Pharmaceutical compositions of beta-lapachone and beta-lapachone analogs with improved tumor targeting potential

Abstract

The present invention relates to polymer-modified quinone-containing and carbonyl-containing therapeutic agents, including polymer-modified β-lapachone compounds, and methods of treating cancer by administering the polymer-modified therapeutic agents to a subject. Polymer-modification of therapeutic agents, such as β-lapachone compounds, provides effective transport of polymer-modified therapeutic agents to tumor cells or tumor tissues by exploiting the EPR effect in tumor tissues.

1 . A composition comprising a carboxyl-containing polymer associated, via a linking agent of formula (II), with one or more quinone-containing therapeutic agents, wherein said linking agent of formula (II) is associated with said one or more quinone-containing therapeutic agents by a quinol-ester bond;
 wherein said linking agent of formula (II) is of the form   
       
         
           
           
               
               
           
         
         where
 each R 3  and R 4  are independently selected from the group consisting of hydrogen, —(C 1 -C 8 ) alkyl, —O—(C 1 -C 8 ) alkyl, —(C 1 -C 4 ) alkyl-aryl, aryl, and heteroaryl; 
 R 5  is selected from the group consisting of hydrogen, —(C 1 -C 8 ) alkyl, —(C 1 -C 8 ) fluoroalkyl, aryl, and heteroaryl; 
 R 6  is selected from the group consisting of -tert-butoxycarbonyl and carbobenzyloxy (CBZ); and 
 m is from 1 to 8; 
 alternatively, when m is 1, R 4  and R 5  may be taken together with the carbon and nitrogen atoms bearing them to form a 4 to 7 membered nitrogen-containing heterocycle. 
 
       
     
     
         2 . The composition of  claim 1 , wherein said one or more quinone-containing therapeutic agents is β-lapachone, and said carboxyl-containing polymer is a polyethylene glycols (PEG)-dicarboxylic acid, poly(styrene-co-maleic anhydride) copolymer (SMA), poly-L-glutamic acid (PGA) or poly-L-aspartic acid (PAA). 
     
     
         3 . The composition of  claim 2 , wherein said carboxyl-containing polymer is a PGA polymer, and said carboxyl-containing polymer comprises one or more residues of the form 
       
         
           
           
               
               
           
         
         where “*” indicates the points of attachment to other residues of said PGA polymer. 
       
     
     
         4 . A pharmaceutical composition comprising a therapeutically effective amount of a composition of  claim 1 . 
     
     
         5 . The pharmaceutical composition of  claim 8 , wherein said pharmaceutical composition is a formulation for oral, parenteral, or intravenous administration. 
     
     
         6 . A composition comprising a carboxyl-containing polymer associated, via a linking agent of formula (II), with β-lapachone, wherein said linking agent of formula (II) is associated with said β-lapachone by a quinol-ester bond. 
     
     
         7 . The composition of  claim 6 , wherein said carboxyl-containing polymer is a PEG-dicarboxylic acid, SMA, PGA or PAA polymer. 
     
     
         8 . A pharmaceutical composition comprising a therapeutically effective amount of a composition of  claim 6 . 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein said pharmaceutical composition is a formulation for oral, parenteral, or intravenous administration.