Biodegradable polymers, complexes thereof for gene therapeutics and drug delivery, and methods related thereto

Abstract

A biodegradable cationic polymer is disclosed, comprising first repeat units derived from a first cyclic carbonyl monomer by ring-opening polymerization, wherein more than 0% of the first repeat units comprise a side chain moiety comprising a quaternary amine group; a subunit derived from a monomeric diol initiator for the ring-opening polymerization; and an optional endcap group. The biodegradable cationic polymers have low cytotoxicity and form complexes with biologically active materials useful in gene therapeutics and drug delivery.

1 . A biodegradable cationic polymer, comprising:
 first repeat units derived from a first cyclic carbonyl monomer by ring-opening polymerization, wherein more than 0% of the first repeat units comprise a side chain moiety comprising a quaternary amine group;   a subunit derived from a monomeric diol initiator for the ring-opening polymerization; and   an optional endcap group.   
     
     
         2 . The cationic polymer of  claim 1 , wherein the more than 0% of the first repeat units comprise a side chain moiety comprising a quaternary amine group and a tertiary amine group. 
     
     
         3 . The cationic polymer of  claim 1 , wherein the side chain moiety of the first repeat units further comprise a side chain carboxylic acid group. 
     
     
         4 . The cationic polymer of  claim 1 , wherein the cationic polymer further comprises a second repeat unit derived from a second cyclic carbonyl monomer, and the second repeat unit comprises a side chain acetal ester group. 
     
     
         5 . The cationic polymer of  claim 1 , wherein the cationic polymer is a polycarbonate. 
     
     
         6 . The cationic polymer of  claim 1 , wherein the cationic polymer is a block copolymer. 
     
     
         7 . The cationic polymer of  claim 1 , wherein the cationic polymer is amphiphilic and self-assembles in water to form nanoparticles having an average particle size of 10 nm to 500 nm at a pH of from 5.0 to 8.0. 
     
     
         8 . A method of forming a biodegradable cationic polymer, comprising:
 forming a first mixture comprising a first cyclic carbonyl monomer, a catalyst, an accelerator, a monomeric diol initiator, and an optional solvent, wherein the first cyclic carbonyl monomer comprises a monovalent leaving group capable of reacting with a tertiary amine to form a quaternary amine;   forming a first polymer comprising first repeat units derived from the first cyclic carbonyl monomer by ring-opening polymerization;   optionally endcapping the first polymer to form a precursor polymer; and   treating the precursor polymer with the tertiary amine to form the cationic polymer, wherein more than 0% of the first repeat units derived from the first cyclic carbonyl monomer comprise a side chain moiety comprising a quaternary amine.   
     
     
         9 . The method of  claim 8 , wherein the tertiary amine is a bis-tertiary amine and the more than 0% of the first repeat units derived from the first cyclic carbonyl monomer comprise the side chain moiety comprising the quaternary amine and a tertiary amine. 
     
     
         10 . The method of  claim 9 , wherein the bis-tertiary amine is selected from the group consisting of N,N,N′,N′-tetramethyl-1,2-ethanediamine (TMEDA), N,N,N′,N′-tetramethyl-1,3-propanediamine (TMPDA), N,N,N′,N′-tetramethyl-1,4-butanediamine (TMBDA), N,N,N′,N′-tetraethyl-1,2-ethanediamine (TEEDA), N,N,N′,N′-tetraethyl-1,3propanediamine (TEPDA), 1,4-bis(dimethylamino)cyclohexane, 1,4-bis(dimethylaminobenzene), N,N,N′,N′-tetraethyl-1,4-butanediamine (TEBDA), 4-dimethylaminopyridine (DMAP), 4,4-dipyridyl-1,4-diazabicyclo[2.2.2]octane (DABCO), 4-pyrrolidinopyridine, 1-methylbenzimidazole, and combinations thereof. 
     
     
         11 . The method of  claim 8 , wherein the tertiary amine comprises a carboxy group and the more than 0% of the first repeat units derived from the first cyclic carbonyl monomer comprise the side chain moiety comprising the quaternary amine and a carboxylic acid. 
     
     
         12 . The method of  claim 8 , wherein the first mixture comprises a hydrophobic second cyclic carbonyl monomer, and the cationic polymer is a random copolymer comprising a second repeat unit derived from the second cyclic carbonyl monomer by ring-opening polymerization;
 wherein the second cyclic carbonyl monomer does not comprise a monovalent leaving group capable of reacting with the tertiary amine to form a side chain moiety comprising any quaternary amine.   
     
