Biodegradable nanoparticles as novel hemoglobin-based oxygen carriers and methods of using the same

Abstract

Compositions of matter and methods for making, storing and administering artificial blood substitutes. Artificial blood substitutes may have oxygen carriers that encapsulate an oxygen-binding compound in a polymer vesicle. Oxygen-binding compounds may include hemoglobin, myoglobin, or other oxygen binding compounds having characteristics similar to hemoglobin. Oxygen carriers may include nanoparticles, polymers and/or polymersomes comprising of poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) and related diblock copolymers of poly(ethylene oxide)-block-poly(γ-methyl ε-caprolactone) (PEO-b-PMCL). The oxygen carriers may have tunable oxygen-binding capacities, uniform and appropriately small size distributions, and human bloodlike viscosities and oncotic properties.

What is claimed is: 
     
         1 . A composition, comprising:
 an oxygen carrier comprising:
 a plurality of polymers; and 
 an oxygen-binding compound, 
   wherein oxygen is dispersed within the plurality of polymers of the oxygen carrier.   
     
     
         2 . A composition, comprising:
 an oxygen carrier comprising:
 a plurality of polymers; and 
 an oxygen-binding compound, 
   wherein oxygen is dispersed within an aqueous core of the oxygen carrier.   
     
     
         3 . A composition, comprising:
 an oxygen carrier comprising:
 a plurality of polymers; and 
 an oxygen-binding compound; and 
   a ligand conjugated to the surface of the oxygen carrier.   
     
     
         4 . A composition, comprising:
 an oxygen carrier comprising:
 a plurality of polymers; 
 an oxygen-binding compound; and 
 at least one allosteric effector. 
   
     
     
         5 . A composition, comprising:
 an oxygen carrier comprising:
 a plurality of polymers; and 
 an oxygen-binding compound; and 
   at least one pharmaceutically active agent optionally contained within the oxygen carrier.   
     
     
         6 . A composition, comprising:
 an oxygen carrier, wherein the oxygen carrier is a polymersome comprising:
 a plurality of polymers; and 
 an oxygen-binding compound, 
 wherein the polymersome has an aqueous interior, and wherein the oxygen-binding compound is within the polymersome; and 
   an allosteric effector compartmentalized within the aqueous interior of the polymersome.   
     
     
         7 . A composition, comprising:
 an oxygen carrier, wherein the oxygen carrier is a polymersome comprising:
 a plurality of polymers; and 
 an oxygen-binding compound, 
 wherein the polymersome has an aqueous interior, and wherein the oxygen-binding compound is within the polymersome; and 
   a pharmaceutically active agent compartmentalized within the aqueous interior of the polymersome.   
     
     
         8 . A composition, comprising:
 an oxygen carrier, wherein the oxygen carrier is a polymersome comprising:
 a plurality of polymers; and 
 an oxygen-binding compound, 
 wherein the polymersome has a hydrophobic membrane, and wherein the oxygen-binding compound is within the polymersome; and 
   a pharmaceutically active agent compartmentalized within the hydrophobic membrane of the polymersome.   
     
     
         9 . A composition, comprising:
 an oxygen carrier, wherein the oxygen carrier is a polymersome comprising:
 a plurality of polymers; and 
 an oxygen-binding compound, 
 wherein the polymersome has a hydrophobic membrane, and wherein the oxygen-binding compound is within the polymersome; and 
   an allosteric effector compartmentalized within the hydrophobic membrane of the polymersome.   
     
     
         10 . The composition of  claim 9 , wherein the allosteric effector is a naturally occurring molecule, a recombinant molecule, a synthetic molecule, or a polymer. 
     
     
         11 . The composition of  claim 9 , wherein the allosteric effector modifies oxygen-binding through hydrogen ions, carbon dioxide, or 2,3-bisphosphoglycerate. 
     
     
         12 . A composition, comprising:
 an oxygen carrier, wherein the oxygen carrier is a polymersome comprising:
 a plurality of polymers; and 
 an oxygen-binding compound, 
 wherein the polymersome has a hydrophilic surface, and wherein the oxygen-binding compound is covalently linked to the hydrophilic surface. 
   
     
     
         13 . A composition, comprising:
 an oxygen carrier, wherein the oxygen carrier is a polymersome comprising:
 a plurality of polymers; and 
 an oxygen-binding compound, 
 wherein the polymersome has a hydrophilic surface; and 
   a pharmaceutically active agent covalently linked to the hydrophilic surface of the polymersome.   
     
