Trivalent Radioisotope Bio-Targeted Radiopharmaceutical, Methods Of Preparation And Use

Abstract

A targeted radiopharmaceutical comprising a targeting species chemically-bonded to a PCTA-chelated Q+3 trivalent radioactive ion of Formula Iis disclosed. Six of R1 through R7 are H and the seventh is a reacted functionality, Z, that forms the chemical bond with the targeting species, T. “g” is a number whose average value is 1 to about 12. X1, X2, and X3, are substituent groups that can coordinate to the Q+3 ion and/or help neutralize the ionic charge. Anion Y− is optionally present to balance the ionic charge. A pharmaceutical composition comprising a theranostic effective amount of a targeted radiopharmaceutical of Formula I in a pharmaceutically acceptable diluent is also contemplated, as are a method for treating and/or diagnosing a mammalian host having a disease, disorder or condition characterized by undesired angiogenesis, tumor growth and/or tumor metastasis.

1 . A targeted radiopharmaceutical that comprises a targeting species chemically-bonded to PCTA-chelated Q +3  radioactive isotope ion, wherein the PCTA chelator has the general structural formula shown below in Formula I 
       
         
           
           
               
               
           
         
       
       wherein
 Q +3  is a trivalent radioactive isotope ion; 
 six of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are H and the seventh contains a reacted functionality, Z, that forms said chemical bond with said targeting species, T; 
 “g” is a number whose average value is 1 to about 12 that indicates the average number of chelated PCTA-chelated trivalent radioactive ions, Q +3 , per each molecule of targeting species, T; 
 X 1 , X 2 , and X 3 , are the same or different substituent groups that can coordinate to said Q +3  radioactive isotope ion and/or help neutralize the ionic charge; and 
 an optional anion, Y − , is optionally present in an amount needed to balance the ionic charge. 
 
     
     
         2 . The targeted radiopharmaceutical according to  claim 1 , wherein said reacted functionality, Z, is selected from the group consisting of one or more of a reacted Michael reaction acceptor, a reacted isocyanato group, an activated carboxyl group, and a 1,4-disubstituted-1,2,3-triazine formed by the reaction of an azide and an alkyne. 
     
     
         3 . The targeted radiopharmaceutical according to  claim 1 , wherein said targeting species, T, is selected from the group consisting of one or more of a chemically-bonded antibody or paratope-containing portion of an antibody, a chemically-bonded hormone, a chemically bonded non-antibody protein, a chemically-bonded cytokine, a chemically bonded aptamer, a chemically bonded nucleic acid or oligonucleotide, a straight chain or cyclic oligopeptide, and a straight chain or branched oligosaccharide. 
     
     
         4 . The targeted radiopharmaceutical according to  claim 1 , wherein each of said X 1 , X 2 , and X 3 , is a —(CH 2 ) n CO 2 M or a —PO 3 M 2  substituent, n is zero or 1, and M is H +  or a alkali metal cation. 
     
     
         5 . The targeted radiopharmaceutical according to  claim 4 , wherein each of said X 1 , X 2 , and X 3 , is a —(CH 2 ) n CO 2 M substituent, n is zero or 1, and M is H +  or a alkali metal cation. 
     
     
         6 . The targeted radiopharmaceutical according to  claim 5 , wherein n is zero. 
     
     
         7 . The targeted radiopharmaceutical according to  claim 1 , wherein Q +3  is an Ac-225, Bi-212, Bi-213, Zr-89 or In-111 ion. 
     
     
         8 . The targeted radiopharmaceutical according to  claim 7 , wherein Q +3  is an Ac-225, Bi-212 or Bi-213 ion. 
     
     
         9 . The targeted radiopharmaceutical according to  claim 7 , wherein Q +3  is a Zr-89 or In-111 ion. 
     
     
         10 . The targeted radiopharmaceutical according to  claim 1 , wherein said targeting species, T, is a chemically-bonded antibody or paratope-containing portion of an antibody. 
     
     
         11 . The targeted radiopharmaceutical according to  claim 10 , wherein said antibody or paratope-containing portion of an antibody is a monoclonal antibody (mAb) or a paratope-containing portion thereof. 
     
     
         12 . The targeted radiopharmaceutical according to  claim 11 , wherein said monoclonal antibody or a paratope-containing portion thereof is the mAb designated ATN-658 produced by hybridoma having ATCC Accession #PTA-8191 or paratope-containing portion of ATN-658. 
     
     
         13 . The targeted radiopharmaceutical according to  claim 11 , wherein said mAb is humanized. 
     
     
         14 . A pharmaceutical composition that comprises a theranostic effective amount of a targeted radiopharmaceutical according to  claim 1  dissolved or dispersed in a pharmaceutically acceptable diluent. 
     
     
         15 . The pharmaceutical composition according to  claim 14 , wherein said pharmaceutically acceptable diluent is an aqueous liquid at ambient temperature and is adapted for parenteral administration. 
     
     
         16 . The pharmaceutical composition according to  claim 15 , wherein said composition is isotonic to the blood of the intended mammalian species host recipient. 
     
     
         17 . The pharmaceutical composition according to  claim 16 , wherein said intended mammalian species host recipient is a human. 
     
     
         18 . A method for treating a mammalian host having a disease, disorder or condition characterized by undesired angiogenesis, tumor growth and/or tumor metastasis comprising administering to said host a pharmaceutical composition of  claim 14  wherein said theranostic effective amount is a targeted cell-killing effective amount of said targeted radiopharmaceutical. 
     
     
         19 . The method according to  claim 18 , wherein the disease, disorder or condition is cancer. 
     
     
         20 . The method according to  claim 19 , wherein said cancer is selected from the group consisting of one or more of lung cancer, ovarian cancer, prostate cancer, brain cancer, bladder cancer, head and neck cancer, pancreatic cancer or colon cancer. 
     
     
         21 . The method according to  claim 18 , wherein said mammalian host is a human. 
     
     
         22 . The method according to  claim 18 , wherein said administration is repeated. 
     
     
         23 . The method according to  claim 21 , wherein said targeted radiopharmaceutical is administered in an amount sufficient to provide about 80 to about 120 kBq/kg body weight to said mammalian host. 
     
     
         24 . The method according to  claim 23 , wherein said administration is repeated. 
     
     
         25 . The method according to  claim 24 , wherein said administration is repeated at about 60-day intervals. 
     
     
         26 . A method for assaying a mammalian host having a disease, disorder or condition characterized by undesired angiogenesis, tumor growth and/or tumor metastasis comprising
 a) administering to said host a pharmaceutical composition of  claim 14  wherein said theranostic amount is a diagnostically effective amount of said targeted radiopharmaceutical;   b) maintaining said host for a time period of about 1 hour to several days for the radiopharmaceutical to bind to the targeted cells; and   c) scanning the maintained host to detect and locate the radiation emitted by the target cell-bound targeted radiopharmaceutical.   
     
     
         27 . The method according to  claim 26 , wherein the disease, disorder or condition is cancer. 
     
     
         28 . The method according to  claim 27 , wherein said cancer is selected from the group consisting of one or more of lung cancer, ovarian cancer, prostate cancer, brain cancer, bladder cancer, head and neck cancer, pancreatic cancer or colon cancer. 
     
     
         29 . The method according to  claim 28 , wherein said mammalian host is a human. 
     
     
         30 . The method according to  claim 26 , wherein said administration is repeated. 
     
     
         31 . The method according to  claim 29 , wherein said targeted radiopharmaceutical is administered in an amount of about 0.5 to about 6.0 mCi to said human.