     
         13 . The method of  claim 12 , wherein the second repeat unit comprises a side chain acetal ester group. 
     
     
         14 . A method of forming a biodegradable cationic block copolymer, comprising:
 forming a reaction mixture comprising a catalyst, an accelerator, a monomeric diol initiator, and an optional solvent;   sequentially adding to the reaction mixture and reacting by ring-opening polymerization a first cyclic carbonyl monomer followed by a second cyclic carbonyl monomer, thereby forming a first block copolymer, wherein the first cyclic carbonyl monomer comprises a monovalent leaving group capable of reacting with a tertiary amine to form a quaternary amine, and the second cyclic carbonyl monomer is not capable of reacting with the tertiary amine to form any quaternary amine;   optionally endcapping the first block copolymer, thereby forming a precursor block copolymer; and   treating the precursor block copolymer with a tertiary amine to form the cationic polymer, wherein the cationic polymer comprises first repeat units derived from the first cyclic carbonyl monomer, and more than 0% of the first repeat units comprise a side chain moiety comprising the quaternary amine.   
     
     
         15 . The method of  claim 14  wherein the sequential reaction is performed in reverse order to form the first block copolymer. 
     
     
         16 . The method of  claim 14 , wherein the first block copolymer is endcapped using a carboxylic anhydride, thereby forming a terminal ester group. 
     
     
         17 . The method of  claim 14 , wherein the first cyclic carbonyl monomer is a compound of formula (1): 
       
         
           
           
               
               
           
         
       
       wherein:
 t is an integer from 0 to 6; 
 each Y is a divalent radical independently selected from the group consisting of 
 
       
         
           
           
               
               
           
         
       
       and 
       
         
           
           
               
               
           
         
       
       and
 each Q 1  is a monovalent radical independently selected from the group consisting of hydrogen, halides, carboxy groups, alkyl groups comprising 1 to 30 carbons, aryl groups comprising 6 to 30 carbon atoms, and groups having the structure 
 
       
         
           
           
               
               
           
         
       
       wherein M 1  is a monovalent radical selected from the group consisting of —R 1 , —NHR 1 , —NR 1 R 1 , and —SW; and each R 1  is a monovalent radical independently selected from the group consisting of alkyl groups comprising 1 to 30 carbons, and aryl groups comprising 6 to 30 carbons; and wherein one or more of the Q 1  groups of the first cyclic carbonyl monomer comprises a monovalent leaving group capable of reacting with a tertiary amine to form a quaternary amine. 
     
     
         18 . The method of  claim 14 , wherein the first cyclic carbonyl monomer is a compound of formula (2): 
       
         
           
           
               
               
           
         
       
       wherein:
 each Q 2  is a monovalent radical independently selected from the group consisting of hydrogen, a halides, carboxy groups, alkyl groups comprising 1 to 30 carbons, aryl groups comprising 6 to 30 carbon atoms, and groups having the structure 
 
       
         
           
           
               
               
           
         
       
       wherein M 1  is a monovalent radical selected from the group consisting of —R 1 , —OR 1 , —NHR 1 , —NR 1 R 1 , or —SR 1 , and each R 1  is a monovalent radical independently selected from the group consisting of alkyl groups comprising 1 to 30 carbons, and aryl groups comprising 6 to 30 carbons;
 R 2  is a monovalent radical independently selected from the group consisting of alkyl groups comprising 1 to 30 carbons, and aryl groups comprising 6 to 30 carbons; 
 Q 3  is a monovalent radical selected from the group consisting of hydrogen, alkyl groups having 1 to 30 carbons, and aryl groups having 6 to 30 carbons; and 
 wherein the R 2  group of the first cyclic carbonyl monomer comprises a monovalent leaving group capable of reacting with a tertiary amine to form a quaternary amine. 
 
     
     
         19 . The method of  claim 14 , wherein the first cyclic carbonyl monomer is a compound of formula (3): 
       
         
           
           
               
               
           
         
       
       wherein
 u is an integer from 1 to 8; 
 each Q 4  is a monovalent radical independently selected from the group consisting of hydrogen, halides, carboxy groups, alkyl groups comprising 1 to 30 carbons, aryl groups comprising 6 to 30 carbon atoms, and groups having the structure 
 
       
         
           
           
               
               
           
         
       
       where M 1  is a monovalent radical selected from —R 1 , —OR 1 , —NHR 1 , —NR 1 R 1 , or —SR 1 ; each R 1  is a monovalent radical independently selected from the group consisting of alkyl groups comprising 1 to 30 carbons, and aryl groups comprising 6 to 30 carbons;
 optionally, a 
 
       
         
           
           
               
               
           
         
       
       group of formula (3) independently represents a —O—, —S—, —NHR 1 , or —NR 1 R 1 ;
 optionally, a 
 
       
         
           
           
               
               
           
         
       
       group of formula (3) independently represents a 
       
         
           
           
               
               
           
         
       
       group;
 and wherein one or more of the Q 4  groups of the first cyclic carbonyl monomer comprises a monovalent leaving group capable of reacting with a tertiary amine to form a quaternary amine. 
 
