Drug formulations for cancer treatment

Abstract

Compounds and pharmaceutical formulations containing these compounds are described. Also described are methods of making and using the compounds. The compounds include nucleobases, nucleobase analogues, or combinations thereof. In one embodiment, a nucleobase analogue is combined with doxorubicin and encapsulated within a liposome for use in inhibiting or preventing the growth of cancer cells. Further described are pharmaceutical compositions containing two or more therapeutically active agents encapsulated within a vesicle, such as a liposome, wherein the molar ratio of the agents provides a synergistic therapeutic effect.

What is claimed herein is: 
     
         1 . A pharmaceutical composition comprising a vesicle comprising both:
 (a) one or more nucleobases having the formula:   
       
         
           
           
               
               
           
         
         wherein: 
         X is carbon, Y is nitrogen, Z is oxygen, sulfur or NR′, wherein R′ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, polyaryl, substituted polyaryl, C 3 -C 20  cyclic, substituted C 3 -C 20  cyclic, heterocyclic, or substituted heterocyclic, 
         wherein the bond between X and R 3  is a double bond, the bond between X and Y is a single bond, R 3  is oxygen, sulfur or NR′, wherein R′ is hydrogen, an alkyl, a substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, polyaryl, substituted polyaryl, C 3 -C 20  cyclic, substituted C 3 -C 20  cyclic, heterocyclic, or substituted heterocyclic, 
         R 1  is a substituted furanose, substituted alkyl, hydrogen, alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, arylthio, substituted arylthio, polyaryl, substituted polyaryl, C 3 -C 20  cyclic, substituted C 3 -C 20  cyclic, heterocyclic, substituted heterocyclic, halogen, haloalkyl, —CN, substituted deoxyfuranose, substituted pyranose, or substituted deoxypyranose, 
         R 2  is hydrogen, an alkyl, a substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, arylthio, substituted arylthio, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, polyaryl, substituted polyaryl, C 3 -C 20  cyclic, substituted C 3 -C 20  cyclic, heterocyclic, or substituted heterocyclic, 
         R 4  is a halogen, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, arylthio, substituted arylthio, polyaryl, substituted polyaryl, C 3 -C 20  cyclic, substituted C 3 -C 20  cyclic, heterocyclic, substituted heterocyclic, or haloalkyl; and 
         R 5  is hydrogen, an alkyl, a substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, polyaryl, substituted polyaryl, C 3 -C 20  cyclic, substituted C 3 -C 20  cyclic, heterocyclic, substituted heterocyclic, halogen, or haloalkyl; and 
         (b) an anthracycline. 
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the anthracycline is selected from the group consisting of doxorubicin, daunorubicin, epirubicin, and idarubicin. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the nucleobase is a 5-fluorouracil analogue having the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is a substituted alkyl, a furanose, a substituted furanose, a substituted deoxyfuranose, a substituted pyranose, or a substituted deoxypyranose. 
       
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein R 1  is a substituted alkyl, wherein the substituents comprise a substituted or unsubstituted non-aromatic hydrophobic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a combination thereof. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the substituted alkyl is a substituted methyl. 
     
     
         6 . The pharmaceutical composition of  claim 4 , wherein at least one of the substituents of the substituted alkyl comprises a hydrophobic amino acid or an amino acid that includes a heteroaryl side chain, optionally the substituted alkyl comprises a hydrophobic amino acid and an amino acid that includes a heteroaryl side chain. 
     
     
         7 . The pharmaceutical composition of  claim 3 , wherein R 1  is a substituted furanose. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein each of the substituents of the substituted furanose independently comprises a substituted or unsubstituted non-aromatic hydrophobic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein each of the substituents of the substituted furanose independently comprises a hydrophobic amino acid or an amino acid that includes a heteroaryl side chain. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein R 1  is a haloalkyl selected from CF 3 , —CH 2 —CF 3 , -and CCl 3 . 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the nucleobase is: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the nucleobase has the formula: 
       
         
           
           
               
               
           
         
         wherein each of R 6 , R 7  and R 8  is independently hydrogen or 
       
       
         
           
           
               
               
           
         
         wherein at least one of R 6 , R 7  or R 8  is Formula III, wherein E is absent, and wherein R′ and R″ are hydrogen. 
       
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein R 6  and R 7  are hydrogens, R 8  is Formula III, E is absent, and wherein R′ and R″ are hydrogens. 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the nucleobase is 5-fluorouracil (5FU) or an analogue thereof. 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein the anthracycline is doxorubicin (DOX) and the nucleobase is 5-fluorouracil (5FU) or an analogue thereof. 
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein the dose of the nucleobase in the vesicle is in the range of between about 0.01 mg/mL and about 5 mg/mL, and
 wherein the dose of the anthracycline in the vesicle is in the range of between about 0.05 mg/mL and about 10 mg/mL.   
     
     
         17 . The pharmaceutical composition of  claim 1 , wherein the molar ratio of nucleobase:anthracycline is less than or equal to 1. 
     
     
         18 . The pharmaceutical composition of  claim 1 , wherein the nucleobase and the anthracycline are present in a molar ratio that provides a synergistic therapeutic effect. 
     
     
         19 . The pharmaceutical composition of  claim 1 , wherein the vesicle is a liposome. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the liposome is coated with a water-soluble, biocompatible polymer. 
     
     
         21 . The pharmaceutical composition of  claim 19 , wherein the liposome comprises at least one lipid selected from the group consisting of cationic, zwitterionic, and PEGylated anionic lipids, and combinations thereof. 
     
     
         22 . The pharmaceutical composition of  claim 19 , wherein the liposome comprises a combination of cationic, zwitterionic, and PEGylated anionic lipids and cholesterol. 
     
     
         23 . The pharmaceutical composition of  claim 19 , wherein liposome comprises 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (mPEG-DSPE), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and/or cholesterol (Chol). 
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein the combination of cationic, zwitterionic, and PEGylated anionic lipids and cholesterol is in a molar ratio of 75:5:10:10 zwitterionic: PEGylated anionic:cationic:Cholesterol. 
     
     
         25 . The pharmaceutical composition of  claim 19 , wherein the liposome comprises at least one cationic lipid. 
     
     
         26 . The pharmaceutical composition of  claim 19 , wherein the liposome comprises at least one cationic lipid and at least one PEGylated anionic lipid.