Unimolecular nanoparticles for efficient delivery of therapeutic rna

Abstract

Provided are a unimolecular nanoparticle, a composition thereof, and methods of use thereof, and includes 1) a dendritic polymer having a molecular weight of about 500-120,000 Da and terminating in hydroxyl, amino or carboxylic acid groups; 2) cationic polymers attached to at least a majority of the terminating groups of the dendritic polymer via a pH-sensitive linker, wherein each cationic polymer comprises a polymeric backbone attached to cationic functional groups and to weakly basic groups by disulfide bonds, wherein the molar ratio of cationic functional groups to weakly basic groups ranges from 1:1-5:1, and has a molecular weight from about 1,000-5,000 Da; and 3) poly(ethylene glycol) attached to a plurality of cationic polymers and having a terminal group selected from a targeting ligand, OH, O-alkyl, NH2 , biotin, or a dye, wherein the terminal group of at least one poly(ethylene glycol) is having a molecular weight of about 1,000-15,000 Da.

1 . A unimolecular nanoparticle and pharmaceutically acceptable salts thereof, wherein the unimolecular nanoparticle comprises a dendritic polymer core, cationic polymers, and outer poly(ethylene glycol) blocks, wherein the cationic polymers link the dendritic polymer core to the outer poly(ethylene glycol) blocks;
 wherein:
 the dendritic polymer having a molecular weight of about 500 to about 120,000 Da and terminating in hydroxyl, amino or carboxylic acid groups; 
 the cationic polymers attached to at least 50% of the terminating groups of the dendritic polymer via a pH-sensitive linker, wherein
 each cationic polymer comprises: a polymeric backbone, cationic functional groups, weakly basic groups, and disulfide bonds,
 wherein: 
  the polymeric backbone is attached to the cationic functional groups and the weakly basic groups by the disulfide bonds, 
  the molar ratio of the cationic functional groups to the weakly basic groups ranges from 1:1 to 5:1, and 
  the cationic polymer has a molecular weight from about 1,000 to about 5,000 Da; and 
 
 
 the outer poly(ethylene glycol) blocks are attached to a plurality of the cationic polymers and have a terminal group selected from the group consisting of a targeting ligand, OH, O-alkyl, NH 2 , biotin, and a dye, wherein the outer poly(ethylene glycol) has a molecular weight of about 1,000 to about 15,000 Da. 
   
     
     
         2 . The unimolecular nanoparticle of  claim 1 , wherein the dendritic polymer is a polyester or a poly(amido-amine). 
     
     
         3 . The unimolecular nanoparticle of  claim 1 , wherein the dendritic polymer is a hyper-branched polymer or a dendrimer. 
     
     
         4 . The unimolecular nanoparticle of  claim 1 , wherein the dendritic polymer has from 3 to 7 generations. 
     
     
         5 . The unimolecular nanoparticle of  claim 1 , wherein the dendritic polymer is a poly(amido-amine) dendrimer having 3 to 4 generations. 
     
     
         6 . The unimolecular nanoparticle of  claim 1 , wherein the dendritic polymer is a hyperbranched polyester having 3 to 4 generations. 
     
     
         7 . The unimolecular nanoparticle of  claim 1 , wherein the pH-sensitive linker comprises an imine, hydrazone, or cis-aconityl group. 
     
     
         8 . The unimolecular nanoparticle of  claim 1 , wherein the cationic polymer comprises a polyamide backbone, disulfide linkers, amino and/or ammonium salt groups, and imidazole and/or imidazolium salt groups. 
     
     
         9 . The unimolecular nanoparticle of  claim 8 , wherein the polyamide backbone is selected from the group consisting of polyasparagine, polyglutamine, polyornithine, and polylysine. 
     
     
         10 . The unimolecular nanoparticle of  claim 8 , wherein the cationic polymers comprise (C 2 -C 6  alkylene)disulfide(C 2 -C 6  alkyl)amino groups and/or salts thereof, and (C 2 -C 6  alkylene)disulfide(C 2 -C 6  alkyl)aminocarbonylimidazole groups and/or salts thereof. 
     
     
         11 . The unimolecular nanoparticle of  claim 8 , wherein the cationic polymers comprise ethylene-disulfide-ethylamino groups and/or salts thereof, and ethylene-disulfide-ethylaminocarbonylimidazole groups and/or salts thereof. 
     
     
         12 . The unimolecular nanoparticle of  claim 1 , wherein the targeting ligand is a cofactor, carbohydrate, peptide, antibody, nanobody, or aptamer. 
     
     
         13 . The unimolecular nanoparticle of  claim 1 , wherein the targeting ligand is selected from the group consisting of folic acid, mannose, GE11, cRGD, KE108, octreotide, TAT cell penetrating peptide, PSMA aptamer, TRC105, 7D12 nanobody, and CTB. 
     
     
         14 . The unimolecular nanoparticle of  claim 1  further comprising a therapeutic RNA within the unimolecular nanoparticle. 
     
     
         15 . The unimolecular nanoparticle of  claim 14 , wherein the therapeutic RNA is an siRNA. 
     
     
         16 . (canceled) 
     
     
         17 . A composition comprising the unimolecular nanoparticle of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         18 . A method of preparing a unimolecular nanoparticle comprising dispersing therapeutic RNA within the unimolecular nanoparticle of  claim 1 . 
     
     
         19 . A method of treating a cancer by administering an effective amount of a unimolecular nanoparticle of  claim 14 , wherein the therapeutic RNA inhibits expression of a gene necessary for survival or growth of the cancer. 
     
     
         20 . A kit comprising a package containing unimolecular nanoparticle of  claim 1 , a package containing an effective amount of siRNA, and directions for use of the kit. 
     
     
         21 . A siRNA-loaded unimolecular nanoparticle comprising the unimolecular nanoparticle of  claim 1  and a siRNA, wherein the loading of siRNA is about 10 wt % to about 20 wt %, based on the total siRNA-loaded unimolecular nanoparticle weight. 
     
     
         22 . A composition comprising the unimolecular nanoparticle and the therapeutic RNA with the unimolecular nanoparticle of  claim 14  and a pharmaceutically acceptable carrier.