Compositions for targeted delivery of siRNA

摘要

The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to hepatocytes in vivo. Targeted RNAi polynucleotides are administered together with co-targeted delivery polymers. Delivery polymers provide membrane penetration function for movement of the RNAi polynucleotides from outside the cell to inside the cell. Reversible modification provides physiological responsiveness to the delivery polymers.

主权项

1. A conjugate delivery system for delivering an RNA interference polynucleotide to a liver cell in vivo comprising: wherein, P is a membrane active polyamine L2 is a disubstituted maleamate linkage, M1 is a charge neutral masking agent containing a galactose derivative having affinity for the asialoglycoprotein receptor, M2 is a charge neutral masking agent containing a polyethylene glycol, y is an integer greater than or equal to 1, z is an integer greater than or equal to zero, the value y+z is greater than 50% of amines on P, N is an RNA interference polynucleotide, A comprises a galactose trimer, positive charge of P is neutralized and membrane activity of P is reversibly inhibited by modification of greater than 50% of P amines by attachment of M1 and M2 through the physiologically pH-labile maleamate linkage linkages L2, and cleavage of L2 restores amines and membrane activity of P.