Reversibly Masked Polymers

Abstract

The present invention is directed to reversibly inactivation of 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 multiple reversible linkages connecting component parts provides for physiologically responsive activity modulation.

1 . A reversibly masked membrane active polymer comprising: a plurality of masking agents covalently linked to said membrane active polymer via physiologically labile bonds wherein the masking agents inhibit membrane activity of the membrane active polymer. 
     
     
         2 . The reversibly masked membrane active polymer of  claim 1  wherein the membrane active polymer comprises a polycation. 
     
     
         3 . The reversibly masked membrane active polymer of  claim 2  wherein membrane active polymer comprises a polyamine. 
     
     
         4 . The reversibly masked membrane active polymer of  claim 3  wherein the plurality of masking agents are linked to amines on the polyamine via physiologically labile bonds. 
     
     
         5 . The reversibly masked membrane active polymer of  claim 4  wherein the physiologically labile bonds are selected from the group consisting of: physiologically labile bond, cellular physiologically labile bond, pH labile bond, very pH labile bond, extremely pH labile bond, maleamate bond, enzymatically cleavable bond, and disulfide bond. 
     
     
         6 . The reversibly masked membrane active polymer of  claim 2  wherein the reversibly masked membrane active polymer has a net charge that is less positively charged than the membrane active polymer. 
     
     
         7 . The reversibly masked membrane active polymer of  claim 5  wherein the membrane active polymer comprises a heteropolymer of having amine-containing monomers and hydrophobic pendent groups. 
     
     
         8 . The reversibly masked membrane active polymer of  claim 5  wherein the membrane active polymer has the general structure comprising:
   -(A)-(B)-(C)-   
       wherein, A contains a pendent amine-containing group, B contains a first hydrophobic pendant group and C contains a second hydrophobic pendent group and B and C are different. 
     
     
         9 . The reversibly masked membrane active polymer of  claim 8  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. 
     
     
         10 . The reversibly masked membrane active polymer of  claim 9  wherein the first hydrophobic pendent group contains two to about six carbon atoms. 
     
     
         11 . The reversibly masked membrane active polymer of  claim 10  wherein the second hydrophobic pendent group contains eight or more carbon atoms. 
     
     
         12 . The reversibly masked membrane active polymer of  claim 1  wherein the membrane active polymer is soluble in aqueous solution. 
     
     
         13 . The reversibly masked membrane active polymer of  claim 12  wherein the membrane active polymer is soluble in aqueous solution at 1 mg/ml or greater. 
     
     
         14 . The reversibly masked membrane active polymer of  claim 1  wherein the masking agents are independently selected from the group consisting of: steric stabilizers, targeting groups and charge modifying agents. 
     
     
         15 . The reversibly masked membrane active polymer of  claim 14  wherein the masking agents inhibit non-specific interactions of the conjugate with serum components or non-target cells. 
     
     
         16 . The reversibly masked membrane active polymer of  claim 14  wherein two or more different masking agents are reversibly linked the membrane active polymer via labile bonds. 
     
     
         17 . The reversibly masked membrane active polymer of  claim 16  wherein at least one of the masking agents consists of a targeting group. 
     
     
         18 . The reversibly masked membrane active polymer of  claim 17  wherein the targeting group is selected from the group consisting of: compound with affinity to cell surface protein, cell receptor ligand, antibody with affinity to a cell surface molecule, cell receptor ligand, saccharide, galactose, galactose derivative, N-acetylgalactosamine, mannose, mannose derivative, vitamins, folate, biotin, peptide, RGD-containing peptide, insulin, aptamer, and EGF. 
     
     
         19 . The reversibly masked membrane active polymer of  claim 14  wherein the masking agents are selected from the group consisting of: dimethylmaleic anhydride, carboxy dimethylmaleic anhydride (CDM), CDM-thioester, CDM derivative, CDM-steric stabilizer, CDM-poly(ethylene glycol) (PEG), CDM-PEG-PDP, CDM-PEG-ligand, CDM-ligand, CDM-galactose, CDM-lactobionic acid (LBA), CDM-Pip-LBA, and CDM-NAG. 
     
     
         20 . The reversibly masked membrane active polymer of  claim 1  wherein the physiologically labile bonds are independently selected from the group consisting of: physiologically labile bond, cellular physiologically labile bond, pH labile bond, very pH labile bond, extremely pH labile bond, a maleamate bond, enzymatically cleavable bond, and disulfide bond. 
     
     
         21 . The reversibly masked membrane active polymer of  claim 1  wherein the membrane active polymer is biodegradable. 
     
     
         22 . The reversibly masked membrane active polymer of  claim 21  wherein the membrane active polymer contains biodegradable bonds within the backbone of the membrane active. 
     
     
         23 . The reversibly masked membrane active polymer of  claim 21  wherein the membrane active polymer contains biodegradable bonds within sidechains of the membrane active polymer. 
     
     
         24 . The reversibly masked membrane active polymer of  claim 21  wherein cleavage of biodegradable bonds in the membrane active polymer reduces membrane activity of the membrane active. 
     
     
         25 . The reversibly masked membrane active polymer of  claim 1  wherein the membrane active polymer is selected from the group consisting of: poly(acrylate), modified poly(alcohol), modified poly(vinyl alcohol), modified poly(lysine), modified poly(amine), modified poly(allylamine), modified poly(vinyl amine), modified poly(amino acid), poly(β-aminoester) and poly(vinyl ether). 
     
     
         26 . The reversibly masked membrane active polymer of  claim 2  wherein an siRNA is linked to said reversibly masked membrane active polymer. 
     
     
         27 . The reversibly masked membrane active polymer of  claim 26  wherein said siRNA is linked to said reversibly masked membrane active polymer via a physiologically labile bond. 
     
     
         28 . The reversibly masked membrane active polymer of  claim 27  wherein the siRNA and the masking agents are linked to the membrane active polymer via orthogonal physiologically labile bonds.