Peptide-nanoparticle conjugates

Abstract

Described herein is a nanoparticle system including a multivalent nanoparticle core having a plurality of β-hairpin peptides conjugated thereto. Also included are pharmaceutical compositions and methods of making the nanoparticle system. Further included are immunotherapy methods including administering the nanoparticle system to a subject in need thereof, such as a human cancer patient.

1 . A nanoparticle system comprising
 a multivalent nanoparticle core comprising a plurality of β-hairpin peptides conjugated thereto.   
     
     
         2 . The nanoparticle system of  claim 1 , wherein the multivalent nanoparticle core comprises a hyperbranched polymer, a dendrimer, a dendron, a hybrid nanoparticle, or a micelle. 
     
     
         3 . The nanoparticle system of  claim 2 , wherein the micelle comprises an amphiphilic dendron-coil, or a dendrimer-exosome hybrid. 
     
     
         4 . The nanoparticle system of  claim 2 , wherein the hybrid nanoparticle comprises a multivalent polymeric scaffold nanoparticle core with β-hairpin peptide covalently attached thereto; and an outer shell encapsulating the polymeric scaffold nanoparticle core, wherein the outer shell comprises a liposome or a polymeric shell. 
     
     
         5 . The nanoparticle system of  claim 2 , wherein the dendrimer is a poly(amido-amine) (PAMAM) dendrimer, a polyester dendrimer, a polypropyleneimine (PPI) dendrimer, a diaminobutane amine polypropylenimine tetramine (DAB-Am 4) dendrimer, a polypropylamine (POPAM) dendrimer, a polylysine dendrimer, a polyester dendrimer, an iptycene dendrimer, a aliphatic poly(ether) dendrimer, an aromatic polyether dendrimer, or a combination thereof. 
     
     
         6 . The nanoparticle system of  claim 1 , wherein the β-hairpin peptide comprises a tumor targeting peptide, a cell-penetrating peptide, a peptide with high affinity for an immune checkpoint inhibitor receptor, or a peptide for treatment of a protein folding disease. 
     
     
         7 . The nanoparticle system of  claim 1 , wherein the β-hairpin peptide comprises a Trpzip peptide. 
     
     
         8 . The nanoparticle system of  claim 1 , wherein the nanoparticle system is further associated with a therapeutic, prophylactic or diagnostic agent. 
     
     
         9 . The nanoparticle system of  claim 8 , wherein the therapeutic agent is a chemotherapeutic agent or a therapeutic nucleic acid, or wherein the diagnostic agent is an imaging agent. 
     
     
         10 . A pharmaceutical composition comprising the nanoparticle system of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         11 . The pharmaceutical composition of  claim 10 , further comprising a therapeutic, prophylactic or diagnostic agent. 
     
     
         12 . A method of making a nanoparticle system, comprising
 contacting multivalent nanoparticle cores comprising multiple reactive end groups with a composition comprising one or more β-hairpin peptides under conditions sufficient to conjugate a plurality of the β-hairpin peptides to the multivalent nanoparticle cores and provide the nanoparticle system.   
     
     
         13 . The method of  claim 12 , wherein the reactive end groups comprise dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide, 1,1′-carbonyldiimidazole, N-succinimidyl S-acetylthioacetate, N-succinimidyl-S-acetylthiopropionate, 2-Mercaptoethylamine, sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate, succinimidyl iodoacetate, succinimidyl 3-(2-pyridyldithio)propionate, N-hydroxysuccinimide ester, N-hydroxy sulfosuccinimide ester, N-γ-maleimidobutyryl-oxysulfosuccinimide ester, nitrophenyl ester, tetrafluoro phenyl ester, pentafluorophenyl ester, thiopyridyl ester, thionitrophenyl ester, or a combination thereof. 
     
     
         14 . The method of  claim 13 , further comprising contacting the multivalent nanoparticle cores comprising multiple reactive end groups with a therapeutic, prophylactic or diagnostic agent. 
     
     
         15 . The method of  claim 13 , wherein the multivalent nanoparticle core comprises a hyperbranched polymer, a dendrimer, a dendron, a hybrid nanoparticle, or a micelle. 
     
     
         16 . The method of  claim 15 , wherein the hybrid nanoparticle comprises a multivalent polymeric scaffold nanoparticle core with the immune checkpoint inhibitor covalently attached thereto; and an outer shell encapsulating the polymeric scaffold nanoparticle core, wherein the outer shell comprises a liposome or a polymeric shell. 
     
     
         17 . The method of  claim 15 , wherein the β-hairpin peptide comprises a tumor targeting peptide, a cell-penetrating peptide, a peptide with high affinity for an immune checkpoint inhibitor receptor, or a peptide for treatment of a protein folding disease. 
     
     
         18 . The method of  claim 15 , wherein the β-hairpin peptide comprises a Trpzip peptide. 
     
     
         19 . An immunotherapy method comprising administering to a subject in need thereof the nanoparticle system of  claim 1 . 
     
     
         20 . The immunotherapy method of  claim 19 , wherein the subject is a human cancer patient or a human patient with an immune disorder.