     
         14 . A composition, comprising:
 an oxygen carrier, wherein the oxygen carrier is a polymersome comprising:
 a plurality of polymers; and 
 an oxygen-binding compound, 
 wherein the polymersome has a hydrophilic surface; and 
   an allosteric effector covalently linked to the hydrophilic surface of the polymersome.   
     
     
         15 . The composition of  claim 14 , wherein the allosteric effector is a naturally occurring molecule, a recombinant molecule, a synthetic molecule or a polymer. 
     
     
         16 . The composition of  claim 14 , wherein the allosteric effector modifies oxygen-binding through hydrogen ions, carbon dioxide, or 2,3-bisphosphoglycerate. 
     
     
         17 . A method of manufacturing a composition, comprising:
 an oxygen carrier comprising:
 preparing an organic solution comprising a plurality of polymers and exposing the organic solution to a plastic, polytetrafluoroethylene, or glass surface; 
 dehydrating the organic solution on the plastic, polytetrafluoroethylene, or glass surface to create a film of polymers; 
 rehydrating the film of polymers in an aqueous solution comprising an oxygen-binding molecule; and 
 cross-linking the polymers in the aqueous solution via chemical modification. 
   
     
     
         18 . The method of  claim 17 , wherein the oxygen-binding molecule is hemoglobin. 
     
     
         19 . The method of  claim 17 , wherein the aqueous solution comprises an allosteric effector, a pharmaceutically active agent, or a combination thereof. 
     
     
         20 . The method of  claim 17 , wherein cross-linking the polymers in the aqueous solution via chemical modification comprises cross-linking the polymers via a photoactive chemical and UV light. 
     
     
         21 . The method of  claim 17 , wherein cross-linking the polymers in the aqueous solution via chemical modification comprises cross-linking the polymers via a chemical modification of 2,2-dimethoxy-2-phenylacetophenone. 
     
     
         22 . The method of  claim 17 , wherein cross-linking the polymers in the aqueous solution via chemical modification comprises lyophilizing the polymers after cross-linking. 
     
     
         23 . The method of  claim 17 , wherein the polymers are purified through a polycarbonate filter with a pore size of between about 50 kilodaltons and about 1 million kilodaltons. 
     
     
         24 . The method of  claim 17 , wherein the organic solution comprises at least one biocompatible polymer and at least one biodegradable polymer. 
     
     
         25 . The method of  claim 24 , wherein the diblock biocompatible polymer is selected from at least one of poly(ethylene oxide) and poly(ethylene glycol) and the diblock biodegradable polymer is selected from at least one of poly(ε-caprolactone) and poly(γ-methyl ε-caprolactone). 
     
     
         26 . The method of  claim 24 , wherein the organic solution comprises a triblock copolymer comprising at least one biocompatible polymer and at least one biodegradable polymer. 
     
     
         27 . The method of  claim 26 , wherein the triblock biocompatible polymer is selected from at least one of poly(ethylene oxide) and poly(ethylene glycol) and the triblock biodegradable polymer is selected from at least one of poly(ε-caprolactone) and poly(γ-methyl ε-caprolactone). 
     
     
         28 . The method of  claim 24 , wherein the organic solution comprises a block copolymer in which at least one block is poly(ethylene oxide) and one block is poly (γ-methyl ε-caprolactone), the poly(ethylene oxide) having a number-average molecular weight between about 1.5 kilodaltons and about 3.8 kilodaltons. 
     
     
         29 . The method of  claim 28 , wherein the poly(ethylene oxide) has a weight fraction between about 10 and about 30 percent of the total weight of the block copolymer. 
     
     
         30 . The method of  claim 28 , wherein the poly(ethylene oxide) has a weight fraction between about 30 and about 50 percent of the total weight of the block copolymer. 
     
     
         31 . The method of  claim 24 , wherein the organic solution comprises a diblock copolymer and at least one polymer block comprising poly(ε-caprolactone) with a number-average molecular weight that is from about 9 kilodaltons to about 23 kilodaltons. 
     
     
         32 . The method of  claim 24 , wherein the organic solution comprises a diblock copolymer and at least one polymer block comprising poly(ε-caprolactone) with a number-average molecular weight that is from about 9.5 kilodaltons to about 22.2 kilodaltons.