddition, product of a [4+1] cycloaddition, carbonate, carbamate, urea, acetal, ketal, or hydrazone, and L3 is C1-C6 alkyl, (OCH2CH2)1-50, C1-C6 alkyl-(OCH2CH2)1-50, or thioether,wherein R29 is C1-C6 alkyl, (OCH2CH2)1-50, C1-C6 alkyl-(OCH2CH2)1-50, O, NH, or N(C1-C6 alkyl),
(vii) S—S-L2-G wherein L2 is wherein n=1-35 and designates a point of attachment of L2 to G, and (viii) S—S-pyridyl, wherein G is a cationic peptide, polyamine, or polycation; x is 2-20 kDa; y is 2-20 kDa; Z is H, SH, C(CH3)2CN orwherein R24 is S—(C1-C12 alkyl), aryl, arylhalide, O—(C1-C12 alkyl), NR25R26 wherein R25 and R26 are independently H, alkyl, aryl, or heteroaryl;
the ratio of x to y is from 2:1 to 1:4; and designates a point of attachment. |
