Polymeric systems and uses thereof in theranostic applications

Abstract

Polymeric systems useful for theranostic applications are disclosed. The polymeric systems comprise a fluorescent or fluorogenic moiety and a therapeutically active agent, each attached to the same or different polymeric moiety. The polymeric systems are designed such that a fluorescent signal is generated in response to a chemical event, preferably upon contacting an analyte (e.g., an enzyme) that is over-expressed in a diseased tissue or organ. Probes useful for inclusion in such polymeric systems, processes of preparing such probes and the polymeric systems, and uses thereof in diagnostic and/or theranostic applications are also disclosed.

What is claimed is: 
     
         1 . A polymeric system comprising a first polymeric moiety comprising a polymeric backbone composed of a plurality of backbone units and having attached to at least a portion of said backbone units a fluorogenic moiety, said fluorogenic moiety being attached to said backbone units via a first cleavable linking moiety such that upon cleavage of said linking moiety, a fluorescent signal is generated,
 the system further comprising a therapeutically active agent, such that:   (i) said fluorogenic moiety is attached to one portion of said backbone units and said therapeutically active agent is attached to another portion of said backbone units;   (ii) said therapeutically active agent forms a part of said fluorogenic moiety;   (iii) said therapeutically active agent is attached to said first cleavable linking moiety; or   (iv) the system further comprises a second polymeric moiety comprising a second polymeric backbone composed of a plurality of backbone units and having attached to at least a portion of said backbone units a therapeutically active agent.   
     
     
         2 . The polymeric system of  claim 1 , wherein upon said cleavage, a fluorescent moiety is generated. 
     
     
         3 . The polymeric system of  claim 2 , wherein said fluorescent moiety is or comprises a cyanine dye. 
     
     
         4 . The polymeric system of  claim 1 , wherein said first cleavable linking moiety is a first biocleavable linking moiety. 
     
     
         5 . The polymeric system of  claim 1 , wherein said first polymeric moiety further comprises a quenching agent. 
     
     
         6 . The polymeric system of  claim 5 , wherein said fluorogenic moiety is attached to one portion of said backbone units and said quenching agent is attached to another portion of said backbone units. 
     
     
         7 . The polymeric system of  claim 1 , wherein said first polymeric moiety is represented by Formula IA: 
       
         
           
           
               
               
           
         
         wherein: 
         A 1 , A 2  and A 4  are backbone units forming said polymeric backbone; 
         F is said fluorogenic moiety; 
         Q is a quenching agent; 
         L 2  is said first cleavable lining moiety; 
         S 2  is a first spacer, linking said fluorogenic moiety to L 2 , or is absent; 
         L 4  is a cleavable or non-cleavable third linking moiety, linking said quenching agent to respective backbone units, or is absent; 
         S 4  is a third spacer linking said quenching agent to said linking moiety L 4 , or is absent; 
         w is an integer having a value such that w/(x+s+w) multiplied by 100 is in the range of from 0 to 99.9; 
         x is an integer having a value such that x/(x+s+w) multiplied by 100 is in the range of from 0.1 to 100; and 
         s is an integer having a value such that s/(x+s+w) multiplied by 100 is in the range of from 0 to 99.9, 
         such that each [A 2 -L 2 -S 2 -F] independently represents a backbone unit having attached thereto the fluorogenic moiety; 
         each [A 4 -L 4 -S 4 -Q] independently represents a backbone unit having attached thereto the quenching agent; and 
         each of said backbone units A 1 , A 2  and A 4  is independently a terminal unit, attached to one other unit, or is attached to two other units, which can be the same of different. 
       
     
     
         8 . The polymeric system of  claim 7 , wherein s is 0. 
     
     
         9 . The polymeric system of  claim 7 , wherein s is a positive integer. 
     
     
         10 . The polymeric system of  claim 9 , wherein a ratio of s to x which is in a range of from 20:1 to 1:20, or from 10:1:10, or from 5:1 to 1:5, or from 2:1 to 1:2, or is 1:1. 
     
