Poly(acrylate) polymers for in vivo nucleic acid delivery

摘要

The present invention is directed membrane active poly(acrylate) polymers and compositions for targeted delivery of RNA interference (RNAi) polynucleotides cells in vivo. RNAi polynucleotides are conjugated to the poly(acrylate) polymers and the polymers are reversibly modified to enable in vivo targeted delivery. Membrane activity of the poly(acrylate) provides for movement of the RNAi polynucleotides from outside the cell to inside the cell. Reversible modification provides physiological responsiveness.

主权项

1. A membrane active poly(acrylate) random copolymer having the structure represented by: wherein:
N is —NH2 or —N—CO—O—C—(CH3)3,Y is —(CH2)a— or —(CH2—CH2—O)b—(CH2)c— wherein a, b, and c are independently 1, 2, 3, 4, 5, or 6,N′ is —NR5H, —NR5R6, —NR5R6R7, nitrogen heterocycle, aldimine, hydrazide, hydrazone, or imidazole, wherein R5, R6, and R7 are independently selected from —CH3 and —CH2—CH3,Y′ is an uncharged linker group containing 1-12 carbon atoms, one or more of which may be substituted for heteroatoms,R is a hydrophobic group having 2-6 carbon atoms or an alkoxy ethyl group,m and p are independently integers greater than zero (0),n is an integer greater than or equal to zero (0),the ratio (m+n)/(p) is 0.67-5.7, andthe polydispersity of the poly(acrylate) random copolymer is less than 1.5.