     
     
         20 . The method of  claim 14 , wherein the first cyclic carbonyl monomer is a compound of formula (4): 
       
         
           
           
               
               
           
         
       
       wherein
 each Q 5  is a monovalent radical independently selected from the group consisting of hydrogen, halides, carboxy groups, alkyl groups comprising 1 to 30 carbons, aryl groups comprising 6 to 30 carbon atoms, and groups having the structure 
 
       
         
           
           
               
               
           
         
       
       wherein M 1  is a monovalent radical selected from —R 1 , —OR 1 , —NHR 1 , —NR 1 R 1 , or —SR 1 ;
 each R 1  is a monovalent radical independently selected from the group consisting of alkyl groups comprising 1 to 30 carbons, and aryl groups comprising 6 to 30 carbons; 
 each Q 6  is a monovalent group independently selected from the group consisting of hydrogen, alkyl groups having 1 to 30 carbons, and aryl groups having 6 to 30 carbons; and 
 each v independently represents an integer from 1 to 6; and 
 wherein one or more of the Q 5  and/or a Q 6  groups of the first cyclic carbonyl monomer comprises a monovalent leaving group capable of reacting with a tertiary amine to form a quaternary amine. 
 
     
     
         21 . The method of  claim 14 , wherein the cationic block copolymer comprises a second repeat unit derived from the second cyclic carbonyl monomer, and the second repeat unit comprises a side chain acetal ester group. 
     
     
         22 . The method of  claim 14 , wherein the initiator is BnMPA. 
     
     
         23 . The method of  claim 14 , wherein the tertiary amine is a bis-tertiary amine selected from the group consisting of N,N,N′,N′-tetramethyl-1,2-ethanediamine (TMEDA), N,N,N′,N′-tetramethyl-1,3-propanediamine (TMPDA), N,N,N′,N′-tetramethyl-1,4-butanediamine (TMBDA), N,N,N′,N′-tetraethyl-1,2-ethanediamine (TEEDA), N,N,N′,N′-tetraethyl-1,3propanediamine (TEPDA), 1,4-bis(dimethylamino)cyclohexane, 1,4-bis(dimethylaminobenzene), N,N,N′,N′-tetraethyl-1,4-butanediamine (TEBDA), 4-dimethylaminopyridine (DMAP), 4,4-dipyridyl-1,4-diazabicyclo[2.2.2]octane (DABCO), 4-pyrrolidinopyridine, 1-methylbenzimidazole, and combinations thereof. 
     
     
         24 . A polymer complex, comprising:
 a negatively charged biologically active material; and   a biodegradable cationic polymer, comprising:
 first repeat units derived from a first cyclic carbonyl monomer by ring-opening polymerization, wherein more than 0% of the first repeat units comprise a side chain moiety comprising a quaternary amine group; 
 a subunit derived from a monomeric diol initiator for the ring-opening polymerization; and 
 an optional endcap group. 
   
     
     
         25 . The polymer complex of  claim 24 , wherein the more than 0% of the first repeat units further comprise a side chain tertiary amine group. 
     
     
         26 . The polymer complex of  claim 24 , wherein the more than 0% of the first repeat units further comprise a side chain carboxylic acid group. 
     
     
         27 . The polymer complex of  claim 24 , wherein the cationic polymer is a polycarbonate. 
     
     
         28 . The polymer complex of  claim 24 , wherein the cationic polymer further comprises a second repeat unit derived from a hydrophobic second cyclic carbonyl monomer by ring opening polymerization, wherein the second repeat unit comprises a side chain acetal ester group. 
     
     
         29 . The polymer complex of  claim 24 , wherein the negatively charged biologically active material is selected from the group consisting of genes, nucleotides, proteins, peptides, drugs, and a combination thereof. 
     
     
         30 . The polymer complex of  claim 24 , wherein the cationic polymer is a block copolymer. 
     
