Compositions and methods for altering macrophage phenotype

Abstract

Disclosed are methods and compositions for repolarizing a tumor associated macrophage (TAM) from M2 to M1 comprising administering to a subject in need thereof an effective dose of a compound comprising a dextran backbone and one or more CD206 targeting moieties conjugated thereto. In certain aspects, the compound further comprises a therapeutic agent selected from: paclitaxel, gemcitabine, lapatinib, and doxorubicin. In further aspect, the therapeutic agent comprises a chelator and at least one metal ion. In certain implementations, the at least one metal ion comprises at least one Cu(II) ions.

1 . A method for repolarizing a tumor associated macrophage (TAM) from an immunosuppressive (M2-like) phenotype to a proinflammatory (M1-like) phenotype comprising:
 administering to a subject in need thereof an effective dose of a compound comprising a carbohydrate backbone, one or more C-type lectin receptor targeting moieties comprising mannose, fucose, or n-acetylglucosamine conjugated thereto, and a therapeutic agent comprising at least one metal ion.   
     
     
         2 . The method of  claim 1 , wherein the therapeutic agent is attached to the carbohydrate backbone via an amino-terminated leash comprising the formula —(CH 2 ) p S(CH 2 ) q —NH—, wherein p and q are integers from 0 to 5. 
     
     
         3 . The method of  claim 2 , wherein the therapeutic agent further comprises at least one chelator. 
     
     
         4 . The method of  claim 3 , wherein the at least one metal ion is bound to the at least one chelator, and wherein the at least one chelator is bound to the amino-terminated leash. 
     
     
         5 . The method of  claim 3 , wherein the at least one chelator comprises DTPA, DOTA, TETA, NETA, NOTA, or a combination thereof. 
     
     
         6 . The method of  claim 1 , wherein the at least one metal ion comprises copper, arsenic, antimony, silver, cadmium, gallium, gadolinium, or a combination thereof. 
     
     
         7 . The method of  claim 3 , wherein the at least one metal ion comprises at least one Cu(II) ion, and wherein the at least one Cu(II) ion is between about 1 Cu(II) ion and a number of Cu(II) ions equal to the number of chelators. 
     
     
         8 . The method of  claim 2 , wherein the at least one metal ion is attached to the amino-terminated leash via a biodegradable linker. 
     
     
         9 . The method of  claim 8 , wherein the biodegradable linker comprises a hydrazone linker. 
     
     
         10 . The method of  claim 1 , wherein the compound is administered in conjunction with at least one other therapy or treatment and, wherein the at least one other treatment or therapy is a chemotherapy, radiation therapy, or immunotherapy. 
     
     
         11 . The method of  claim 10 , wherein the at least one other treatment or therapy is anti-CTLA4 immunotherapy. 
     
     
         12 . The method of  claim 10 , wherein the combined administration of the compound and the at least one treatment or therapy is synergistically effective relative to administration of either alone. 
     
     
         13 . The method of  claim 1 , wherein the one or more C-type lectin receptor targeting moieties is attached to the carbohydrate backbone via an amino-terminated leash having the formula —(CH 2 ) p S(CH 2 ) q —NH—, wherein p and q are integers from 0 to 5. 
     
     
         14 . The method of  claim 1 , wherein administration of the composition to the subject has reduced toxicity relative to an equivalent dose of the therapeutic agent not conjugated to the composition. 
     
     
         15 . The method of  claim 1 , wherein the compound comprises a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         each X is independently H, L1-A, or L2-R; 
         each L1 and L2 are independently amino-terminated leashes; 
         each A independently comprises a therapeutic agent or H bound to the amino-terminated leash, wherein the amino-terminated leash has the formula —(CH 2 ) p S(CH 2 ) q —NH— with an optional attachment with amide, amidine, and/or hydrazone group, wherein p and q are integers from 0 to 5, and wherein the therapeutic agent comprises one or more metal ions; 
         each R independently comprises a mannose-binding C-type lectin receptor targeting moiety or H; 
         and n is an integer greater than zero; and 
         wherein at least one R comprises the mannose-binding C-type lectin receptor targeting moiety and at least one A comprises the therapeutic agent. 
       
     
     
         16 . The method of  claim 15 , wherein the therapeutic agent further comprises at least one chelator. 
     
     
         17 . The method of  claim 15 , wherein the at least one metal ion comprises copper, arsenic, antimony, silver, cadmium, gallium, gadolinium, or a combination thereof. 
     
     
         18 . A compound for repolarizing a tumor associated macrophage (TAM) from an immunosuppressive (M2-like) phenotype to a proinflammatory (M1-like) phenotype comprising a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         each X is independently H, L1-A, or L2-R; 
         each L1 and L2 are independently amino-terminated leashes; 
         each A independently comprises a therapeutic agent or H; 
         each R independently comprises a mannose-binding C-type lectin receptor targeting moiety or H; 
         and n is an integer greater than zero; and 
         wherein at least one R comprises a mannose-binding C-type lectin receptor targeting moiety selected from the group consisting of mannose, fucose, and n-acetylglucosamine and at least one A comprises a therapeutic agent. 
       
     
     
         19 . The compound of  claim 18 , wherein the amino-terminated leashes comprise the formula —(CH 2 ) p S(CH 2 ) q —NH—, wherein p and q are integers from 0 to 5. 
     
     
         20 . The compound of  claim 18 , wherein the therapeutic agent comprises paclitaxel, gemcitabine, lapatinib, doxorubicin, a bisphosphonate, at least one metal ion, or at least one metal ion and at least one chelator.