Stimuli-responsive systems for controlled drug delivery
A method of delivering a therapeutic agent by providing a cross-linked polymer encapsulating the therapeutic agent to a site in a patient. The degradation rate of the cross-linked polymer is correlated with a local concentration of an indicator, and the therapeutic agent is released as the cross-linked polymer degrades.
1. A material for delivery of a therapeutic agent in response to an indicator, comprising:
conjugates that include a therapeutic agent covalently linked to a polymer, wherein the polymer includes two or more indicator analogs; and
polyfunctional cross-linking agents that cross-link conjugates by non-covalently interacting with indicator analogs on different conjugates, wherein:
the material is insoluble in the absence of an indicator that competes with the indicator analogs for non-covalent interactions with the cross-linking agents;
conjugates are released from the material in the presence of the indicator at a rate that varies within physiological concentrations of the indicator;
the indicator is glucose;
the indicator analogs comprise glucose and/or mannose residues; and
the therapeutic agent is insulin or an insulin secretogue.
2. The material of claim 1 wherein the polyfunctional cross-linking agents are covalently linked to the polymer.
3. The material of claim 1 wherein the material is comprised of a plurality of particles.
4. The material of claim 3 wherein the particles have a size from about 100 nm to about 300 nm.
5. The material of claim 3 wherein the particles have a size from about 300 nm to about 500 nm.
6. The material of claim 3 wherein the particles have a size from about 500 nm to about 5 μm.
7. The material of claim 3 wherein the particles have a size from about 5 μm to about 50 μm.
8. The material of claim 3 wherein the particles have a size from about 50 μm to about 100 μm.
9. The material of claim 1 wherein the therapeutic agent is covalently linked to the polymer by a bond that is susceptible to enzymatic cleavage.
10. The material of claim 1 wherein the indicator analog is a portion of a side group of the polymer.
11. The material of claim 1 wherein the polymer is derivatized with the indicator or the indicator analog.
12. The material of claim 1 wherein the indicator analog is incorporated into the backbone of the polymer chain.
13. The material of claim 1 wherein the polymer is selected from poly(lactic acid) (PLA), poly(glycolic acid) (PGA), PLA-PGA co-polymers (PLGA), poly(anhydrides), poly(hydroxy acids), poly(ortho esters), poly(propylfumerates), poly(caprolactones), polyamides, polyamino acids, polyacetals, biodegradable polycyanoacrylates, biodegradable polyurethanes, polysaccharides, co-polymers of the above, adducts of the above, and mixtures of the above.
14. The material of claim 1 wherein the polymer is selected from carboxylated polysaccharides, —NH2 pendant polysaccharides, hydroxylated polysaccharides, alginate, collagen-glycosaminoglycan, collagen, dextran, pullulan, mannan, amylose, amylopectin, glycogen, cellulose, hyaluronate, chondroitin, dextrin, chitosan, co-polymers of aminated and non-aminated amino acids, co-polymers of hydroxylated and non-hydroxylated amino acids, co-polymers of carboxylated and non-carboxylated amino acids, co-polymers of the above, adducts of the above, and mixtures of the above.
15. The material of claim 1 wherein the polyfunctional cross-linking agents include a protein selected from phytohemoagglutinins, human mannan binding protein (MBP), human pulmonary surfactant protein A (SP-A), human pulmonary surfactant protein D, CL-43 and conglutinin.
16. The material of claim 15 wherein the phytohemoagglutinin is selected from concanavalin A (Con A) and phytohemoagglutinins derived from pisum sativum (pea), lathyrus odoratus (sweet pea), lens culinaris (lentil), narcissus pseudonarcissus (daffodil), vicia faba (fava bean), and vicia sativa (garden vetch).
17. The material of claim 1 wherein the polyfunctional cross-linking agents include a polyfunctional binding protein.
18. The material of claim 1 wherein the polyfunctional cross-linking agents include a plurality of monofunctional binding proteins or binding fragments of proteins linked to one another.
19. The material of claim 18 wherein the polyfunctional cross-linking agents include a plurality of monofunctional binding proteins or binding fragments of proteins covalently attached to a polymer.
20. The material of claim 1 further comprising a fluorophore.
21. The material of claim 20 wherein the fluorophore is covalently or non-covalently linked to the polymer, the therapeutic agent, or a polyfunctional cross-linking agent.
22. The material of claim 1 wherein the polymer is a polysaccharide and the polyfunctional cross-linking agents include a plant lectin or a mammalian analog to a plant lectin.
23. The material of claim 1 wherein the polymer is dextran or mannose-derivatized dextran, the polyfunctional cross-linking agents include concanavalin A, and the therapeutic agent is insulin.
24. The material of claim 1 wherein the polyfunctional cross-linking agents are not covalently linked to the polymer.
25. The material of claim 24 wherein the polymer is a polysaccharide, the polyfunctional cross-linking agents include a lectin, and the therapeutic agent is insulin.
26. The material of claim 1 wherein the polyfunctional cross-linking agents include concanavalin A.
27. The material of claim 1 wherein the polyfunctional cross-linking agents include a chemically modified concanavalin A.
28. The material of claim 1 wherein the polyfunctional cross-linking agents include a pegylated concanavalin A.
29. The material of claim 1 wherein the therapeutic agent is insulin
30. The material of claim 1 wherein the therapeutic agent is an insulin secretogue.
31. The material of claim 30 wherein the insulin secretogue is a sulfonylurea.
32. The material of claim 31 wherein the sulfonylurea is glibenclamide.
33. The material of claim 30 wherein the insulin secretogue is GLP-1 or a GLP-1 analogue.
34. The material of claim 33 wherein the GLP-1 analogue is exanitide.
35. The material of claim 1 wherein the indicator analog includes glucosamine or mannosamine.
36. The material of claim 1 wherein the polyfunctional cross-linking agents bind glucose and mannose.
37. A method comprising administering a material of claim 1 to a patient.
38. The method of claim 37 wherein the material is administered by subcutaneous injection.
39. The method of claim 37 wherein the polyfunctional cross-linking agents include concanavalin A.
40. The method of claim 37 wherein the polyfunctional cross-linking agents include a chemically modified concanavalin A.
41. The method of claim 37 wherein the polyfunctional cross-linking agents include a pegylated concanavalin A.
42. The method of claim 37 wherein the therapeutic agent is insulin
43. The method of claim 37 wherein the therapeutic agent is an insulin secretogue.
44. The method of claim 43 wherein the insulin secretogue is a sulfonylurea.
45. The method of claim 44 wherein the sulfonylurea is glibenclamide.
46. The method of claim 37 wherein the insulin secretogue is GLP-1 or a GLP-1 analogue.
47. The method of claim 46 wherein the GLP-1 analogue is exanitide.
48. The method of claim 37 wherein the indicator analog includes glucosamine or mannosamine.
49. The method of claim 37 wherein the polyfunctional cross-linking agents bind glucose and mannose.