Multifunctional zwitterionic polymer conjugates

Abstract

The present invention provides random copolymers containing zwitterions and one or more functional agents, and methods of preparing such random copolymers.

1 . A random copolymer of Formula I: 
       
         
           
           
               
               
           
         
         wherein 
         each M 1  and M 2  are independently selected from the group consisting of acrylate, methacrylate, acrylamide, methacrylamide, styrene, vinyl-pyridine and vinyl-pyrrolidone; 
         R 1  is selected from the group consisting of H, L 1 -A 1 , LG 1  and L 1 -LG 1 ; 
         each R 2  is independently selected from the group consisting of H, C 1-20  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 3-8  cycloalkyl, C 3-8  heterocycloalkyl, aryl, heteroaryl, A 2 , L 2 -A 2 , LG 2 , L 2 -LG 2 , I 2  and L 2 -I 2 ; 
         ZW is a zwitterionic moiety; 
         I is an initiator fragment and I′ is a radical scavenger, such that the combination of I-I′ is an initiator, I 1 , for the polymerization of the random copolymer of Formula I; 
         alternatively, I′ is selected from the group consisting of H and C 1-6  alkyl; 
         I 2  is an initiator; 
         each of L 1  and L 2  is a linker; 
         each of A 1  and A 2  is a functional agent; 
         each of LG 1  and LG 2  is a linking group; 
         subscripts x and y 1  are each independently an integer of from 1 to 1000; 
         subscript z is an integer of from 1 to 10; 
         subscript s is an integer of from 1 to 100; and 
         subscript n is an integer of from 1 to 20, 
         wherein either R 1  is L 1 -A 1  or one of R 2  is L 2 -A 2 . 
       
     
     
         2 . The random copolymer of  claim 1 , wherein the random copolymer has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The random copolymer of  claim 1 , wherein the random copolymer has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The random copolymer of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The random copolymer of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The random copolymer of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The random copolymer of  claim 1 , wherein at least one R 2  is selected from the group consisting of H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  heteroalkyl, C 3-8  cycloalkyl, C 3-8  heterocycloalkyl, aryl, and heteroaryl. 
     
     
         8 . The random copolymer of  claim 1 , wherein the random copolymer has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The random copolymer of  claim 8 , wherein the random copolymer has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The random copolymer of  claim 8 , wherein the random copolymer has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The random copolymer of  claim 10 , having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The random copolymer of  claim 1 , wherein each of L 1  and L 2  is a cleavable linker independently selected from the group consisting of hydrolyzable linkers, enzymatically cleavable linkers, pH sensitive linkers, disulfide linkers, photolabile linkers, and self-immolative or double prodrug linkers. 
     
     
         13 . The random copolymer of  claim 1 , wherein at least one of L 1  and L 2  is a cleavable linker independently selected from the group consisting of hydrolyzable linkers, enzymatically cleavable linkers, pH sensitive linkers, disulfide linkers, photolabile linkers, and self-immolative or double prodrug linkers. 
     
     
         14 . The random copolymer of  claim 1 , wherein the functional agent is a bioactive agent selected from the group consisting of a drug, a therapeutic protein and a targeting agent. 
     
     
         15 . The random copolymer of  claim 1 , wherein the radical scavenger I′ is a halogen. 
     
     
         16 . The random copolymer of  claim 1 , wherein the initiator I 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . The random copolymer of  claim 1 , wherein the random copolymer is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . The random copolymer of  claim 1 , wherein the random copolymer has the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         PC is phosphorylcholine; 
         HEMA is hydroxyethyl methacrylate; 
         GMA is glycidyl methacrylate; and 
         Glu is glutamic acid. 
       
     
     
         19 . The random copolymer of  claim 1 , wherein the random copolymer has the formula: 
       
         
           
           
               
               
           
         
         wherein the block copolymer has the formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         20 . The random copolymer of  claim 1 , wherein the random copolymer has the formula: 
       
         
           
           
               
               
           
         
         wherein 
         subscripts x and y 1  are such that the Mn of the polymer portion is about 95,000 g/mol; 
         A 1  is an antibody; and 
         L-CTP has the formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         21 . The random copolymer of  claim 1 , wherein the random copolymer has the formula: 
       
         
           
           
               
               
           
         
         wherein 
         subscripts x, y 1a  and y 1b  are such that the Mn of the polymer portion is about 107,100 g/mol; 
         A 1  is an antibody; and 
         L-CTP has the formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         22 . The random copolymer of  claim 1 , wherein the random copolymer has the formula: 
       
         
           
           
               
               
           
         
         wherein subscripts x and y 1  are such that the Mn of the polymer portion is about 95,000 g/mol; 
         A 1  is an IgG; and 
         L-CTP has the formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         23 . The random copolymer of  claim 1 , wherein each of A 1  and A 2  is independently selected from the group consisting of an antibody, an antibody fragment, a Fab, IgG, a peptide, a protein, an enzyme, an oligonucleotide, a polynucleotide, nucleic acids, and an antibody drug conjugate (ADC). 
     
     
         24 . The random copolymer of  claim 1 , wherein A 1  is independently selected from an antibody, an antibody fragment, a Fab, a scFv, an immunoglobulin domain, an IgG, and A 2  is independently selected from an anti-cancer agent, a toxin, a small molecule drug, a chemotherapy agent, a kinase inhibitor, an anti-inflammatory agent, and an antifibrotic agent. 
     
     
         25 . The random copolymer of  claim 1 , wherein R 1  is LG 1 , and L 2 -A 2  is independently selected from an anti-cancer agent, a toxin, a small molecule drug, a chemotherapy agent, a kinase inhibitor, an anti-inflammatory agent, and an antifibrotic agent. 
     
     
         26 . A process for preparing a random copolymer, the process comprising: contacting a mixture of a first monomer and a second monomer with an initiator, I I , under conditions sufficient to prepare a random copolymer via free radical polymerization, wherein the first monomer comprises a phosphorylcholine, and each of the second monomer and initiator independently comprise at least one of a functional agent or a linking group for linking to the functional agent. 
     
     
         27 . The process of  claim 26 , wherein the mixture further comprises a catalyst and a ligand. 
     
     
         28 . A random copolymer comprising a first monomer comprising phosphorylcholine; a second monomer comprising a functional agent or a linking group; and an initiator moiety comprising a functional agent or a linking group, wherein the functional agent is linked to the second monomer or the initiator moiety via a linker.