In vivo polynucleotide delivery conjugates having enzyme sensitive linkages

A compound for reversibly modifying an amphipathic membrane active polyamine having the structure represented by:

• wherein
• R comprises a steric stabilizer
• R1 is a side chain of the hydrophobic amino acid,
• R2 is a side chain of the hydrophilic uncharged amino acid, wherein said hydrophilic uncharged amino acid is uncharged at neutral pH,
• —Y— is —NH—, or —O—,
• R5 is at position 2, 4, or 6 and is —CH2—O—C(O)—Z wherein —Z is
• R6 is independently hydrogen, alkyl, —(CH2)m—CH3, —(CH2)—(CH3)2, or halide at each of positions 2, 3, 4, 5, or 6 except for the position occupied by R5 and n and m are independently integers from 0 to 4.

A delivery polymer for delivering a polynucleotide to a cell in vivo comprising:

• M1y-P-M2z
• wherein:
• P is an amphipathic membrane active polyamine,
• M1 comprises a targeting ligand linked to P via a dipeptide-amidobenzyl-carbamate linkage,
• M2 comprises a steric stabilizer linked to P via a dipeptide-amidobenzyl-carbamate linkage,
• y and z are each integers greater than or equal to zero,
• y+z has a value greater than 50% of the primary amines on polyamine P as determined by the quantity of amines on P in the absence of any masking agents, and
• the dipeptide-amidobenzyl-carbamate linkage has the structure represented by:
• R-A1A2-amidobenzyl-carbamate-P
• wherein
• R comprises the targeting ligand of M1 or the steric stabilizer of M2,
• A1 is a hydrophobic amino acid, and
• A2 is a hydrophilic uncharged amino acid linked to A1 via an amide bond, wherein said hydrophilic uncharged amino acid is uncharged at neutral pH, and
• P is the amphipathic membrane active polymer.