Compositions and methods for detecting and treating tumors containing acidic areas

Abstract

Improved compounds have been developed which are structured to be sequestered with very high specificity in acidic areas of tissues. When the compounds contain a radioisotope effective to report the presence of the compound the compounds are for detecting tumors containing hypoxic/acidic areas. When the compounds contain radioisotopes effective to kill cells the compounds are for treating tumors containing hypoxic/acidic areas. Methods for detecting and treating tumors with such compounds are also disclosed.

1 . A precursor compound structured to be sequestered with high specificity in acidic areas of a tissue, comprising:
 (a) a molecular weight in a range of 300 to 2,000 daltons;   (b) two to six carboxylic acid moieties;
 i) each of the carboxylic acid moieties is separated from any of the adjacent carboxylic acid moieties by at least 4 intervening atoms; 
 ii) the average of the pKa values of the individual carboxylic acid moieties is in a range of 5.0 to 7.4; 
   (c) zero to nine alpha amino acids; and,   (d) a structural element capable of readily, efficiently, and stably binding at least one radioisotope;   wherein, the compound has pH-dependent hydrophilic/lipophilic properties such that when the compound is contacted with a given quantity of animal cells for 30 minutes at 37 deg. C. in a minimal medium buffered at pH 6.4, the compound is sequestered at least 25-fold more than when contacted with the same quantity of the animal cells for 30 minutes at 37 deg. C. in the minimal medium buffered at pH 7.4.   
     
     
         2 . A precursor compound of  claim 1 , wherein the radioisotope is a radiohalogen. 
     
     
         3 . A compound structured to be selectively sequestered with high specificity in acidic areas of a tissue, comprising:
 (a) a molecular weight in a range of 300 to 2,000 daltons;   (b) two to six carboxylic acid moieties;
 i) each of the carboxylic acid moieties is separated from any of the adjacent carboxylic acid moieties by at least 4 intervening atoms; 
 ii) the average of the pKa values of the individual carboxylic acid moieties is in a range of 5.0 to 7.4; 
   (c) zero to nine alpha amino acids; and,   (d) at least one stably-bound radioisotope;   wherein, the compound has pH-dependent hydrophilic/lipophilic properties such that when the compound is contacted with a given quantity of animal cells for 30 minutes at 37 deg. C. in a minimal medium buffered at pH 6.4, the compound is sequestered at least 25-fold more than when contacted with the same quantity of the animal cells for 30 minutes at 37 deg. C. in the minimal medium buffered at pH 7.4.   
     
     
         4 . The compound of  claim 3 , wherein the radioisotope is a radiohalogen. 
     
     
         5 . The compound of  claim 3 , which contains a radioisotope that emits radiation of a type selected from the group:
 i) gamma ray;   ii) X-ray; and,   iii) positron.   
     
     
         6 . The compound of  claim 5 , wherein the radioisotope is selected from the group:
 i) iodine-123; and,   ii) iodine-124.   
     
     
         7 . The compound of  claim 3 , which contains a radioisotope that emits an alpha particle. 
     
     
         8 . The compound of  claim 7 , wherein the radioisotope is astatine-211. 
     
     
         9 . The compound of  claim 3 , which contains a radioisotope that emits a beta particle. 
     
     
         10 . The compound of  claim 9 , wherein the radioisotope is iodine-131. 
     
     
         11 . The compound of  claim 10 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         12 . A diagnostic method for detecting acidic areas in a living subject, comprising the steps of:
 (a) viding the precursor compound of  claim 1 ;   (b) providing a radioisotope whose chemical form is capable of readily, efficiently, and stably binding to the precursor compound, and whose emission is effective to report the radioisotope's presence within the subject to a detector outside of the subject;   (c) contacting the precursor compound with the radioisotope under conditions that give efficient and stable binding of the radioisotope to the compound;   (d) introducing the resultant compound containing the radioisotope into the subject;   (e) waiting for between 15 minutes and 48 hours;   (f) scanning the subject with equipment effective for assessing for the presence of the radioisotope within the subject.   
     
     
         13 . The diagnostic method of  claim 12 , which includes first carrying out at least one of the steps selected from the group consisting of:
 i) introducing into the subject at least one substance effective to raise the pH of the urine;   ii) introducing into the subject at least one substance effective to raise the pH at sites of inflammation; and,   iii) introducing into the subject at least one substance effective to lower the pH in tumors.   
     
     
         14 . The diagnostic method of  claim 13 , wherein:
 i) the substance effective to raise the pH of the urine is acetazolamide;   ii) the substance effective to raise the pH at sites of inflammation is sodium bicarbonate;   iii) one substance effective to lower the pH in tumors is meta-iodobenzylguanidine; and,   iv) one substance effective to lower the pH in tumors is glucose.   
     
     
         15 . A diagnostic method for detecting acidic areas in a living subject, comprising the steps of:
 (a) providing the compound of  claim 5 ;   (b) introducing the compound into the subject;   (c) waiting for between 15 minutes and 48 hours; and,   (d) scanning the subject with equipment effective to assess for the presence of the compound within the subject.   
     
     
         16 . The diagnostic method of  claim 15 , which includes first carrying out at least one of the steps selected from the group consisting of:
 i) introducing into the subject at least one substance effective to raise the pH of the urine;   ii) introducing into the subject at least one substance effective to raise the pH at sites of inflammation; and,   iii) introducing into the subject at least one substance effective to lower the pH in tumors.   
     
     
         17 . The diagnostic method of  claim 16 , wherein:
 i) the substance effective to raise the pH of the urine is acetazolamide;   ii) the substance effective to raise the pH at sites of inflammation is sodium bicarbonate;   iii) one substance effective to lower the pH in tumors is meta-iodobenzylguanidine; and,   iv) one substance effective to lower the pH in tumors is glucose.   
     
