Self Assembled Films for Protein and Drug Delivery Applications

Abstract

Provided are systems for controlled release of proteins from decomposable thin films constructed by layer-by-layer deposition. Such films generally comprise alternating layers of polymers and proteins, and may further comprise additional layers of polyions. In some embodiments, decomposable thin films and methods of using such films allow proteins to be released over an extended period of time and/or retention of as much as 100% of function of released protein.

1 . A decomposable thin film comprising:
 a plurality of multilayer units comprising a first layer having a first charge and a second layer having a second charge, wherein:
 at least a portion of the multilayers comprise a protein, 
 decomposition of the thin film is characterized by sequential removal of at least a portion of the layers having the first charge and degradation of layers having the second charge and by release of the protein from the corresponding layer, and 
 the decomposable thin film comprises at least one degradable polyelectrolyte layer, wherein the degradable polyelectrolyte is hydrolyzable. 
   
   
   
       2 . The decomposable thin film of  claim 1 , wherein:
 the thin film comprises alternating cationic and anionic layers, and   decomposition of the thin film is characterized by hydrolytic degradation of at least a portion of a layer selected from the group consisting of the cationic layers, the anionic layers, and both.   
   
   
       3 . The decomposable thin film of  claim 1 , wherein at least a portion of the degradable polyelectrolyte layers comprises a polyelectrolyte selected from the group consisting of a synthetic polyelectrolyte, a natural polyelectrolyte, and both. 
   
   
       4 . The decomposable thin film of  claim 1 , wherein at least a portion of the degradable polyelectrolyte layers comprises a polymer selected from polyesters, polyanhydrides, polyorthoesters, polyphosphazenes, polyphosphoesters, and combinations thereof. 
   
   
       5 . The decomposable thin film of  claim 4 , wherein the polymer is a polyester selected from the group consisting of poly(β-amino ester)s, poly(L-lactide-co-L-lysine), poly(serine ester), poly(4-hydroxy-L-proline ester), poly[-(4-aminobutyl)-L-glycolic acid], and any combination thereof. 
   
   
       6 . The decomposable thin film of  claim 5 , wherein the polyester is a poly(β-amino ester) selected from the group consisting of 
     
       
         
         
             
             
         
       
       wherein:
 linker A and linker B are each independently selected from the group consisting of carbon chains of 1 to 30 carbon atoms, heteroatom-containing carbon chains of 1 to 30 atoms, and carbon chains and heteroatom-containing carbon chains with at least one substituent selected from the group consisting of branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiol groups; 
 R 1  and R 2  are each independently selected from the group consisting of hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carboxyl ester, carbonyldioxyl, amide, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, a substituted alkanoyl group, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which may be substituted with at least one substituent selected from the group consisting of branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiol groups; and 
 n is an integer greater than or equal to 5. 
 
     
   
   
       7 . The decomposable thin film of  claim 6 , wherein the poly(β-amino ester) is 
     
       
         
         
             
             
         
       
     
   
   
       8 . The decomposable thin film of  claim 7 , wherein the poly(β-amino ester) is 
     
       
         
         
             
             
         
       
     
   
   
       9 . The decomposable thin film of  claim 7 , wherein the poly(β-amino ester) is 
     
       
         
         
             
             
         
       
     
   
   
       10 . The decomposable thin film of  claim 1 , wherein at least a portion of the degradable polyelectrolyte layers comprises a polymer selected from poly(styrene sulfonate), poly(acrylic acid), linear poly(ethylene imine), poly(diallyl dimethyl ammonium chloride), poly(allylamine hydrochloride), and combinations thereof. 
   
   
       11 . The decomposable thin film of  claim 1 , wherein the degradation is characterized by at least one characteristic selected from the group consisting of hydrolytic, thermal, enzymatic, and photolytic. 
   
   
       12 . The decomposable thin film of  claim 1 , wherein at least a portion of the degradable polyelectrolyte layers comprises a biodegradable polymer. 
   
   
       13 . The decomposable thin film of  claim 12 , wherein the biodegradable polymer is selected from polyhydroxyacids; polypropylfumarates; polycaprolactones; polyamides; poly(amino acids); polyacetals; polyethers; biodegradable polycyanoacrylates; biodegradable polyurethanes; polysaccharides; and co-polymers, mixtures, and adducts thereof. 
   
   
       14 . The decomposable thin film of  claim 1 , wherein the thin film is adapted and constructed as a hollow shell. 
   
   
       15 . The decomposable thin film of  claim 1 , wherein the thin film is deposited on a non-planar substrate. 
   
   
       16 . The decomposable thin film of  claim 15 , wherein the thin film is deposited on a substrate having a shape selected from particles, tube, sphere, strand, coiled strand, and capillary network. 
   
   
       17 . The decomposable thin film of  claim 15 , wherein degradation of the thin film enables dissolution of the substrate material. 
   
   
       18 . The decomposable thin film of  claim 15 , wherein the substrate comprises a drug. 
   
   
       19 . The decomposable thin film of  claim 1 , wherein the thin film is disposed on a substrate, wherein the surface properties of the substrate vary across a surface of the substrate. 
   
   
       20 . The decomposable thin film of  claim 1 , wherein the thin film is disposed on a substrate comprising a material selected from metals, metal oxides, plastics, ceramics, silicon, glasses, mica, graphite, hydrogels, polymers, and any combination thereof. 
   
   
       21 . The decomposable thin film of  claim 1 , wherein the protein is a growth factor. 
   
