Synthetic diblock copolypeptide hydrogels for use in the central nervous system

Abstract

This invention relates, e.g., to a composition suitable for administration to the central nervous system (CNS), comprising a block copolypeptide hydrogel, which comprises a biologically active material that is mixed with the hydrogel or that is attached to the polypeptide chain of the hydrogel, wherein the composition is suitable for administration to the CNS. Also disclosed are methods of making and using compositions of the invention as depots or as scaffolds for cell migration, and pharmaceutical compositions and kits for implementing methods of the invention.

1 . (canceled) 
     
     
         2 . A hydrogel composition suitable for administration to the central nervous system (CNS), comprising:
 a synthetic copolypeptide having from about 100 to about 600 residues and comprising:   a hydrophilic segment and a hydrophobic segment; and   a biologically active material is mixed with the hydrogel and/or that is attached to the copolypeptide backbone of the hydrogel; and water   wherein the composition is suitable for administration to the CNS.   
     
     
         3 . The composition of  claim 2 , wherein the biologically active material is a therapeutic agent, a diagnostic agent, or a protein or peptide that provides a migration guidance cue. 
     
     
         4 . The composition of  claim 2 , wherein the biologically active material is hydrophilic and is mixed with the hydrogel. 
     
     
         5 . The composition of  claim 2 , wherein the biologically active material is hydrophobic and is mixed with the hydrogel. 
     
     
         6 . The composition of  claim 2 , wherein the biologically active material is entrapped in a nanocarrier, which is mixed with the hydrogel. 
     
     
         7 . The composition of  claim 2 , wherein the biologically active material is covalently attached to the polypeptide backbone of the hydrogel. 
     
     
         8 . The composition of  claim 7 , wherein the biologically active material is a peptide, polypeptide, sugar, oligosaccharide, polysaccharide, glycoprotein, oligonucleotide, MRI contrast agents, radioisotope or fluorescent probe. 
     
     
         9 . The composition of  claim 8 , wherein the biologically active material is a peptide or polypeptide which functions as a migration guidance cue. 
     
     
         10 . The composition of  claim 2 , wherein the biologically active material is a diagnostic or therapeutic agent, and is mixed in the hydrogel, or is covalently attached to the polypeptide backbone of the hydrogel. 
     
     
         11 . The composition of  claim 2 , wherein the copolypeptide comprises
 poly-L-leucine (L), poly-L-isoleucine (I), poly-L-phenylalanine (F), poly-L-alanine (A), or poly-L-valine (V), or a mixture of these amino acids, as a hydrophobic domain, and   poly-L-lysine (K), poly-L-ornithine (O), poly-L-arginine (R), poly-L-homoarginine (RH) or poly-L-glutamate (E), or a mixture of these amino acids, as a hydrophilic domain.   
     
     
         12 . The composition of  claim 2 , wherein the copolypeptide comprises
 poly-D-leucine (L), poly-D-isoleucine (I), poly-D-phenylalanine (F), poly-D-alanine (A), or poly-D-valine (V), or a mixture of these amino acids, as a hydrophobic domain, and   poly-D-lysine (K), poly-D-ornithine (O), poly-D-arginine (R), poly-D-homoarginine (RH) or poly-D-glutamate (E), or a mixture of these amino acids, as a hydrophilic domain.   
     
     
         13 . The composition of  claim 2 , wherein the copolypeptide comprises poly-L-leucine (L) as a hydrophobic domain, and racemic poly-D/L-lysine (rac-K) as a hydrophilic domain. 
     
     
         14 . The composition of  claim 2 , wherein the copolypeptide consists essentially of poly-L-leucine (L) as a hydrophobic domain and poly-L-lysine (K) as a hydrophilic domain. 
     
     
         15 . A method for making a composition suitable for administration to the central nervous system (CNS), comprising providing a copolypeptide hydrogel and mixing or attaching a biologically active material to the copolypeptide backbone of the hydrogel, wherein the composition is suitable for administration to the CNS. 
     
     
         16 . The method of  claim 16 , wherein the biologically active material is a peptide or a protein of interest and further comprising covalently attaching the peptide or a protein of interest to the copolypeptide backbone of the hydrogel, by
 a) thiolating the peptide or protein of interest, alkene-functionalizing a group of the polypeptide backbone, and thiol-ene coupling (TEC) a thiolated group of the peptide or protein which has been thiolated to an alkene-functionalized group of the polypeptide backbone, or   b) thiolating a group of the polypeptide backbone, alkene-functionalizing the peptide or protein of interest, and thiol-ene coupling (TEC) a thiolated group of the polypeptide backbone which has been thiolated to an alkene-functionalized group of the peptide or protein or   c) amine coupling.   
     
     
         17 . A method for providing a scaffold for cell migration in the central nervous system (CNS), comprising functionalizing a copolypeptide hydrogel with a protein or peptide that provides a migration guidance cue wherein the composition is suitable for administration to the CNS. 
     
     
         18 . A method for stimulating cell migration or angiogenesis or for stimulating the in-growth of nerve fibers, in a brain, comprising introducing into the brain the composition of  claim 10 . 
     
     
         19 . A kit for performing one or more of the methods of the invention, comprising
 a) a copolypeptide of  claim 2 , which has been lyophilized, and, optionally, an aqueous solution comprising a therapeutic agent, an imaging agent, or a submicron particle encapsulating an agent of interest, with which the lyophilized block copolypeptide can be reconstituted; or   b) a copolypeptide of  claim 2 , which been chemically functionalized with a biomolecule of interest, and which has been lyophilized, and, optionally, an aqueous solution with which the functionalized, lyophilized block copolypeptide can be reconstituted.