Extended-linear polymeric contrast agents, and synthesizing methods, for medical imaging

Abstract

Linear extended polymeric paramagnetic chelates for use as MRI contrast agents are synthesized by conjugating DTPA chelator moieties to higher than 90% of the monomer residues of the polyamino acid backbone chain. The resulting polymer can be labeled with Gd, since each chelator moiety holds a Gd ion, and the resulting conformation is of an unfolded, extended linear type, capable of entering small pores and moving around obstacles in the extracellular space of tissues. The efficient production of these extended polymers is critical for the application of such contrast agents to medical imaging. One such agent is a reptating polymer containing technetium-99.

What is claimed is:  
     
         1 . A contrast agent for use in acquiring MRI images for the purpose of assessing tumor angiogenesis, said contrast agent comprising a reptating polymer containing gadolinium.  
     
     
         2 . The contrast agent of  claim 1  wherein length of the polymer is in a range of about 150-500 residues.  
     
     
         3 . The contrast agent of  claim 1  wherein length of the polymer is in a range of about 150-250 residues.  
     
     
         4 . The contrast agent of  claim 1  wherein length of the polymer is in a range of about 140-150 residues.  
     
     
         5 . A method of making extended linear reptating polymers comprising the steps of: 
 dissolving at least one poly-L-lysine salt in an aqueous sodium bicarbonate solution to form a polylysine/sodium bicarbonate solution;    cooling the polylysine/sodium biocarbonate solution to a temperature of about 0° C.;    combining diethylenetriaminepentaacetic acid (DTPA) and at least one acid acceptor in a dipolar aprotic solvent to form a second solution;    cooling the second solution to a temperature below about −35° C.;    adding at least one alkylchloroformate to the second solution to form a mixture;    adding said mixture to the polylysine/sodium bicarbonate solution to form a second mixture; and    isolating a resulting DTPA substituted polymer from the second mixture.    
     
     
         6 . The method of  claim 5  wherein said aqueous sodium bicarbonate solution has a pH in the range of between about 8 and about 9½.  
     
     
         7 . The method of  claim 6  wherein said at least one acid acceptor comprises tiriethylamine.  
     
     
         8 . The method of  claim 6  wherein said dipolar aprotic solvent comprises acetonitrile.  
     
     
         9 . The method of  claim 6  wherein said at least one alkyl chloroformate comprises isobutylchloroformate.  
     
     
         10 . The method of  claim 6  wherein said poly-L-lysine salt comprises poly-L-lysine bydrobromide.  
     
     
         11 . The method of  claim 6  wherein said polylysine/sodium bicarbonate solution is cooled to at least −35° C.  
     
     
         12 . The method of  claim 6  wherein said polylysine/sodium bicarbonate solution is cooled to about −43° C.  
     
     
         13 . The method of  claim 6  wherein said polylysine/sodium bicarbonate solution is cooled to about −45° C.  
     
     
         14 . The method of  claim 6  wherein the step of adding the mixture to the polylysine/sodium bicarbonate solution is performed with said polylysine/sodium bicarbonate solution cooled to about 0° C.  
     
     
         15 . The method of  claim 5  wherein said aqueous sodium bicarbonate solution has a pH of about 9.  
     
     
         16 . The method of  claim 15  wherein said at least one acid acceptor comprises triethylamine.  
     
     
         17 . The method of  claim 15  wherein said dipolar aprotic solvent comprises acetonitrile.  
     
     
         18 . The method of  claim 15  wherein said at least one alkyl chloroformate comprises isobutylchloroformate.  
     
     
         19 . The method of  claim 15  wherein said poly-L-lysine salt comprises poly-L-lysine hydrobromide.  
     
     
         20 . The method of  claim 15  wherein said polylysine/sodium bicarbonate solution is cooled to at least −35° C.  
     
     
         21 . The method of  claim 15  wherein said polylysine/sodium bicarbonate solution is cooled to about −43° C.  
     
     
         22 . The method of  claim 15  wherein said polylysine/sodium bicabronate solution is cooled to about −45° C.  
     
     
         23 . An extended linear reptating polymer prepared according to the process of  claim 5 .  
     
     
         24 . An extended linear reptating polymer prepared according to the process of  claim 7 .  
     
     
         25 . An extended linear reptating polymer prepared according to the process of  claim 8 .  
     
     
         26 . An extended linear reptating polymer prepared according to the process of  claim 9 .  
     
     
         27 . An extended linear reptating polymer prepared according to the process of claim  10 . 4 .