Multicomponent Degradable Cationic Polymers

Abstract

Degradable polymers were synthesized that self-assemble with DNA to form particles that are effective for gene delivery. Small changes to polymer synthesis conditions, particle formulation conditions, and polymer structure provides significant changes to efficacy in a cell-type dependent manner. Polymers presented here are more effective than commercially available materials, such as LIPOFECTAMINE 2000™, FUGENE®, or polyethylenimine (PEI), for gene delivery to cancerous fibroblasts or human primary fibroblasts. The presently disclosed materials may be useful for cancer therapeutics and regenerative medicine.

1 - 57 . (canceled) 
     
     
         58 . A polymer or particle formulation thereof represented by formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R forms a diester, 
 each of R 1  to R 9  is independently selected from hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carboxyl ester, carbonyldioxyl, amide, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, a substituted alkanoyl group, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which may be substituted with at least one substituent selected from the group consisting of branched or unbranched alkyl, branched and unbranched alkenyl, alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiohydroxyl groups; 
 R′ comprises an alcohol, 
 R″ comprises an amine-containing heterocyclic or carbocyclic end group, and 
 n is an integer from 1 to 10,000. 
 
       
     
     
         59 . The polymer or particle of  claim 58 , wherein the polymer is represented by the formula: 
       
         
           
           
               
               
           
         
         wherein:
 R forms a diester, 
 R′ comprises an alcohol, 
 R″ comprises an amine-containing carbocyclic or heterocyclic end group, and 
 n is an integer from 1 to 10,000. 
 
       
     
     
         60 . The polymer or particle of  claim 58 , wherein R forms a butyl diester group. 
     
     
         61 . The polymer or particle of  claim 58 , wherein side chain R′ forms a butyl alcohol. 
     
     
         62 . The polymer or particle of  claim 58 , wherein end group R″ comprises a heterocyclic group selected from pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, and tetrahydrofuranyl. 
     
     
         63 . The polymer or particle of  claim 58 , wherein acrylate-terminated polymer is first synthesized by reaction of the diacrylate backbone and amine side chain at a molar ratio of 1:1.1 to 1.2:1; followed by end-capping with amine-containing end groups. 
     
     
         64 . The polymer or particle of  claim 58 , wherein n is an integer of from 1 to 1000. 
     
     
         65 . The polymer or particle of  claim 58 , wherein n is an integer of from 1 to 100. 
     
     
         66 . The polymer or particle of  claim 58 , wherein n is an integer of from 5 to 20. 
     
     
         67 . The polymer or particle of  claim 58 , wherein the polymer has a molecular weight of from 5 to 10 kDa. 
     
     
         68 . The polymer or particle of  claim 58 , wherein the polymer has a molecular weight of from 10 to 15 kDa. 
     
     
         69 . The polymer or particle of  claim 58 , wherein the polymer has a molecular weight of from 15 to 25 kDa. 
     
     
         70 . The polymer or particle of  claim 58 , wherein the polymer has a molecular weight of from 25 to 50 kDa. 
     
     
         71 . The polymer or particle of  claim 58 , wherein the polymer is formulated as a particle encapsulating an agent selected from DNA, RNA, peptide, or protein. 
     
     
         72 . The polymer or particle of  claim 71 , wherein the RNA is siRNA, miRNA, or smRNA. 
     
     
         73 . The polymer or particle of  claim 58 , wherein the polymer is formulated as a particle encapsulating a chemotherapeutic agent. 
     
     
         74 . The polymer or particle of  claim 58 , wherein the polymer is formed from 1,4-butanediol diacrylate backbone monomers (B4) reacted with 4-amino-1-butanol side chain monomers (S4), and reacted with 1-(3-aminopropyl)pyrrolidine end groups (E7). 
     
     
         75 . The polymer or particle of  claim 74 , wherein acrylate-terminated polymer is first synthesized by reaction of the diacrylate backbone and amine side chain at a molar ratio of 1:1.1 to 1.2:1; followed by end-capping with amine-containing end groups. 
     
     
         76 . The polymer or particle of  claim 74 , wherein n is an integer of from 1 to 1000. 
     
     
         77 . The polymer or particle of  claim 74 , wherein n is an integer of from 1 to 100. 
     
     
         78 . The polymer or particle of  claim 74 , wherein n is an integer of from 5 to 20. 
     
     
         79 . The polymer or particle of  claim 74 , wherein the polymer has a molecular weight of from 5 to 10 kDa. 
     
     
         80 . The polymer or particle of  claim 74 , wherein the polymer has a molecular weight of from 10 to 15 kDa. 
     
     
         81 . The polymer or particle of  claim 74 , wherein the polymer has a molecular weight of from 15 to 25 kDa. 
     
     
         82 . The polymer or particle of  claim 74 , wherein the polymer has a molecular weight of from 25 to 50 kDa. 
     
     
         83 . The polymer or particle of  claim 74 , wherein the polymer is formulated as a particle encapsulating an agent selected from DNA, RNA, peptide, or protein. 
     
     
         84 . The polymer or particle of  claim 83 , wherein the RNA is siRNA, miRNA, or smRNA. 
     
     
         85 . The polymer or particle of  claim 74 , wherein the polymer is formulated as a particle encapsulating a chemotherapeutic agent.