Cationic mucic acid polymer-based delivery systems

Abstract

The present disclosure is directed to nanoparticle delivery systems for delivering biological agents, pharmaceutical compositions of comprising these nanoparticles, and methods of using these compositions. Certain embodiments of the present disclosure provide nanoparticles comprising polymers comprising alternating charged and uncharged segments comprising one or more of the following structural units of Formula (I) Formula (III):wherein A is an uncharged segment comprising polyalkylene glycol; and B is a cationically charged segment comprising at least one polyhydroxy linkage.

What is claimed: 
     
         1 . A polymer comprising alternating charged and uncharged segments comprising one or more of the structural units -[-(A)-(B)-]- or -[-(B)-(A)-]-; wherein:
 A is an uncharged segment comprising a polyalkylene glycol; and   B is a cationically charged segment comprising a polyhydroxy linkage which contains at least one pair of vicinal diols.   
     
     
         2 . The polymer of  claim 1 , wherein the polyalkylene glycol has the structure: 
       
         
           
           
               
               
           
         
         wherein x is from 1 to 6. 
       
     
     
         3 . The polymer of  claim 2 , wherein x is 2. 
     
     
         4 . The polymer of  claim 3 , wherein the polyalkylene glycol has a number average molecular weight from about 500 Daltons (Da) to about 50,000 kDa. 
     
     
         5 . The polymer of  claim 1 , wherein the polyhydroxy linkage containing at least one pair of vicinal diols comprises mucic acid. 
     
     
         6 . The polymer of  claim 5 , wherein B comprises at least one repeating subunit having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The polymer of  claim 1 , wherein B comprises at least one repeating subunit having the structure: 
       
         
           
           
               
               
           
         
       
       wherein m is from 1 to 10. 
     
     
         8 . The polymer of  claim 1 , wherein B comprises a repeating subunit of the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 m is independently at each occurrence from 1 to 10; and 
 n is independently at each occurrence from 1 to 5. 
 
     
     
         9 . The polymer of  claim 8  wherein m is 5 and n is 1. 
     
     
         10 . The polymer of  claim 1 , further comprising a boronic acid-containing polymer having the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 R A  is an electron-withdrawing group; 
 n is from 0 to 4; 
 s is from 20-1200; 
 L is a linking group, and 
 X 5  is C 1-6  alkyl optionally substituted with —OH, —COOH, —C(═O)—O-alkyl, —C(═O)—O-aryl, —NH 2 , —NH(alkyl), N(alkyl) 2 , or a salt or protected analogue thereof. 
 
     
     
         11 . The polymer of  claim 10 , wherein:
 R A  is —NO 2 ;   n is 1; and   the boronic acid moiety has one of the following structures:   
       
         
           
           
               
               
           
         
       
     
     
         12 . The polymer of  claim 10 , wherein L is selected from the group consisting of:
 —(C 0-2 -alkylene)-NH—C(═O)—(C 0-2 -alkylene)-, (C 0-2 -alkylene)-C(═O)—NH—(C 0-2 -alkylene)-, —(C 0-2 -alkylene)-O—C(═O)—(C 0-2 -alkylene)-, —(C 0-2 -alkylene)-C(═O)—O—(C 0-2 -alkylene)-, —NH—C(═O)—, —C(═O)—NH—, —O—C(═O)—, and —C(═O)—O—.   
     
     
         13 . A nanoparticle comprising the polymer of  claim 8 . 
     
     
         14 . The nanoparticle of  claim 13  further comprising a biological agent, wherein the biological agent is:
 (a) encapsulated within the nanoparticle; or 
 (b) covalently bound to the polymer, optionally through a reversible linkage. 
 
     
     
         15 . The nanoparticle of  claim 14 , wherein the biological agent is a polynucleotide. 
     
     
         16 . The nanoparticle of  claim 15 , wherein the polynucleotide is selected from the group consisting of genomic DNA, cDNA, mRNA, siRNA, shRNA, miRNA, an antisense oligonucleotide, a chimeric polynucleotide and a plasmid. 
     
     
         17 . The nanoparticle of  claim 14 , wherein the biological agent is a small molecule therapeutic. 
     
     
         18 . The nanoparticle of  claim 17 , wherein the small molecule therapeutic is selected from the group consisting of an antibiotic, a steroid, and a chemotherapeutic. 
     
     
         19 . The nanoparticle of  claim 18 , wherein the chemotherapeutic is selected from the group consisting of epothilones, camptothecin-based drugs and taxol. 
     
     
         20 . The nanoparticle of  claim 17 , wherein the biological agent is covalently bound to the polymer through a biodegradable linkage. 
     
     
         21 . A nanoparticle comprising the polymer of  claim 10 . 
     
     
         22 . The nanoparticle of  claim 21  further comprising a targeting ligand conjugated to the boronic acid-containing polymer through a condensation linkage to X 5 , wherein the targeting ligand is selected from the group consisting of transferrin, a ligand for a cellular receptor, an antibody, and a cellular receptor protein or fragment thereof. 
     
     
         23 . The nanoparticle of  claim 22  containing a single molecule of the targeting ligand. 
     
     
         24 . The nanoparticle of  claim 22  further comprising a biological agent, wherein the biological agent is:
 (a) encapsulated within the nanoparticle; or 
 (b) covalently bound to the polymer, optionally through a reversible linkage. 
 
     
     
         25 . The nanoparticle of  claim 24 , wherein the biological agent is a polynucleotide. 
     
     
         26 . The nanoparticle of  claim 25 , wherein the polynucleotide is selected from the group consisting of genomic DNA, cDNA, mRNA, siRNA, shRNA, miRNA, an antisense oligonucleotide, a chimeric polynucleotide and a plasmid. 
     
     
         27 . The nanoparticle of  claim 24 , wherein the biological agent is a small molecule therapeutic. 
     
     
         28 . The nanoparticle of  claim 27 , wherein the small molecule therapeutic is selected from the group consisting of an antibiotic, a steroid, and a chemotherapeutic. 
     
     
         29 . The nanoparticle of  claim 28 , wherein the chemotherapeutic is selected from the group consisting of epothilones, camptothecin-based drugs and taxol. 
     
     
         30 . The nanoparticle of  claim 27 , wherein the biological agent is covalently bound to the polymer through a biodegradable linkage. 
     
     
         31 . A pharmaceutical composition comprising the nanoparticle of  claim 14  and a pharmaceutically acceptable vehicle, carrier or excipient. 
     
     
         32 . A pharmaceutical composition comprising the nanoparticle of  claim 24  and a pharmaceutically acceptable vehicle, carrier or excipient. 
     
     
         33 . A method for treating a subject in need of a biologically active agent, the method comprising administering to the subject the nanoparticle of  claim 14 , wherein said nanoparticle comprises the biologically active agent. 
     
     
         34 . A method for treating a subject in need of a biologically active agent, the method comprising administering to the subject the nanoparticle of  claim 24 , wherein said nanoparticle comprises the biologically active agent. 
     
     
         35 . A method for treating a subject in need of a biologically active agent, the method comprising administering to the subject the pharmaceutical composition of  claim 31 , wherein said nanoparticle comprises the biologically active agent. 
     
     
         36 . A method for treating a subject in need of a biologically active agent, the method comprising administering to the subject the pharmaceutical composition of  claim 32 , wherein said nanoparticle comprises the biologically active agent.