     
         11 . The polymeric system of  claim 5 , wherein said quenching agent forms a part of said fluorogenic moiety. 
     
     
         12 . The polymeric system of  claim 10 , wherein said fluorogenic moiety comprises a fluorescent moiety linked by said first cleavable linking moiety or by a degradable spacer to said quenching agent. 
     
     
         13 . The polymeric system of  claim 12 , wherein said fluorogenic moiety is represented by formulae III or III*: 
       
         
           
           
               
               
           
         
         wherein: 
         the curled line indicates an attachment point to said first cleavable linking moiety, or to a spacer that is linked to said first linking moiety; 
         F* is said fluorescent moiety; 
         Q is said quenching agent; 
         S′ is a spacer, or is absent; 
         S′″ is a spacer, or is absent; and 
         S″ is a multifunctional spacer which connects said fluorogenic moiety to said first cleavable moiety, or to an additional spacer which is connected to said cleavable linking moiety. 
       
     
     
         14 . The polymeric system of  claim 13 , wherein at least S″ in Formula III is a degradable spacer. 
     
     
         15 . The polymeric system of  claim 13 , wherein at least S″ and S′ in Formula III* is a degradable spacer. 
     
     
         16 . The polymeric system of  claim 1 , wherein said fluorogenic moiety is attached to one portion of said backbone units and said therapeutically active agent is attached to another portion of said backbone units, and wherein said therapeutically active agent is attached to said backbone units via a second cleavable linking moiety. 
     
     
         17 . The polymeric system of  claim 16 , being represented by Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         A 1 , A 2 , A 3  and A 4  are each backbone units covalently linked to one another and forming said polymeric backbone; 
         D is said therapeutically active agent; 
         F is said fluorogenic moiety; 
         Q is said quenching agent; 
         L 2  is said first linking moiety; 
         L 3  is said second linking moiety or absent; 
         L 4  is a linking moiety linking said quenching agent, or is absent; 
         each of S 2 , S 3  and S 4  is independently a spacer or absent; 
         w is an integer having a value such that w/(x+y+w+s) multiplied by 100 is in the range of from 0 to 99.9; 
         x is an integer having a value such that x/(x+y+w+s) multiplied by 100 is in the range of from 0.1 to 100; 
         y is an integer having a value such that y/(x+y+w+s) multiplied by 100 is in the range of from 0 to 99.9; and 
         s is an integer having a value such that s/(x+y+w+s) multiplied by 100 is in the range of from 0 to 99.9, 
         such that each [A 3 -L 3 -S 3 -D] independently represents a backbone unit having attached thereto said therapeutically active agent; 
         each [A 2 -L 2 -S 2 -F] independently represents a backbone unit having attached thereto said fluorogenic moiety; and 
         each [A 4 -L 4 -S 4 -Q] independently represents a backbone unit having attached thereto said quenching agent, 
         wherein when s is 0, said quenching agent forms a part of said fluorogenic moiety, and when y is 0, said therapeutically active agent forms a part of said fluorogenic moiety. 
       
     
     
         18 . The polymeric system of  claim 16 , wherein said second linking moiety is a biocleavable linking moiety. 
     
     
         19 . The polymeric system of  claim 1 , wherein the system further comprises a second polymeric moiety comprising a second polymeric backbone composed of a plurality of backbone units and having attached to at least a portion of said backbone units a therapeutically active agent, and wherein said therapeutically active agent is attached to said backbone units via a second cleavable linking moiety. 
     
     
         20 . The polymeric system of  claim 19 , wherein said second linking moiety is a biocleavable linking moiety. 
     
     
         21 . The polymeric system of  claim 1 , wherein said therapeutically active agent forms a part of said fluorogenic moiety, or is attached to said first cleavable linking moiety, and wherein upon said cleavage, said therapeutically active agent is released. 
     
     
         22 . The polymeric system of  claim 21 , wherein upon said cleavage, a fluorescent moiety is generated. 
     
     
         23 . The polymeric system of  claim 22 , wherein said fluorescent moiety is or comprises a cyanine dye.