Multi-arm polymer prodrugs

Abstract

Provided herein are water-soluble prodrugs, compositions comprising such prodrugs, and related methods of making and administering the same. The prodrugs of the invention comprise a water-soluble polymer having three or more arms, at least three of which are typically covalently attached to an active agent, e.g., a small molecule. The conjugates of the invention provide an optimal balance of polymer size and structure for achieving improved drug loading, since the conjugates of the invention possess three or more active agents releasably attached to a multi-armed water-soluble polymer. The prodrugs of the invention are therapeutically effective, and exhibit improved properties in-vivo when compared to unmodified parent drug.

What is claimed is: 
     
         1 . A method of treating cancer in a human subject, the method comprising:
 administering a therapeutically effective amount of a composition comprising a prodrug having a structure:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, where n ranges from 40 to 500, to a subject having one or more cancerous solid tumors. 
     
     
         2 . The method of  claim 1 , wherein the cancerous solid tumor type is selected from the group consisting of colorectal, ovarian, breast, non-small cell lung and prostate. 
     
     
         3 . The method of  claim 1 , wherein the overall nominal average molecular weight of the prodrug ranges from about 20,000 to about 80,000 daltons. 
     
     
         4 . The method of  claim 1 , wherein the overall nominal average molecular weight of the prodrug is about 20,000 daltons. 
     
     
         5 . The method of  claim 1 , wherein the composition comprises prodrug molecules having an average of from 2.3 to 3.0 molecules of irinotecan per multi-armed polyethylene glycol. 
     
     
         6 . The method of  claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier. 
     
     
         7 . The method of  claim 6 , wherein the composition comprises sorbitol and lactic acid. 
     
     
         8 . The method of  claim 1 , wherein the composition is administered parenterally. 
     
     
         9 . The method of  claim 8 , wherein the composition is administered by intravenous infusion. 
     
     
         10 . The method of  claim 1 , wherein the composition is in the form of a sterile aqueous preparation. 
     
     
         11 . The method of  claim 1 , wherein the dosage of prodrug administered comprises from about 10.0 to about 60 mg irinotecan/kg body weight of the subject. 
     
     
         12 . The method of  claim 1 , wherein the composition is administered once very one, two, or three weeks. 
     
     
         13 . The method of  claim 1 , wherein prior to administering, the composition is in the form of a sterile lyophilized solid, and the sterile lyophilized solid composition is reconstituted in an aqueous vehicle. 
     
     
         14 . The method of  claim 13 , wherein the aqueous vehicle is 5% dextrose injection or 0.9% sodium chloride injection solution. 
     
     
         15 . The method of  claim 1 , wherein the composition is administered in combination with a second anticancer agent.