   
       22 . The decomposable thin film of  claim 21 , wherein the growth factor is selected from the group consisting of vascular endothelial growth factor (VEGF), bone morphogenic protein 2 (BMP-2), bone morphogenic protein 4 (BMP-4), and basic fibroblast growth factor (bFGF). 
   
   
       23 . The decomposable thin film of  claim 1 , wherein the protein is a clotting factor. 
   
   
       24 . The decomposable thin film of  claim 23 , wherein the clotting factor is selected from the group consisting of factor I (fibrinogen), factor II (prothrombin), factor III (tissue thromboplastin), factor V (proaccelerin), factor VII (stable factor), factor VIII (antihemophilic factor), factor IX (plasma thromboplastin component), factor X (thrombokinase), factor XI (plasma thromboplastin antecedent), factor XII (Hageman factor), and factor XIII (fibrin stabilizing factor). 
   
   
       25 . The decomposable thin film of  claim 1 , wherein the protein is an enzyme polypeptide. 
   
   
       26 . The decomposable thin film of  claim 25 , wherein the enzyme polypeptide is lysozyme. 
   
   
       27 . The decomposable thin film of  claim 1 , wherein the multilayer units comprise bilayer units of the structure (polyelectrolyte layer having the first charge/protein layer having the second charge). 
   
   
       28 . The decomposable thin film of  claim 1 , wherein
 the multilayer units each further comprise two layers, each layer having either the first charge or the second charge; and   each layer within the multilayer unit is adjacent to a layer having a different charge.   
   
   
       29 . The decomposable thin film of  claim 28 , wherein the multilayer units comprise tetralayer units of the structure (polyelectrolyte having the first charge/first biopolymer having the second charge/protein layer having the first charge/second biopolymer having the second charge). 
   
   
       30 . The decomposable thin film of  claim 29 , wherein the first biopolymer and the second biopolymer are the same. 
   
   
       31 . The decomposable thin film of  claim 29 , wherein at least one of the biopolymers is a polysaccharide. 
   
   
       32 . The decomposable thin film of  claim 31 , wherein the polysaccharide is selected from the group consisting of heparan sulfate, chondroitin sulfate, hyaluronic acid, and dextran sulfate. 
   
   
       33 . The decomposable thin film of  claim 1 , wherein the film comprises at least 10 multilayer units. 
   
   
       34 . The decomposable thin film of  claim 33 , wherein the film comprises at least 20 multilayer units. 
   
   
       35 . The decomposable thin film of  claim 34 , wherein the film comprises at least 30 multilayer units. 
   
   
       36 . The decomposable thin film of  claim 35 , wherein the film comprises at least 40 multilayer units. 
   
   
       37 . The decomposable thin film of  claim 36 , wherein the film comprises at least 50 multilayer units. 
   
   
       38 . The decomposable thin film of  claim 37 , wherein the film comprises at least 60 multilayer units. 
   
   
       39 . The decomposable thin film of  claim 38 , wherein the film comprises at least 70 multilayer units. 
   
   
       40 . The decomposable thin film of  claim 39 , wherein the film comprises at least 80 multilayer units. 
   
   
       41 . A method of releasing a protein from a thin film comprising:
 providing a decomposable thin film comprising a plurality of multilayers including a first layer having a first charge and a second layer having a second change, wherein the protein is associated with at least one of the layers and the decomposable thin film includes at least one degradable polyelectrolyte layer, wherein the degradable polyelectrolyte is hydrolyzable; and   placing the thin film in a medium in which at least a portion of the thin film decomposes via the substantially sequential removal of at least a portion of the layers having the first charge and degradation of layers having the second charge.   
   
   
       42 . The method of  claim 41 , wherein the protein is released from the thin film with linear kinetics over a period of at least 5 days. 
   
   
       43 . The method of  claim 41 , wherein the protein is released from the thin film with linear kinetics over a period of at least 10 days. 
   
   
       44 . The method of  claim 41 , wherein the protein is released from the thin film with linear kinetics over a period of at least 14 days. 
   
   
       45 . The method of  claim 41 , wherein the protein continues to be released from the thin film over a period of at least 5 days. 
   
   
       46 . The method of  claim 45 , wherein the protein continues to be released from the thin film over a period of at least 10 days. 
   
   
       47 . The method of  claim 46 , wherein the protein continues to be released from the thin film over a period of at least 15 days. 
   
   
       48 . The method of  claim 47 , wherein the protein continues to be released from the thin film over a period of at least 20 days. 
   
   
       49 . The method of  claim 48 , wherein the protein continues to be released from the thin film over a period of at least 25 days. 
   
   
       50 . The method of  claim 49 , wherein the protein continues to be released from the thin film over a period of at least 30 days. 
   
   
       51 . The method of  claim 50 , wherein the protein continues to be released from the thin film over a period of at least 34 days. 
   
   
       52 . The method of  claim 41 , wherein protein released from the thin film has at least 50% activity after release from the thin film. 
   
   
       53 . The method of  claim 52 , wherein protein released from the thin film has at least 60% activity after release from the thin film. 
   
   
       54 . The method of  claim 53 , wherein protein released from the thin film has at least 70% activity after release from the thin film. 
   
   
       55 . The method of  claim 54 , wherein protein released from the thin film has at least 80% activity after release from the thin film. 
   
   
       56 . The method of  claim 55 , wherein the protein released from the thin film has at least 90% activity after release from the thin film.