Anthracycline Derivatives

Abstract

The present invention relates to new anthracycline derivatives and their use in cancer therapy and diagnosis. These anthracycline derivatives can be radiolabelled and used as an imaging agent in cancer diagnosis. The radiolabelled anthracycline derivatives can also be used together with a drug delivery system, in particular including a two-step targeting strategy, for treating solid and disseminated tumours. These drug delivery system can advantageously be used for treatment and diagnosis of breast cancer.

1 . An anthracycline derivative (drug precursor) having the general formula I,  
     
       
         
         
             
             
         
       
     
     wherein: 
 R is either a double-bound oxygen atom, a hydroxyl group in both stereoisomeric forms, or  
 R 1  is either CH 3 , CH 2 OH;  
 R 2  is a Y—Ar-Z group, wherein:  
 Y is a spacer molecule;  
 Ar is a conventional monocyclic aromatic group or stable aromatic boron cage compound, where the conventional aromatic group comprises a substituent capable of being directly radiolabelled using electrophilic aromatic substitution or an activating group, which can be exchanged for a radionuclide or which comprises a halogen such that the aromatic residue can undergo halogen-halogen exchange reactions; and  
 Z is optionally a chemical group that increases the hydrophilicity; and salts thereof.  
 
   
   
       2 . The anthracycline derivative according to  claim 1 , wherein the conventional monocyclic aromatic group is a phenyl or pyridine group, and the stable aromatic boron cage compound is a stable closo-carborane.  
   
   
       3 . The anthracycline derivative according to  claim 1 , wherein the derivative is:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       4 . A radiotherapeutic drug comprising the anthracycline derivative defined in  claim 1 , where the anthracycline derivative comprises a radioactive nuclide, or a stable nuclide that can be activated by external radiation with neutrons or photons.  
   
   
       5 . The radiotherapeutic drug according to  claim 4 , where the radioactive nuclide is selected from the group consisting of  123-125 I,  131 I,  18 F,  76-77 Br,  211 At,  90 Y,  32 P,  67 Cu, and  189 Re, and the stable nuclide is selected from the group consisting of  10 B and  157 Gd.  
   
   
       6 - 7 . (canceled)  
   
   
       8 . A drug delivery system comprising a DNA-interacting agent, said DNA-interacting agent comprising the anthracycline derivative according to  claim 1  or a radiotherapeutic drug comprising the anthracycline derivative comprising a radioactive nuclide or a stable nuclide that can be activated by external radiation with neutrons or photons.  
   
   
       9 . The drug delivery system according to  claim 8 , wherein said drug delivery system comprises a carrier capable of enclosing or binding pharmaceutically active agents including said DNA-interacting agent.  
   
   
       10 . The drug delivery system according to  claim 9 , wherein said carrier is a lipid carrier, a polymeric carrier, or a lipid/polymer composite particle.  
   
   
       11 . The drug delivery system according to  claim 10 , where the drug delivery system includes two-step targeting comprising: (a) a cell-targeting agents provided on the carrier to target specific cells or tissue, and (b) a DNA-targeting agent (the DNA-interacting agents) provided inside or bound to the carrier in order to target the radioactive nuclide to the cell nucleus.  
   
   
       12 . Drug delivery system according to  claim 11 , where the cell targeting agent is selected from a group consisting of ligands, antibodies, and antibody fragments.  
   
   
       13 . The drug delivery system according to  claim 12 , where the cell targeting agent comprises epidermal growth factor (EGF), or a molecule binding to tumour-specific, mutated EGF receptor.  
   
   
       14 . Method for cancer therapy and/or diagnosis, comprising the steps of administering to a subject in need thereof a therapeutically efficient amount of the drug delivery system according to  claim 8  and subsequently optionally irradiating the tumour area when the tumour has been located.  
   
   
       15 . Method for breast cancer therapy, comprising the steps of administering to a subject in need thereof a therapeutically efficient amount of the drug delivery system according to  claim 8 , and subsequently optionally irradiating the tumour area when the tumour has been located.  
   
   
       16 . Method for cancer therapy of disseminated cancer, comprising the steps of administering to a subject in need thereof a therapeutically efficient amount of the drug delivery system according to  claim 8 , and subsequently optionally irradiating the tumour area when the tumour has been located.  
   
   
       17 . Method for cancer therapy of multi-drug resistant (MDR) tumours overexpressing P-glycoprotein (PGP), comprising the steps of administering to a subject in need thereof a therapeutically efficient amount of the drug delivery system according to  claim 8 , and subsequently optionally irradiating the tumour area when the tumour has been located.  
   
   
       18 . The anthracycline derivative according to  claim 1 , wherein Y is of the formula —(CH 2 ) n — or —(CH 2 CH 2 O) n —, where n=1-8.  
   
   
       19 . The anthracycline derivative according to  claim 1 , wherein Ar contains a trialkylstannyl group substituent or a halogen substituent.  
   
   
       20 . The anthracycline derivative according to  claim 1 , wherein Z is a sugar group.  
   
   
       21 . A method of cancer diagnosis, comprising administering the radiotherapeutic drug of  claim 4  as an imaging agent.  
   
   
       22 . A method of targeting DNA, comprising administering the radiotherapeutic drug of  claim 4  as a DNA-targeting agent.