Polyglutamate-amino acid conjugates and methods

Abstract

Various biodegradable polyglutamate-amino acids comprising recurring units of the general formulae (I) and (II) are prepared. Such polymers are useful for variety of drug, biomolecule and imaging agent delivery applications.

1 . A polymer conjugate comprising a recurring unit of the formula (I) and a recurring unit of the formula (II):  
       
         
           
           
               
               
           
         
         wherein:  
         each n is independently 1 or 2;  
         each A 1  is oxygen or NR 5 ;  
         each A 2  is oxygen;  
         R 1  and R 2  are each independently selected from the group consisting of C 1-10  alkyl, C 6-20  aryl, ammonium, alkali metal, a polydentate ligand, a polydentate ligand precursor with protected oxygen atoms, and a compound that comprises an agent; 
 wherein the agent is selected from the group consisting of an anticancer drug, a targeting agent, an optical imaging agent, and a magnetic resonance imaging agent;  
 wherein at least one of R 1  and R 2  is a group that comprises an agent;  
 
         R 3  and R 4  are each independently selected from the group consisting of hydrogen, ammonium, and an alkali metal;  
         wherein the polymer conjugate comprises an amount of the agent in the range of about 1 to about 50% (weight/weight) based on the mass ratio of the agent to the polymer conjugate;  
         R 5  is hydrogen or C 1-4  alkyl; and  
         wherein the amount of the agent, the percentage of the recurring unit of the formula (I) and the percentage of the recurring unit of the formula (II) are selected to provide a polymer conjugate solubility that is greater than that of a comparable polyglutamic acid conjugate that comprises substantially the same amount of the agent, the polymer conjugate solubility being greater when a tested polymer conjugate solution, comprising at least 5 mg/mL of the polymer conjugate in 0.9 wt. % aqueous NaCl at about 22° C., has greater optical clarity over a broader pH range than that of a comparable tested polyglutamic acid conjugate solution.  
       
     
     
         2 . The polymer conjugate of  claim 1 , further comprising a recurring unit of the formula (III):  
       
         
           
           
               
               
           
         
         wherein R 6  is hydrogen, ammonium, or an alkali metal.  
       
     
     
         3 . The polymer conjugate of  claim 1 , wherein the compound that comprises the agent further comprises a linker group.  
     
     
         4 . The polymer conjugate of  claim 1 , wherein the agent is an optical imaging agent.  
     
     
         5 . The polymer conjugate of  claim 4 , wherein the optical imaging agent is selected from the group consisting of an acridine dye, a coumarine dye, a rhodamine dye, a xanthene dye, cyanine dye, and a pyrene dye.  
     
     
         6 . The polymer conjugate of  claim 1 , wherein the agent is an anticancer drug.  
     
     
         7 . The polymer conjugate of  claim 6 , wherein the anticancer drug is selected from the group consisting of a taxane, camptothecin, and doxorubicin.  
     
     
         8 . The polymer conjugate of  claim 7 , wherein the taxane is selected from the group consisting of paclitaxel and docetaxel.  
     
     
         9 . The polymer conjugate of  claim 8 , wherein paclitaxel is conjugated to the recurring unit of formula (I) at the oxygen atom attached to the C2′-carbon.  
     
     
         10 . The polymer conjugate of  claim 8 , wherein paclitaxel is conjugated to the recurring unit of formula (I) at the oxygen atom attached to the C7-carbon.  
     
     
         11 . The polymer conjugate of  claim 1 , wherein the agent is a magnetic resonance imaging agent.  
     
     
         12 . The polymer conjugate of  claim 11 , wherein the magnetic resonance imaging comprises a Gd(III) compound.  
     
     
         13 . The polymer conjugate of  claim 12 , wherein the Gd(III) compound comprises:  
       
         
           
           
               
               
           
         
       
     
     
         14 . The polymer conjugate of  claim 1 , wherein the polydentate ligand comprises:  
       
         
           
           
               
               
           
         
         wherein each R 7  is independently hydrogen, ammonium, or an alkali metal.  
       
     
     
         15 . The polymer conjugate of  claim 1 , wherein the polydentate ligand precursor with protected oxygen atoms comprises:  
       
         
           
           
               
               
           
         
       
     
     
         16 . The polymer conjugate of  claim 1 , wherein the polymer comprises about 1 mole % to about 30 mole % of the recurring unit of formula (I) based on the total moles of recurring units of formulae (I) and (II).  
     
     
         17 . The polymer conjugate of  claim 1 , wherein the polymer conjugate comprises about 1 mole % to about 20 mole % of the recurring unit of formula (I) based on the total moles of recurring units of formulae (I) and (II).  
     
     
         18 . The polymer conjugate of  claim 1 , wherein the polymer conjugate comprises about 1 mole % to about 10 mole % of the recurring unit of formula (I) based on the total moles of recurring units of formulae (I) and (II).  
     
     
         19 . The polymer conjugate of  claim 2 , wherein the polymer conjugate comprises about 1 mole % to about 99 mole % of the recurring unit of formula (I) based on the total moles of recurring units of formulae (I), (II) and (III).  
     
     
         20 . The polymer conjugate of  claim 19 , wherein the polymer conjugate comprises about 1 mole % to about 30 mole % of the recurring unit of formula (I) based on the total moles of recurring units of formulae (I), (II) and (III)  
     
     
         21 . The polymer conjugate of  claim 19 , wherein the polymer conjugate comprises about 1 mole % to about 20 mole % of the recurring unit of formula (I) based on the total moles of recurring units of formulae (I), (II) and (III).  
     
     
         22 . The polymer conjugate of  claim 19 , wherein the polymer conjugate comprises about 1 mole % to about 10 mole % of the recurring unit of formula (I) based on the total moles of recurring units of formulae (I), (II) and (III).  
     
