Patch loaded with dual-sensitive vesicles for enhanced glucose-responsive insulin delivery
A composition comprising an amphiphilic polymeric material that is both hydrogen peroxide- and hypoxia-sensitive is described. The composition can further include a glucose-oxidizing enzyme and insulin, a bioactive derivative thereof, and/or another therapeutic agent (e.g., another diabetes treatment agent). The polymeric material can form vesicles that comprise single or multiple layers of the polymeric material that enclose the glucose-oxidizing enzyme and the insulin, bioactive derivative and/or other therapeutic agent. The vesicles can be loaded into microneedles to, for example, prepare microneedle arrays for skin patches. Methods of delivering insulin to a subject using the compositions, vesicles, microneedles, and/or microneedle array skin patches are also described.
1. A composition comprising:
(a) an amphiphilic polymeric material comprising a polymer conjugated to a hydrogen peroxide-sensitive hydrophobic group and a hypoxia-sensitive hydrophobic group, wherein said hydrogen peroxide-sensitive group comprises a hydrogen peroxide-sensitive moiety that can be oxidized in the presence of hydrogen peroxide to form a hydrophilic moiety and said hypoxia-sensitive hydrophobic group comprises a hypoxia-sensitive moiety that can be reduced in the presence of a hypoxic environment to form a hydrophilic moiety;
(b) an insulin or a bioactive derivative thereof; and
(c) a glucose oxidizing agent.
2. The composition of claim 1 , wherein the polymer is biodegradable.
3. The composition of claim 1 , wherein the polymer comprises a diblock copolymer.
4. The composition of claim 1 , wherein the polymer comprises a polyamino acid; a poly(ethylene glycol)(PEG); or a combination thereof.
5. The composition of claim 1 , wherein the hydrogen peroxide-sensitive moiety comprises a thioether.
6. The composition of claim 1 , wherein the hypoxia-sensitive moiety comprises a nitroimidazole.
7. The composition of claim 1 , wherein the hydrogen peroxide-sensitive hydrophobic group and/or the hypoxia-sensitive hydrophobic group is covalently bound to the polymer.
8. The composition of claim 1 , wherein said amphiphilic polymeric material comprises poly(ethylene glycol) (PEG) and polyserine modified with 2-nitroimidazole via a thioether moiety.
9. The composition of claim 1 , wherein the glucose oxidizing agent is glucose oxidase (GOx).
10. The composition of claim 1 , wherein the insulin is selected from a human insulin, a recombinant human insulin, insulin from a non-human animal, a fast-acting insulin, a rapid-acting insulin analog, an intermediate-acting insulin, and/or a long-acting insulin.
11. The composition of claim 1 , wherein the insulin is recombinant human insulin.
12. The composition of claim 1 , wherein the amphiphilic polymeric material forms a vesicle encapsulating said insulin or bioactive derivative thereof and said glucose oxidizing agent.
13. A nanoparticle comprising the composition of claim 1 .
14. A vesicle comprising an amphiphilic polymeric material, wherein the amphiphilic polymeric material comprises a polymer conjugated to a hydrogen peroxide-sensitive hydrophobic group and a hypoxia-sensitive hydrophobic group, wherein said hydrogen peroxide-sensitive group comprises a hydrogen peroxide-sensitive moiety that can be oxidized in the presence of hydrogen peroxide to form a hydrophilic moiety and said hypoxia-sensitive hydrophobic group comprises a hypoxia-sensitive moiety that can be reduced in the presence of a hypoxic environment to form a hydrophilic moiety, and further wherein (i) an insulin or a bioactive derivative thereof and (ii) a glucose oxidizing agent are contained within said vesicle.
15. The vesicle of claim 14 , wherein the polymer comprises a polyamino acid; a poly(ethylene glycol)(PEG); or a combination thereof.
16. The vesicle of claim 14 , wherein the hydrogen peroxide-sensitive moiety comprises a thioether.
17. The vesicle of claim 14 , wherein the hypoxia-sensitive moiety comprises a nitroimidazole.
18. The vesicle of claim 14 , wherein the insulin or bioactive derivative thereof is recombinant human insulin.
19. The vesicle of claim 14 , wherein the glucose oxidizing agent is glucose oxidase (GOx).
20. A microneedle array comprising vesicles of claim 14 , optionally wherein said microneedle array comprises a plurality of microneedles, wherein each of said plurality of microneedles has a length of between about 20 and about 1000 microns, further optionally wherein each of the plurality of microneedles has a length of about 600 microns.
21. The microneedle array of claim 20 , wherein the microneedle array is provided as part of a skin patch, optionally wherein said patch comprises one or more backing layers and/or skin-compatible adhesives.
22. A closed-loop insulin delivery system comprising a microneedle array of claim 20 .
23. A method of delivering an insulin or a bioactive insulin derivative to a subject in need thereof, the method comprising providing a microneedle array of claim 20 , and applying said array to a skin surface of said subject, wherein when glucose comes into contact with the microneedle array, it is oxidized, thereby (1) creating a hypoxic environment that results in the reduction of the hypoxia-sensitive moiety to form a hydrophilic moiety and (2) producing hydrogen peroxide that results in the oxidation of the hydrogen peroxide-sensitive moiety to form a hydrophilic moiety, leading to disruption of vesicles and release of an insulin or a bioactive insulin derivative contained in the vesicles.
24. The method of claim 23 , wherein the delivery of the insulin or bioactive insulin derivative is at a rate corresponding to the glucose concentration coming into contact with the microneedle array.
25. The method of claim 23 , wherein the subject is a mammal.
26. The method of claim 23 , wherein the subject is diabetic.
27. A method of preparing a microneedle array for the glucose-sensitive delivery of insulin or a bioactive derivative thereof, the method comprising:
(a) preparing an aqueous solution of a vesicle of claim 14 ;
(b) dispersing said aqueous solution into a mold comprising a plurality of microneedle cavities, thereby providing a filled mold;
(c) drying the filled mold to remove water; and
(d) removing the mold to provide a microneedle array.
28. The method of claim 27 , further comprising cross-linking polymeric materials in the microneedle array.
29. The method of claim 27 , wherein step (b) is performed under vacuum.
30. The method of claim 27 , wherein after step (b), the mold is centrifuged to compact the vesicles into the microneedle cavities.
31. The method of claim 27 , wherein step (c) is performed in a vacuum desiccator.
32. The method of claim 27 , wherein the mold comprises silicone.
33. The method of claim 27 , wherein the cross-linking is performed by exposure to UV irradiation.
34. The composition of claim 4 , wherein the polyamino acid is polyserine.
35. The vesicle of claim 15 , wherein the polyamino acid is polyserine.