Endosomolytic Poly-Beta-Aminoester Polymers

Abstract

The present invention is directed to membrane active polymers useful for cellular delivery of compounds. Described are polyconjugates systems that incorporate targeting, anti-opsonization, anti-aggregation, and transfection activities into small biocompatible in vivo delivery conjugates. The use of reversible modification provides for physiologically responsive activity modulation.

1 . A membrane active random poly-β-aminoester comprising: a plurality of amine-containing monomers, a plurality of first hydrophobic monomers, and a plurality of second hydrophobic monomers wherein said first and second hydrophobic monomers are different. 
     
     
         2 . The membrane active poly-β-aminoester of  claim 1  wherein said first and second hydrophobic monomers contain hydrophobic groups selected from the list consisting of: alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, and aralkynyl group, each of which may be linear, branched, or cyclic and may can contain one or more substitutions or heteroatoms, sterol, steroid, and steroid derivative. 
     
     
         3 . The membrane active poly-β-aminoester of  claim 2  wherein said first hydrophobic monomer contain of lower hydrophobic groups and said second hydrophobic groups contain higher hydrophobic groups. 
     
     
         4 . The membrane active poly-β-aminoester of  claim 3  wherein said first hydrophobic monomers contain butyl groups and said second hydrophobic monomers contain octadecyl groups. 
     
     
         5 . The membrane active poly-β-aminoester of  claim 3  wherein the amine monomers, first hydrophobic monomers and second hydrophobic monomers are present in a ratio of about 5.4-7.5 amine monomers to about 3-3.5 lower alkyl monomers to about 1 higher alkyl monomer. 
     
     
         6 . The membrane active poly-β-aminoester of  claim 1  wherein the poly-β-aminoester further comprises one or more third hydrophobic monomers wherein said third hydrophobic monomers are different from said first and second hydrophobic monomers. 
     
     
         7 . The membrane active poly-β-aminoester of  claim 6  wherein said third hydrophobic monomers contain hydrophobic groups selected from the group consisting of: aryl group, aralkyl group, aralkenyl group, aralkynyl group, sterol, steroid, and steroid derivative. 
     
     
         8 . The membrane active poly-β-aminoester of  claim 1  wherein the poly-β-aminoester further comprises one or more monomers containing targeting groups. 
     
     
         9 . The membrane active poly-β-aminoester of  claim 8  wherein the targeting groups are selected from the group consisting of: cell receptor ligand, saccharide, galactose, galactose derivative, mannose, mannose derivative, aptamer, folate, biotin, vitamin, vitamin A, vitamin D, peptide, and Arg-Gly-Asp (RGD)-containing peptide. 
     
     
         10 . A reversibly masked membrane active random poly-β-aminoester comprising: a plurality of amine-containing monomers, a plurality of first hydrophobic monomers, and a plurality of second hydrophobic monomers wherein said first and second hydrophobic monomers are different and wherein one or more amines of the amine-containing monomers are linked to masking agents via physiologically labile bonds thereby inhibiting membrane activity of the membrane active random poly-β-aminoester. 
     
     
         11 . The reversibly masked membrane random poly-β-aminoester of  claim 10  wherein said first and second hydrophobic monomers contain hydrophobic groups selected from the list consisting of: alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, and aralkynyl group, each of which may be linear, branched, or cyclic and may can contain one or more substitutions or heteroatoms, sterol, steroid, and steroid derivative. 
     
     
         12 . The reversibly masked membrane active random poly-β-aminoester of  claim 11  wherein said first hydrophobic monomer contain of lower hydrophobic groups and said second hydrophobic groups contain higher hydrophobic groups. 
     
     
         13 . The reversibly masked membrane active random poly-β-aminoester of  claim 12  wherein said first hydrophobic monomers contain butyl groups and said second hydrophobic monomers contain octadecyl groups. 
     
     
         14 . The reversibly masked membrane active random poly-β-aminoester of  claim 12  wherein the amine monomers, first hydrophobic monomers and second hydrophobic monomers are present in a ratio of about 5.4-7.5 amine monomers to about 3-3.5 lower alkyl monomers to about 1 higher alkyl monomer. 
     
     
         15 . The reversibly masked membrane active random poly-β-aminoester of  claim 10  wherein the poly-β-aminoester further comprises one or more third hydrophobic monomers wherein said third hydrophobic monomers are different from said first and second hydrophobic monomers. 
     
     
         16 . The reversibly masked membrane active random poly-β-aminoester of  claim 15  wherein said third hydrophobic monomers contain hydrophobic groups selected from the group consisting of: aryl group, aralkyl group, aralkenyl group, aralkynyl group, sterol, steroid, and steroid derivative. 
     
     
         17 . The reversibly masked membrane active random poly-β-aminoester of  claim 10  wherein the poly-β-aminoester further comprises one or more monomers containing targeting groups. 
     
     
         18 . The reversibly masked membrane active random poly-β-aminoester of  claim 17  wherein the targeting groups are selected from the group consisting of: cell receptor ligand, saccharide, galactose, galactose derivative, mannose, mannose derivative, aptamers, folate, biotin, vitamin A, vitamin D, peptide, and Arg-Gly-Asp (RGD)-containing peptide. 
     
     
         19 . The reversibly masked membrane active random poly-β-aminoester of  claim 10  wherein said masking agents are selected from the group consisting of: targeting groups, steric stabilizers, charge modifiers, and combinations of targeting groups, steric stabilizers, and charge modifiers.