     
         23 . The polymer conjugate of  claim 1 , wherein at least one n is 1.  
     
     
         24 . The polymer conjugate of  claim 1 , wherein at least one n is 2.  
     
     
         25 . The polymer conjugate of  claim 1 , wherein the alkali metal is sodium.  
     
     
         26 . The polymer conjugate of  claim 1 , wherein the broader pH range is at least about 3 pH units.  
     
     
         27 . The polymer conjugate of  claim 1 , wherein the broader pH range is at least about 8 pH units.  
     
     
         28 . The polymer conjugate of  claim 1 , wherein the broader pH range is at least about 9 pH units.  
     
     
         29 . The polymer conjugate of  claim 1 , wherein the broader pH range includes at least one pH value in the range of about 2 to about 5.  
     
     
         30 . The polymer conjugate of  claim 1 , wherein the tested polymer conjugate solution comprises at least about 10 mg/mL of the polymer conjugate.  
     
     
         31 . The polymer conjugate of  claim 1 , wherein the tested polymer conjugate solution comprises at least about 25 mg/mL of the polymer conjugate.  
     
     
         32 . The polymer conjugate of  claim 1 , wherein the tested polymer conjugate solution comprises at least about 100 mg/mL of the polymer conjugate.  
     
     
         33 . The polymer conjugate of  claim 1 , wherein the tested polymer conjugate solution comprises at least about 150 mg/mL of the polymer conjugate.  
     
     
         34 . A method of making the polymer conjugate of  claim 1 , comprising dissolving or partially dissolving a polymeric reactant in a solvent to form a dissolved or partially dissolved polymeric reactant; and reacting the dissolved or partially dissolved polymeric reactant with a second reactant, wherein the second reactant comprises at least one selected from the group consisting of the polydentate ligand, the polydentate ligand precursor with protected oxygen atoms and the compound that comprises the agent.  
     
     
         35 . The method of  claim 34 , wherein the polymeric reactant comprises a recurring unit of the formula (IV):  
       
         
           
           
               
               
           
         
         wherein  
         each n is independently 1 or 2;  
         each A 3  is oxygen; and  
         R 7  and R 8  are each independently selected from the group consisting of hydrogen, ammonium, and an alkali metal.  
       
     
     
         36 . The method of  claim 34 , wherein the polymeric reactant comprises a recurring unit of formula (V):  
       
         
           
           
               
               
           
         
         wherein R 9  is hydrogen, ammonium, or an alkali metal.  
       
     
     
         37 . The method of  claim 34 , wherein the second reactant comprises a substituent selected from the group consisting of hydroxy and amine.  
     
     
         38 . The method of  claim 34 , wherein the agent is selected from the group consisting of an anticancer drug, a targeting agent, an optical imaging agent, and a magnetic resonance imaging agent.  
     
     
         39 . The method of  claim 38 , wherein the optical imaging agent is selected from the group consisting of an acridine dye, a coumarine dye, a rhodamine dye, a xanthene dye, cyanine dye, and a pyrene dye.  
     
     
         40 . The method of  claim 38 , wherein the anticancer drug is selected from the group consisting of a taxane, camptothecin, and doxorubicin.  
     
     
         41 . The method of  claim 40 , wherein the taxane is selected from the group consisting of paclitaxel and docetaxel.  
     
     
         42 . The method of  claim 41 , wherein paclitaxel is conjugated to the recurring unit of formula (I) at the oxygen atom attached to the C2′-carbon.  
     
     
         43 . The method of  claim 41 , wherein paclitaxel is conjugated to the recurring unit of formula (I) at the oxygen atom attached to the C7-carbon.  
     
     
         44 . The method of  claim 38 , wherein the magnetic resonance imaging comprises a Gd(III) compound.  
     
     
         45 . The method of  claim 44 , wherein the Gd(III) compound comprises:  
       
         
           
           
               
               
           
         
       
     
     
         46 . The method of  claim 34 , wherein the polydentate ligand comprises:  
       
         
           
           
               
               
           
         
         wherein each R 7  is independently hydrogen, ammonium, or an alkali metal.  
       
     
     
         47 . The method of  claim 34 , wherein the polydentate ligand precursor with protected oxygen atoms comprises:  
       
         
           
           
               
               
           
         
       
     
     
         48 . The method of  claim 34 , further comprising reacting the dissolved or partially dissolved polymeric reactant in the presence of a coupling agent.  
     
     
         49 . The method of  claim 48 , wherein the coupling agent is selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), 1,3-dicyclohexyl carbodiimide (DCC), 1,1′-carbonyl-diimidazole (CDI), N,N′-disuccinimidyl carbonate (DSC), N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), 2-[(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HBTU), 2-[(6-chloro-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate, bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, 2-[(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), and benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate (BOP).  
     
     
         50 . The method of  claim 34 , wherein the solvent is a polar aprotic solvent.  
     
     
         51 . The method of  claim 50 , wherein the solvent is selected from the group consisting of N,N-dimethylform amide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyridone (NMP), and N,N-dimethylacetamide (DMAc).  
     
     
         52 . The method of  claim 34 , further comprising reacting the dissolved or partially dissolved polymeric reactant in the presence of a catalyst.  
     
     
         53 . The method of  claim 52 , wherein the catalyst is 4-dimethylaminopyridine (DMAP).  
     
     
         54 . A pharmaceutical composition comprising the polymer conjugate of  claim 1  and at least one selected from a pharmaceutically acceptable excipient, a carrier, and a diluent.  
     
     
         55 . A method of treating, ameliorating, or diagnosing a disease or condition comprising administering an effective amount of the polymer conjugate of any one of  claims 1  to  33  to a mammal in need thereof.