     
         31 . A method of forming a polymer complex, comprising:
 contacting a first aqueous mixture comprising a biodegradable cationic polymer with a second aqueous mixture comprising a negatively charged biologically active material to form a third aqueous mixture comprising the polymer complex, wherein the biodegradable cationic polymer comprises: first repeat units derived from a first cyclic carbonyl monomer by ring-opening polymerization, a subunit derived from a monomeric diol initiator for the ring-opening polymerization, and an optional endcap group, wherein more than 0% of the first repeat units comprise a side chain moiety comprising a quaternary amine group.   
     
     
         32 . A method of treating a cell, comprising:
 contacting the cell with nanoparticles of a polymer complex comprising a biodegradable cationic polymer and a negatively charged biologically active material; wherein the biodegradable cationic polymer comprises: first repeat units derived from a first cyclic carbonyl monomer by ring-opening polymerization, a subunit derived from a monomeric diol initiator for the ring-opening polymerization, and an optional endcap group, wherein more than 0% of the first repeat units comprise a side chain moiety comprising a quaternary amine group.   
     
     
         33 . The method of  claim 32 , wherein said contacting induces 0% to 15% hemolysis. 
     
     
         34 . The method of  claim 32 , wherein the nanoparticles have 0% to 20% cytotoxicity. 
     
     
         35 . The method of  claim 32 , wherein the biologically active material is a gene, and the cell expresses the gene. 
     
     
         36 . A biodegradable amphiphilic cationic polymer, comprising:
 two polymer chains comprising respective first ends, respective second ends, and respective first repeat units;   a monomeric linking group comprising two backbone heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur; wherein i) the respective first ends of the two polymer chains are each linked to one of the two backbone heteroatoms, ii) the respective second ends optionally comprise respective endcap groups, and iii) the respective first repeat units comprise respective first backbone functional groups independently selected from the group consisting of ester, carbonate, carbamate, urea, thiocarbamate, thiocarbonate, or dithiocarbonate, and more than 0% of the respective first repeat units comprise respective side chain quaternary amine groups.   
     
     
         37 . The cationic polymer of  claim 36 , wherein the two backbone heteroatoms are oxygen atoms. 
     
     
         38 . The cationic polymer of  claim 36 , wherein the cationic polymer in aqueous solution at a pH of 5.0 to 8.0 self-assembles into nanoparticles having an average particle size of 10 nm to 500 nm, as measured by dynamic light scattering using a He—Ne laser beam at 658 nm and a scattering angle of 90°. 
     
     
         39 . The cationic polymer of  claim 36 , wherein the cationic polymer is biodegradable in accordance with ASTM D6400. 
     
     
         40 . The cationic polymer of  claim 36 , wherein the first side chains further comprise respective tertiary amine groups. 
     
     
         41 . The cationic polymer of  claim 36 , wherein the two polymer chains comprise respective second repeat units comprising i) respective second backbone functional groups independently selected from the group consisting of ester, carbonate, carbamate, urea, thiocarbamate, thiocarbonate, or dithiocarbonate, and ii) respective second side chains comprising respective latent carboxylic acid groups capable of forming carboxylic acid groups in an endosomal environment. 
     
     
         42 . The cationic polymer of  claim 36 , wherein the two polymer chains are block copolymer chains. 
     
     
         43 . A polymer complex, comprising:
 a negatively charged biologically active material; and   the biodegradable amphiphilic cationic polymer of  claim 36 .   
     
     
         44 . A method of forming a polymer complex, comprising:
 contacting a first aqueous mixture comprising the biodegradable amphiphilic cationic polymer of  claim 36  with a second aqueous mixture comprising a negatively charged biologically active material to form a third aqueous mixture comprising the polymer complex.   
     
     
         45 . A method of treating a cell, comprising:
 contacting the cell with nanoparticles of the polymer complex of  claim 43 .   
     
     
         46 . A method of forming a biodegradable cationic polymer, comprising:
 forming a first mixture comprising i) a first cyclic carbonyl monomer, ii) an organocatalyst, iii) an accelerator, iv) a monomeric initiator comprising two nucleophilic initiator groups, the two nucleophilic initiator groups independently selected from the group consisting of alcohols, amines, and thiols, and v) an optional solvent, wherein the first cyclic carbonyl monomer comprises a monovalent leaving group capable of reacting with a tertiary amine to form a quaternary amine;   agitating the first mixture, thereby forming a first polymer comprising first repeat units derived from the first cyclic carbonyl monomer by ring-opening polymerization;   optionally endcapping the first polymer; and   treating the first polymer or the endcapped first polymer with the tertiary amine, thereby forming the cationic polymer, wherein more than 0% of the first repeat units derived from the first cyclic carbonyl monomer comprise a side chain moiety comprising a quaternary amine.