| 摘要 |
Described herein are copolymers, and methods of making and utilizing such copolymers. Such copolymers have at least two blocks: a first block that has at least one unit that is hydrophilic at physiologic pH, and a second block that has hydrophobic groups. This second block further has at least one unit with a group that is anionic at about physiologic pH. The described 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 copolymer disrupts the membrane and enters the intracellular environment. In specific examples, the copolymer is endosomolytic. |
| 主权项 |
1. A composition comprising:
(a) a copolymer comprising a diblock copolymer, the diblock copolymer having the chemical Formula I: wherein A0, A1, A2, A3, and A4 are independently selected from the group consisting of —C—, —C—C—, —C(O)(C)aC(O)O—, —O(C)aC(O)— and —O(C)bO—; wherein,
a is 1-4;b is 2-4; Y4 is selected from the group consisting of hydrogen, -(1C-10C)alkyl, -(3C-6C)cycloalkyl, —O(1C-10C)alkyl, —C(O)O(1C-10C)alkyl, —C(O)NR6(1C-10C) and aryl, any of which is optionally substituted with one or more fluorine groups; Y0, Y1 and Y2 are independently selected from the group consisting of a covalent bond, —(1C-10C)alkyl-, —C(O)O(2C-10C) alkyl-, —OC(O)(1C-10C) alkyl-, —O(2C-10C)alkyl-, —S(2C-10C)alkyl-, and —C(O)NR6(2C-10C) alkyl-; Y3 is selected from the group consisting of a covalent bond, -(1C-10C)alkyl- and -(6C-10C)aryl-; wherein tetravalent carbon atoms of A0-A4 that are not fully substituted with R1-R5 and Y0-Y4 are completed with an appropriate number of hydrogen atoms; R1, R2, R3, R4, R5, and R6 are independently selected from the group consisting of hydrogen, —CN, alkyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, any of which is optionally substituted with one or more fluorine atoms; Q0 is a residue selected from the group consisting of residues which are hydrophilic at physiologic pH; conjugatable residues; functionalizable residues; and hydrogen; Q1 is a residue which is hydrophilic at normal physiological pH; Q2 is a residue which is positively charged at normal physiological pH; Q3 is a residue which is negatively charged at normal physiological pH, but undergoes protonation at lower pH; m is a mole fraction of 0 to less than 1.0; n is a mole fraction of greater than 0 to 1.0; wherein m+n=1; p is a mole fraction of 0.1-0.9; q is a mole fraction of 0.1 to 0.9; r is present up to a mole fraction of 0.8; wherein p+q+r=1; v is from 1 to 25 kDa; and w is from 1 to 50 kDa; and (b) a therapeutic agent. |
