Polymeric prodrug with a self-immolative linker

Abstract

A cascade carrier linked prodrug is described comprising a biologically active moiety and a masking group having at least one nucleophile and being distinct from the carrier.

What is claimed is: 
     
         1 . A polymeric cascade prodrug comprising:
 an amine containing biologically active moiety,   a polymeric carrier,   a masking group having at least one nucleophile and being distinct from the carrier, wherein the prodrug is predominantly non-enzymatically cleavable.   
     
     
         2 . The prodrug of  claim 1 , wherein the biologically active moiety is selected from the group consisting of biopolymers and small molecule biologically active agents. 
     
     
         3 . The prodrug of  claim 2 , wherein the biopolymer is selected from the group consisting of proteins, polypeptides, oligonucleotides and peptide nucleic acids. 
     
     
         4 . The prodrug of  claim 1 , wherein the half-life of the prodrug in suitably buffered human blood plasma of pH 7.4 is at least 50% of the half-life of the prodrug in enzyme-free buffer pH 7.4. 
     
     
         5 . The prodrug of  claim 1 , wherein the predominantly non-enzymatic cleavage comprises a step of hydrolysis. 
     
     
         6 . The prodrug of  claim 1 , wherein the predominantly non-enzymatic cleavage comprises a step of intramolecular cyclization or catalysis. 
     
     
         7 . The prodrug of  claim 1 , wherein the at least one nucleophile is a primary, secondary or tertiary amino group. 
     
     
         8 . The prodrug of  claim 1 , wherein the nucleophile is in a suitable distance to a first temporary linkage with an aromatic activating group capable of undergoing a 1,(4+2p) elimination reaction (with p=0, 1, 2, 3, 4, . . . ) after cleavage of the first temporary linkage. 
     
     
         9 . The prodrug of  claim 8 , wherein the activating group is connected to the amino group of a drug molecule through a second temporary bond which is cleaved as a consequence of the 1,(4+2p) elimination. 
     
     
         10 . The prodrug of  claim 8 , wherein the attachment of a polymeric carrier to the activating group is by means of a permanent bond. 
     
     
         11 . The prodrug of  claim 1 , wherein the polymeric carrier is a hydrogel. 
     
     
         12 . The prodrug of  claim 1 , wherein the polymeric carrier is a branched or hyperbranched polymer. 
     
     
         13 . The prodrug of  claim 1  wherein the polymeric carrier is a dendrimer or dense star polymer. 
     
     
         14 . The prodrug of  claim 1 , wherein the polymeric carrier is a biopolymer. 
     
     
         15 . The prodrug of  claim 14 , wherein the polymeric carrier is a protein.