Targeted synthetic nanocarriers with ph sensitive release of immunostimulatory agents

Abstract

This invention relates to compositions, and related methods, of synthetic nanocarriers that target sites of action in cells, such as antigen presenting cells (APCs), and comprise immunomodulatory agents that dissociate from the synthetic nanocarriers in a pH sensitive manner. Also disclosed are compositions and methods relating to synthetic nanocarriers that encapsulate labile immunomodulatory agents that dissociate from the synthetic nanocarriers in a pH sensitive manner.

1 . A method, comprising:
 determining that immunomodulatory agents coupled to synthetic nanocarriers dissociate from the synthetic nanocarriers according to the following relationship:   IArel(4.5)24%/IArel(7.4)24%≧1.2, wherein IArel(4.5)24% is defined as a weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=4.5 for 24 hours divided by the sum of the weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=4.5 for 24 hours plus a weight of immunomodulatory agent retained in the synthetic nanocarrier upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=4.5 for 24 hours, expressed as weight percent, and taken as an average across a sample of the synthetic nanocarriers, and wherein IArel(7.4)24% is defined as a weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=7.4 for 24 hours divided by the sum of the weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=7.4 for 24 hours plus a weight of immunomodulatory agent retained in the synthetic nanocarrier upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=7.4 for 24 hours, expressed as weight percent, and taken as an average across a sample of the synthetic nanocarriers; and   causing the synthetic nanocarriers to be administered to a subject.   
     
     
         2 . A method, comprising:
 causing the release of immunomodulatory agents in a subject where the immunomodulatory agents are coupled to synthetic nanocarriers and determined to dissociate from the synthetic nanocarriers according to the following relationship:   IArel(4.5)24%/IArel(7.4)24%≧1.2, wherein IArel(4.5)24% is defined as a weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=4.5 for 24 hours divided by the sum of the weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=4.5 for 24 hours plus a weight of immunomodulatory agent retained in the synthetic nanocarrier upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=4.5 for 24 hours, expressed as weight percent, and taken as an average across a sample of the synthetic nanocarriers, and wherein IArel(7.4)24% is defined as a weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=7.4 for 24 hours divided by the sum of the weight of immunomodulatory agent released upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=7.4 for 24 hours plus a weight of immunomodulatory agent retained in the synthetic nanocarrier upon exposure of the synthetic nanocarrier to an in vitro aqueous environment at a pH=7.4 for 24 hours, expressed as weight percent, and taken as an average across a sample of the synthetic nanocarriers.   
     
     
         3 . The method of  claim 1 , wherein the immunomodulatory agents are coupled to the synthetic nanocarriers via immunomodulatory agent coupling moieties. 
     
     
         4 . The method of  claim 1 , wherein the immunomodulatory agents are encapsulated within the synthetic nanocarriers. 
     
     
         5 . The method of  claim 1 , wherein the immunomodulatory agents comprise an adjuvant. 
     
     
         6 . The method of  claim 5 , wherein the adjuvant comprises a Toll-like receptor (TLR) agonist. 
     
     
         7 . The method of  claim 6 , wherein the TLR agonist is a TLR 3 agonist, TLR 7 agonist, TLR 8 agonist, TLR 7/8 agonist, or a TLR 9 agonist. 
     
     
         8 . The method of  claim 6 , wherein the TLR agonist comprises an immunostimulatory nucleic acid, an imidazoquinoline, or an adenine derivative. 
     
     
         9 . The method of  claim 8 , wherein the imidazoquinoline comprises an imidazoquinoline amine, an imidazopyridine amine, a 6,7-fused cycloalkylimidazopyridine amine, an imidazoquinoline amine, imiquimod, or resiquimod. 
     
     
         10 . The method of  claim 1 , wherein the synthetic nanocarriers further comprise a B cell antigen and/or a T cell antigen. 
     
     
         11 . The method of  claim 1 , wherein the synthetic nanocarriers comprise lipid-based nanoparticles, polymeric nanoparticles, metallic nanoparticles, surfactant-based emulsions, dendrimers, buckyballs, nanowires, virus-like particles, peptide or protein-based particles, nanoparticles that comprise a combination of nanomaterials, spheroidal nanoparticles, cubic nanoparticles, pyramidal nanoparticles, oblong nanoparticles, cylindrical nanoparticles, or toroidal nanoparticles. 
     
     
         12 . The method of  claim 11 , wherein the synthetic nanocarriers comprise polymeric nanoparticles. 
     
     
         13 . The method of  claim 12 , wherein the polymeric nanoparticles comprise one or more biodegradable polymers. 
     
     
         14 . The method of  claim 13 , wherein the biodegradable polymers comprise poly(lactide), poly(glycolide), or poly(lactide-co-glycolide). 
     
     
         15 . The method of  claim 13 , wherein the immunomodulatory agents are coupled to the one or more biodegradable polymers via immunomodulatory agent coupling moieties. 
     
     
         16 . The method of  claim 15 , wherein the immunomodulatory agent coupling moieties comprise an amide bond. 
     
     
         17 . The method of  claim 15 , wherein the immunomodulatory agent coupling moieties comprise an ester bond. 
     
     
         18 . The method of  claim 1 , wherein the synthetic nanocarriers are administered to the subject. 
     
     
         19 . The method of  claim 1 , wherein an immune response is induced or enhanced in the subject. 
     
     
         20 . The method of  claim 1 , wherein the subject has cancer, an infectious disease, a non-autoimmune metabolic disease, a degenerative disease, or an addiction.