Endosomolytic Modified Poly(Alcohol) and Poly(Amine) 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 heteropolymer comprising: a modified poly(alcohol) wherein hydroxyl groups on the poly(alcohol) are independently modified to contain cationic nitrogen-containing groups and hydrophobic pendent groups. 
     
     
         2 . The membrane active heteropolymer of  claim 1  wherein the modified poly(alcohol) comprises a modified poly(alcohol) wherein hydroxyl groups on the poly(alcohol) are independently modified to contain cationic nitrogen-containing groups, first hydrophobic pendent groups, and second hydrophobic pendent groups wherein said first and second hydrophobic pendent groups are different. 
     
     
         3 . The membrane active heteropolymer of  claim 2  wherein said first and second hydrophobic pendent groups are 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. 
     
     
         4 . The membrane active heteropolymer of  claim 3  wherein said first hydrophobic pendent groups consist of a lower hydrophobic groups and said second hydrophobic groups consist of higher hydrophobic groups. 
     
     
         5 . The membrane active heteropolymer of  claim 4  wherein said first hydrophobic pendent groups consist of a butyl groups and said second hydrophobic groups consist of octadecyl groups. 
     
     
         6 . The membrane active heteropolymer of  claim 4  wherein said cationic nitrogen-containing groups, lower hydrophobic groups and higher hydrophobic groups are present in a 6:3:1 ratio. 
     
     
         7 . The membrane active heteropolymer of  claim 4  wherein the heteropolymer further comprises one or more third hydrophobic pendent groups wherein said third hydrophobic pendent group is different from said first or second hydrophobic pendent group. 
     
     
         8 . The membrane active heteropolymer of  claim 7  wherein said third hydrophobic pendent group is selected from the group consisting of: aryl group, aralkyl group, aralkenyl group, aralkynyl group, sterol, steroid, and steroid derivative. 
     
     
         9 . The membrane active heteropolymer of  claim 1  wherein the modified poly(alcohol) comprises modified poly(vinyl alcohol). 
     
     
         10 . The membrane active heteropolymer of  claim 1  wherein the modified poly(vinyl alcohol) comprises a polymer selected from the group consisting of: poly(carbonate), poly(carbamate), mixed poly(carbonate)/poly(carbamate), poly(thiocarbonate), and poly(phosphocarbonate). 
     
     
         11 . A reversibly masked membrane active heteropolymer comprising: a modified poly(alcohol) wherein hydroxyl groups on the poly(alcohol) are independently modified to contain cationic nitrogen-containing groups and hydrophobic pendent groups wherein one or more of said cationic nitrogen-containing groups are linked to masking agents via physiologically labile bonds. 
     
     
         12 . The reversibly masked membrane active heteropolymer of  claim 11  wherein the modified poly(alcohol) comprises a modified poly(alcohol) wherein hydroxyl groups on the poly(alcohol) are independently modified to contain cationic nitrogen-containing groups, first hydrophobic pendent groups, and second hydrophobic pendent groups wherein said first and second hydrophobic pendent groups are different and wherein one or more of said amine groups are linked to masking agents via physiologically labile bonds. 
     
     
         13 . The reversibly masked membrane active heteropolymer of  claim 12  wherein said first and second hydrophobic pendent groups are 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. 
     
     
         14 . The reversibly masked membrane active heteropolymer of  claim 13  wherein said first hydrophobic pendent groups consist of a lower hydrophobic groups and said second hydrophobic groups consist of higher hydrophobic groups. 
     
     
         15 . The reversibly masked membrane active heteropolymer of  claim 14  wherein said first hydrophobic pendent groups consist of a butyl groups and said second hydrophobic groups consist of octadecyl groups. 
     
     
         16 . The reversibly masked membrane active heteropolymer of  claim 14  wherein said cationic nitrogen-containing groups, lower hydrophobic groups and higher hydrophobic groups are present in a 6:3:1 ratio. 
     
     
         17 . The reversibly masked membrane active heteropolymer of  claim 14  wherein the heteropolymer further comprises one or more third hydrophobic pendent groups wherein said third hydrophobic pendent group is different from said first or second hydrophobic pendent group. 
     
     
         18 . The reversibly masked membrane active heteropolymer of  claim 17  wherein said third hydrophobic pendent group is selected from the group consisting of: aryl group, aralkyl group, aralkenyl group, aralkynyl group, sterol, steroid, and steroid derivative. 
     
