Caspase-3-triggered molecular self-assembling pet probes and uses thereof

Abstract

Embodiments of the synthesis, radiolabeling and biological applications of an activatable tracer that undergoes intramolecular cyclization and aggregation upon activation by cleavage of a blocking moiety are provided. The probes of the disclosure allow for target-controlled self-assembly of small molecules in living subjects for imaging and drug delivery. The aggregated nanoprobes of the disclosure may be detectable optically, by PET detection, magnetic resonance imaging, and the like depending on the detectable reporter attached to the nanoprobe.

1 - 20 . (canceled) 
     
     
         21 . A compound comprising formula I: 
       
         
           
           
               
               
           
         
         wherein the scaffold comprises a terminal aromatic nitrile group and a disulfide group, and wherein: 
         n=0-6; 
         R 1  is a detectable label; 
         R 2  is a moiety specifically cleavable from the scaffold by an enzyme; 
         R 3  is an unsubstituted or substituted straight-chain alkyl group, an unsubstituted or substituted branched-chain group, an aromatic group, or a substituted aromatic group; 
         X is a phenyl or a substituted phenyl; and 
         Y is an aromatic nitrile group. 
       
     
     
         22 . The compound of  claim 21 , wherein X is a phenyl group. 
     
     
         23 . The compound of  claim 21 , wherein Y is a pyrimidine nitrile group. 
     
     
         24 . The compound of  claim 21  having the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 24 , wherein R 1  is selected from a fluorescent dye, a positron emission tomography (PET) detectable moiety, and a magnetic resonance detectable moiety. 
     
     
         26 . The compound of  claim 24 , wherein R 2  is a peptide having the amino acid sequence Aspartate-Glutamate-Valine-Aspartate (DEVD) and is specifically cleavable from the scaffold by caspase 3/7, a peptide having the amino acid sequence Isoleucine-Glutamate-Phenylalanine-Aspartate (IEFD) or the amino acid sequence Isoleucine-Glutamate-Proline-Aspartate (IEPD) and specifically cleavable from the scaffold by granzyme-B, a β-galactosidase-cleavable-moiety, or methionine, and wherein n=0-6. 
     
     
         27 . The compound of  claim 21 , wherein the fluorescent dye is a cyanine dye. 
     
     
         28 . The compound of  claim 27 , wherein the cyanine dye is Cy5 or Cy5.5. 
     
     
         29 . The compound of  claim 25 , wherein the PET detectable moiety is an  18 F-labelled moiety. 
     
     
         30 . The compound of  claim 25 , wherein the PET detectable moiety is a  64 Cu-labelled moiety,  48 V-labelled moiety,  52 Fe-labelled moiety,  55 Co-labelled moiety,  94 mTc-labelled moiety or  68 Ga-labelled moiety. 
     
     
         31 . The compound of  claim 25 , wherein the magnetic resonance detectable moiety is a gadolinium ion, and wherein the gadolinium ion is attached to the scaffold by a metal chelating group. 
     
     
         32 . The compound of  claim 21 , wherein R 2  is a glycoside specifically cleavable from the scaffold by β-galactosidase. 
     
     
         33 . The compound of  claim 32 , wherein the glycoside has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         34 . A method of generating an image of a tissue in an animal or human subject, the method comprising the steps of:
 (i) administering to an animal or human subject a pharmaceutically acceptable composition comprising the compound represented by formula I of claim  1 .