Targeted polymeric conjugates and uses thereof

Abstract

Polymeric conjugates comprising a polymeric backbone having attached thereto a bone targeting moiety and a therapeutically active agent, wherein the bone targeting moiety is attached to one end of the polymeric backbone via a branching unit such that a molar ratio of the bone targeting moiety to the polymer is at least 2:1, are disclosed. Pharmaceutical compositions containing these conjugates and uses thereof in the treatment of bone related disorders are also disclosed.

What is claimed is: 
     
         1 . A conjugate comprising a polymeric backbone having attached thereto a therapeutically active agent and a bone targeting moiety, said therapeutically active agent being attached to one end of said polymeric backbone and said bone targeting moiety being attached to another end of said polymeric backbone via a branching unit, said branching unit being arranged in a dendritic structure composed of a cascade of branching moieties, wherein a molar ratio of said bone targeting moiety to said polymer and is at least 2:1. 
     
     
         2 . The conjugate of  claim 1 , being represented by the general Formula I:
   D-L 1 -[B*]-P-[B 1 ] m   0 -[B 2 ] m   1 -[B 3 ] m   2  . . . [Bg-L 2 ] m   g-1 -[T] m   g    Formula I
   wherein:   D is said therapeutically active agent;   P is said polymeric backbone;   T is said bone targeting moiety;   B* is a branching unit or is absent;   L 1  is a linking moiety, linking said therapeutically active agent to said one end of said polymeric backbone;   L 2  is a second linking moiety, linking said targeting moiety to said another end of said polymer, via said branching unit, or is absent;   B 1 , B 2 , B 3  . . . Bg are each independently a branching moiety, wherein B 1 , B 2 , B 3  . . . Bg together form said branching unit having said dendritic structure;   m is an integer that equals 2, 3, 4, 5 or 6, representing the ramification number of said dendritic structure; and   g is an integer that ranges from 1 to 20, representing the number of generations of said dendritic structure.   
     
     
         3 . The conjugate of  claim 1 , wherein said branching unit comprises at least one trifunctional moiety which comprises at least 3 functional groups, each of said functional groups being independently selected from the group consisting of an amine, a carboxylate, a thiocarboxylate, hydroxy, thiol, carbamate, thiocarbamate, sulfonate, sulfinate, sulfonamide, phosphonate, phosphinate, phosphoryl, urea and thiourea. 
     
     
         4 . The conjugate of  claim 3 , wherein said trifunctional moiety is selected from the group consisting of glutamic acid, beta-glutamic acid, amino adipic acid aspartic acid, lysine, and 3-hydroxy-2-amine propanol. 
     
     
         5 . The conjugate of  claim 1 , wherein said therapeutically active agent is useful in treating a bone-related disease or disorder. 
     
     
         6 . The conjugate of  claim 1 , wherein said therapeutically active agent is paclitaxel (PTX). 
     
     
         7 . The conjugate of  claim 1 , wherein said therapeutically active agent is attached to said polymeric backbone via a biocleavable linking moiety. 
     
     
         8 . The conjugate of  claim 7 , wherein said biocleavable linking moiety is selected from the group consisting of a hydrolytically-cleavable linking moiety, a pH-sensitive linking moiety and an enzymatically-cleavable linking moiety. 
     
     
         9 . The conjugate of  claim 7 , wherein said biocleavable moiety is a hydrolytically-cleavable linking moiety. 
     
     
         10 . The conjugate of  claim 9 , wherein said hydrolytically-cleavable linking moiety comprises an ester bond. 
     
     
         11 . The conjugate of  claim 10 , wherein said hydrolytically-cleavable linking moiety is derived from succinic acid. 
     
     
         12 . The conjugate of  claim 8 , wherein said enzymatically-cleavable linking moiety is cleaved by an enzyme that is overexpressed in a diseased bone tissue. 
     
     
         13 . The conjugate of  claim 1 , wherein said polymeric backbone is derived from a poly(alkylene glycol). 
     
     
         14 . The conjugate of  claim 13 , wherein said polymeric backbone is derived from poly(ethylene glycol) (PEG). 
     
     
         15 . The conjugate of  claim 1 , wherein said bone targeting moiety is a bisphosphonate moiety. 
     
     
         16 . The conjugate of  claim 15 , wherein said bisphosphonate is alendronate. 
     
     
         17 . The conjugate of  claim 1 , wherein said polymer is a poly(ethylene glycol), said bone targeting moiety is alendronate, and said therapeutically active agent is paclitaxel. 
     
     
         18 . The conjugate of  claim 17 , wherein said branching unit comprises at least 3 beta-glutamic acid moieties arranged in said dendritic structure. 
     
     
         19 . The conjugate of  claim 18 , wherein said paclitaxel is attached to said terminus backbone unit via a hydrolytically-cleavable linking moiety. 
     
     
         20 . The conjugate of  claim 19 , wherein said hydrolytically-cleavable linking moiety comprises an ester bond. 
     
     
         21 . The conjugate of  claim 20 , having the structure: 
       
         
           
           
               
               
           
         
         wherein n is an integer that ranges from 10 to 1000. 
       
     
     
         22 . The conjugate of  claim 1 , further comprising a labeling agent attached thereto. 
     
     
         23 . A pharmaceutical composition comprising, as an active ingredient, the conjugate of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         24 . The pharmaceutical composition of  claim 23 , being packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of a bone related disease or disorder. 
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein said conjugate comprises a labeling agent, the composition being packaged in a packaging material and identified in print, in or on said packaging material, for use in monitoring a bone related disease or disorder. 
     
     
         26 . A method of treating a bone related disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the conjugate of  claim 1 . 
     
     
         27 . A method of monitoring a bone related disease or disorder in a subject, the method comprising:
 administering to the subject the conjugate of  claim 22 ; and employing an imaging technique for monitoring a distribution of the conjugate within the body or a portion thereof.   
     
     
         28 . A conjugate comprising a polymeric backbone having attached to one end thereof a bisphophonate moiety, said bisphophonate being attached to said polymeric backbone via a branching unit, said branching unit being arranged in a dendritic structure composed of a cascade of branching moieties, wherein a mol ratio of said bisphosphonate to said polymer is at least 2:1. 
     
     
         29 . The conjugate of  claim 28 , wherein said polymeric backbone is derived from a poly(alkylene glycol). 
     
     
         30 . A conjugate comprising polymeric backbone having attached thereto a therapeutically active agent, said therapeutically active agent being attached to one end of said polymeric backbone, wherein said polymeric backbone further comprises a reactive group attached to another end of said polymeric backbone via a branching unit, said branching unit being arranged in a dendritic structure composed of a cascade of branching moieties, wherein a molar ratio of said functional group to said polymer and is at least 2:1, wherein said therapeutically active agent is useful in the treatment of a bone related disease or disorder. 
     
     
         31 . A process of preparing the conjugate of  claim 1 , the process comprising:
 attaching said therapeutically active agent to a onjugate comprising said polymeric backbone having attached to one end thereof said bisphophonate moiety, said bisphophonate being attached to said polymeric backbone via said branching unit, wherein a mol ratio of said bisphosphonate to said polymer is at least 2:1, thereby preparing the conjugate.