     
         18 . A therapeutic method for treatment of tumors containing acidic areas, comprising the steps of:
 (a) providing the precursor compound of  claim 1 ;   (b) providing a radioisotope whose chemical form is capable of readily, efficiently, and stably binding to the precursor compound, and whose emission is effective to kill cells;   (c) contacting the precursor compound with the radioisotope under conditions that give efficient and stable binding of the radioisotope to the precursor compound;   (d) introducing the resultant compound containing the radioisotope into the subject.   
     
     
         19 . The therapeutic method of  claim 18 , which also includes first carrying out at least one of the steps selected from the group consisting of:
 i) introducing into the subject at least one substance effective to raise the pH of the urine;   ii) introducing into the subject at least one substance effective to raise the pH at sites of inflammation; and,   iii) introducing into the subject at least one substance effective to lower the pH in tumors.   
     
     
         20 . The therapeutic method of  claim 19 , wherein:
 i) the substance effective to raise the pH of the urine is acetazolamide;   ii) the substance effective to raise the pH at sites of inflammation is sodium bicarbonate;   iii) one substance effective to lower the pH in tumors is meta-iodobenzylguanidine; and,   iv) one substance effective to lower the pH in tumors is glucose.   
     
     
         21 . A therapeutic method for treatment in a living subject of tumors containing acidic areas, comprising the steps of:
 (a) providing the compound of  claim 3 , wherein the radioisotope is effective to kill cells; and   (b) introducing the compound into the subject.   
     
     
         22 . The therapeutic method of  claim 21 , which also includes first carrying out at least one of the steps selected from the group consisting of:
 i) introducing into the subject at least one substance effective to raise the pH of the urine;   ii) introducing into the subject at least one substance effective to raise the pH at sites of inflammation; and,   iii) introducing into the subject at least one substance effective to lower the pH in tumors.   
     
     
         23 . The therapeutic method of  claim 22 , wherein:
 i) the substance effective to raise the pH of the urine is acetazolamide;   ii) the substance effective to raise the pH at sites of inflammation is sodium bicarbonate;   iii) one substance effective to lower the pH in tumors is meta-iodobenzylguanidine; and,   iv) one substance effective to lower the pH in tumors is glucose.   
     
     
         24 . An alpha/beta therapeutic method for treatment of tumors containing acidic areas, comprising the steps of:
 (a) providing the compound of  claim 7  containing an alpha-emitting radioisotope;   (b) providing the compound of  claim 9  containing a beta-emitting radioisotope; and,   (c) introducing these compounds into the subject.   
     
     
         25 . The alpha/beta therapeutic method of  claim 24 , wherein the alpha-emitting radioisotope is astatine-211 and the beta-emitting radioisotope is iodine-131. 
     
     
         26 . The alpha/beta therapeutic method of  claim 24 , which also includes first carrying out at least one of the steps selected from the group consisting of:
 i) introducing into the subject at least one substance effective to raise the pH of the urine;   ii) introducing into the subject at least one substance effective to raise the pH at sites of inflammation; and,   iii) introducing into the subject at least one substance effective to lower the pH in tumors.   
     
     
         27 . The alpha/beta therapeutic method of  claim 26 , wherein:
 i) the substance effective to raise the pH of the urine is acetazolamide;   ii) the substance effective to raise the pH at sites of inflammation is sodium bicarbonate;   iii) one substance effective to lower the pH in tumors is meta-iodobenzylguanidine; and,   iv) one substance effective to lower the pH in tumors is glucose.   
     
     
         28 . An alpha/beta therapeutic method for treatment of tumors containing acidic areas, comprising the steps of:
 (a) providing an acid-targeted compound containing at least two carboxylic acid moieties and an alpha-emitting radioisotope, and having pH-dependent hydrophilic/lipophilic properties such that when the compound is contacted with a given quantity of animal cells for 30 minutes at 37 deg. C. in a minimal medium buffered at pH 6.4, the compound is sequestered at least 25-fold more than when contacted with the same quantity of the animal cells for 30 minutes at 37 deg. C. in the minimal medium buffered at pH 7.4;   (b) providing an acid-targeted compound containing at least two carboxylic acid moieties and a beta-emitting radioisotope, and having pH-dependent hydrophilic/lipophilic properties such that when the compound is contacted with a given quantity of animal cells for 30 minutes at 37 deg. C. in a minimal medium buffered at pH 6.4, the compound is sequestered at least 25-fold more than when contacted with the same quantity of the animal cells for 30 minutes at 37 deg C. in the minimal medium buffered at pH 7.4; and,   (c) introducing these compounds into the subject.   
     
     
         29 . The alpha/beta therapeutic method of  claim 28 , wherein the alpha-emitting radioisotope is astatine-211 and the beta-emitting radioisotope is iodine-131. 
     
     
         30 . The alpha/beta therapeutic method of  claim 28 , which also includes first carrying out at least one of the steps selected from the group consisting of:
 i) introducing into the subject at least one substance effective to raise the pH of the urine;   ii) introducing into the subject at least one substance effective to raise the pH at sites of inflammation;   iii) introducing into the subject at least one substance effective to lower the pH in tumors.   
     
     
         31 . The alpha/beta therapeutic method of  claim 30 , wherein:
 i) the substance effective to raise the pH of the urine is acetazolamide;   ii) the substance effective to raise the pH at sites of inflammation is sodium bicarbonate;   iii) one substance effective to lower the pH in tumors is meta-iodobenzylguanidine; and,   iv) one substance effective to lower the pH in tumors is glucose.