     
         19 . The reversibly masked membrane active heteropolymer of  claim 11  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. 
     
     
         20 . The reversibly masked membrane active heteropolymer of  claim 11  wherein the modified poly(alcohol) comprises modified poly(vinyl alcohol). 
     
     
         21 . The reversibly masked membrane active heteropolymer of  claim 20  wherein the modified poly(alcohol) comprises a polymer selected from the group consisting of: poly(carbonate), poly(carbamate), mixed poly(carbonate)/poly(carbamate), poly(thiocarbonate), and poly(phosphocarbonate). 
     
     
         22 . A membrane active heteropolymer comprising: a modified poly(amine) wherein amine groups on the poly(amine) are independently modified to contain amine groups, first hydrophobic pendent groups, and second hydrophobic pendent groups wherein said first and second hydrophobic pendent groups are different. 
     
     
         23 . The membrane active heteropolymer of  claim 22  wherein the modified poly(amine) comprises a polymer selected from the group consisting of: modified poly(allylamine), modified poly(vinyl amine), and modified poly(amino acid). 
     
     
         24 . The membrane active heteropolymer of  claim 23  wherein the modified poly(amino acid) comprises a modified poly(lysine) or a modified poly(ornithine). 
     
     
         25 . The membrane active heteropolymer of  claim 22  wherein said first and second hydrophobic pendent groups are 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. 
     
     
         26 . The membrane active heteropolymer of  claim 25  wherein said first hydrophobic pendent group consists of a lower hydrophobic group and said second hydrophobic groups consists of a higher hydrophobic group. 
     
     
         27 . The membrane active heteropolymer of  claim 26  wherein said first hydrophobic pendent group consists of a butyl group and said second hydrophobic groups consists of an octadecyl group. 
     
     
         28 . The membrane active heteropolymer of  claim 26  wherein said amine groups, lower hydrophobic groups and higher hydrophobic groups are present in a 6:3:1 ratio. 
     
     
         29 . The membrane active heteropolymer of  claim 26  wherein the heteropolymer further comprises one or more third hydrophobic pendent groups wherein said third hydrophobic pendent group is different from said first or second hydrophobic pendent group. 
     
     
         30 . The membrane active heteropolymer of  claim 29  wherein said third hydrophobic pendent group is selected from the group consisting of: aryl group, aralkyl group, aralkenyl group, aralkynyl group, sterol, steroid, and steroid derivative. 
     
     
         31 . A membrane active heteropolymer comprising: a modified poly(amine) wherein amine groups on the poly(amine) are independently modified to contain amine groups, first hydrophobic pendent groups, and second hydrophobic pendent groups wherein said first and second hydrophobic pendent groups are different. 
     
     
         32 . The membrane active heteropolymer of  claim 31  wherein the modified poly(amine) comprises a polymer selected from the group consisting of: modified poly(allylamine), modified poly(vinyl amine), and modified poly(amino acid). 
     
     
         33 . The membrane active heteropolymer of  claim 32  wherein the modified poly(amino acid) comprises a modified poly(lysine) or a modified poly(ornithine). 
     
     
         34 . The membrane active heteropolymer of  claim 31  wherein said first and second hydrophobic pendent groups are 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. 
     
     
         35 . The membrane active heteropolymer of  claim 34  wherein said first hydrophobic pendent group consists of a lower hydrophobic group and said second hydrophobic groups consists of a higher hydrophobic group. 
     
     
         36 . The membrane active heteropolymer of  claim 35  wherein said first hydrophobic pendent group consists of a butyl group and said second hydrophobic groups consists of an octadecyl group. 
     
     
         37 . The membrane active heteropolymer of  claim 35  wherein said amine groups, lower hydrophobic groups and higher hydrophobic groups are present in a 6:3:1 ratio. 
     
     
         38 . The membrane active heteropolymer of  claim 35  wherein the heteropolymer further comprises one or more third hydrophobic pendent groups wherein said third hydrophobic pendent group is different from said first or second hydrophobic pendent group. 
     
     
         39 . The membrane active heteropolymer of  claim 38  wherein said third hydrophobic pendent group is selected from the group consisting of: aryl group, aralkyl group, aralkenyl group, aralkynyl group, sterol, steroid, and steroid derivative. 
     
     
         40 . The reversibly masked membrane active heteropolymer of  claim 31  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.