Biodegradable nanoparticles as novel hemoglobin-based oxygen carriers and methods of using the same
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.
1. An oxygen carrier composition comprising:
a polymersome comprising a plurality of cross-linked block copolymer chains, wherein each block copolymer chain comprises:
at least one hydrophilic polymer block;
at least one hydrophobic polymer block; and
at least one polymerizable group conjugated to the at least one hydrophobic polymer block or hydrophilic polymer block;
an initiator molecule, wherein the initiator molecule activates a polymerization reaction between the polymerizable groups and the polymer blocks of different copolymer chains to create cross links; and
an oxygen-binding compound containing a heme group.
2. The composition of claim 1 , wherein the oxygen-binding compound is within the polymersome.
3. The composition of claim 1 , wherein the oxygen-binding compound is a naturally occurring protein, a recombinant protein, a recombinant polypeptide, a synthetic polypeptide, a chemical synthesized by an animal, a synthetic small molecule, a carbohydrate, a nucleic acid, a lipid or a polymer.
4. The composition of claim 1 , wherein the oxygen-binding compound is a compound derived from one or more of a naturally occurring protein, a recombinant protein, a recombinant polypeptide, a synthetic polypeptide, a chemical synthesized by an animal, a synthetic small molecule, a carbohydrate, a nucleic acid, a lipid and a polymer.
5. The composition of claim 1 , wherein the oxygen-binding compound is hemoglobin.
6. The composition of claim 1 , wherein the oxygen-binding compound is a derivative of hemoglobin.
7. The composition of claim 1 , wherein at least one polymer block in each of the plurality of block copolymer chains is a biodegradable polymer and at least one polymer block of each of the plurality of block copolymer chains is a biocompatible polymer.
8. The composition of claim 7 , wherein at least one hydrophilic polymer block in each of the plurality of block copolymer chains is poly(ethylene oxide) or poly(ethylene glycol).
9. The composition of claim 8 , wherein at least one hydrophobic polymer block in each of the plurality of block copolymer chains is poly(ε-caprolactone), and wherein the at least one polymerizable group is attached to a poly(ε-caprolactone) terminus.
10. The composition of claim 8 , further comprising one of a poly(peptide), a poly(saccharide) or a poly(nucleic acid).
11. The composition of claim 8 , wherein each block copolymer chain comprises a biodegradable diblock copolymer of poly(ethylene oxide) and poly(ε-caprolactone).
12. The composition of claim 11 , wherein the poly(ethylene oxide) has a number-average molecular weight from about 1.5 kiloDalton to about 4.0 kiloDalton.
13. The composition of claim 11 , wherein a weight fraction of the poly(ethylene oxide) is from about 11 to about 20 percent of the total weight of the block copolymer.
14. The composition of claim 11 , wherein the poly(ethylene oxide) has a number-average molecular weight from about 1.5 to about 3.8 kiloDalton and a weight fraction from about 10 to about 30 percent of the total weight of the block copolymer.
15. The composition of claim 1 , wherein at least one hydrophilic polymer block in each of the plurality of block copolymer chains is poly(ethylene oxide) or poly(ethylene glycol) having a weight fraction from about 30 to about 50 percent of the total weight of the block copolymer chain.
16. The composition of claim 1 , wherein at least one hydrophobic polymer block in each of the plurality of block copolymer chains is poly(ε-caprolactone) having a weight fraction from about 50 to about 70 percent of the total weight of the block copolymer chain.
17. The composition of claim 1 , wherein at least one hydrophobic polymer block in each of the plurality of block copolymer chains comprises poly(ε-caprolactone) with a number-average molecular weight from about 9 kiloDalton to about 23 kiloDalton.
18. The composition of claim 1 , wherein the number-average molecular weight is from about 9.5 kiloDalton to about 22.2 kiloDalton.
19. The composition of claim 1 , wherein:
the at least one hydrophilic polymer block of each of the plurality of block copolymer chains comprises poly(ethylene oxide) having a number-average molecular weight of about 2 kiloDalton; and
the at least one hydrophobic polymer block of each of the plurality of block copolymer chains comprises poly(ε-caprolactone) having a number-average molecular weight of about 12 kiloDalton.
20. The composition of claim 19 , wherein the poly(ethylene oxide) has a number average molecular weight that is from about 1.8 kiloDalton to about 1.9 kiloDalton and the poly(ε-caprolactone) has a number average molecular weight that is from about 8 kiloDalton to about 9.5 kiloDalton.
21. The composition of claim 2 , wherein the polymersome has an aqueous interior.
22. The composition of claim 2 , wherein the polymersome has a hydrophobic polymersome membrane.
23. The composition of claim 2 , wherein the polymersome has a hydrophilic surface.
24. The composition of claim 1 , wherein the polymersome has a diameter from about 50 nm to about 5 μm.
25. The composition of claim 1 , wherein the polymersome has a membrane thickness from about 5 nm to about 30 nm.
26. The composition of claim 1 , wherein the polymersome is biodegradable.
27. The composition of claim 7 , wherein each block copolymer chain further comprises at least one additional hydrophilic polymer chosen from poly(ethylene oxide), poly(acrylic acid), poly(ethylene glycol), or any combination thereof.
28. The composition of claim 7 , wherein the at least one hydrophobic polymer block further comprises at least one additional hydrophobic polymer chosen from poly(caprolactone), poly(methylcaprolactone), poly(menthide), poly(lactide), poly(glycolide), poly(methylglycolide), poly(dimethylsiloxane), poly(isobutylene), poly(styrene), poly(ethylene), poly(propylene oxide), or any combination thereof.
29. A kit, comprising:
(i) a pharmaceutical composition comprising an oxygen carrier, wherein the oxygen carrier comprises:
a plurality of cross-linked block copolymer chains, wherein each block copolymer chain comprises:
at least one hydrophilic polymer block;
at least one hydrophobic polymer block; and
at least one polymerizable group conjugated to the at least one hydrophobic polymer block or hydrophilic polymer block;
an initiator molecule, wherein the initiator molecule activates a polymerization reaction between the polymerizable groups and the polymer blocks of different copolymer chains to create cross links; and
an oxygen-binding compound containing a heme group; and
(ii) an implement for administering the oxygen carrier intravenously, via inhalation, topically, per rectum, per the vagina, transdermally, subcutaneously, intraperitoneally, intrathecally, intramuscularly, or orally.
30. A kit comprising a first container and a second container, wherein the first container comprises an oxygen carrier and wherein the second container comprises a rehydration mixture, wherein the oxygen carrier is lyophilized or dried, and comprises:
a plurality of cross-linked block copolymer chains, wherein each block copolymer chain comprises:
at least one hydrophilic polymer block;
at least one hydrophobic polymer block; and
at least one polymerizable group conjugated to the at least one hydrophobic polymer block or hydrophilic polymer block;
an initiator molecule, wherein the initiator molecule activates a polymerization reaction between the polymerizable groups and the polymer blocks of different copolymer chains to create cross links; and
an oxygen-binding compound containing a heme group.