Self-regulated peptide hydrogel for insulin delivery
A glucose binding amphiphilic peptide hydrogel insulin delivery system that is responsive to glucose concentrations under physiological conditions is provided. Insulin is encapsulated in a glucose binding hydrogel, made from self-assembling amphiphilic peptides including a hydrophobic domain including a beta sheet forming region coupled to a charged hydrophilic domain modified to contain a glucose binding segment. The formulations are designed to release insulin as a function of blood glucose level, maintaining the patients' blood glucose level in an optimum range and avoiding both hyper- and hypoglycemia.
1. Self-assembling glucose binding peptides comprising
(a) a hydrophilic region comprising a charged segment which enhances solubility of the self-assembling peptide in an aqueous environment,
(b) a hydrophobic region,
(c) a beta-sheet forming region, and
(d) an organic borate glucose binding moiety,
wherein the hydrophilic and hydrophobic regions, present in distinct regions, sequentially along the backbone of the self-assembling peptide, are covalently linked via the beta-sheet forming region,
wherein the self-assembling peptides are between six and about 200 α-amino acid residues,
wherein the self-assembling peptides self-assemble under physiological conditions, of pH of approximately 7-7.5, to form a hydrogel, and
wherein binding of glucose to the glucose binding moiety increases the permeability of the hydrogel.
2. The self-assembling glucose binding peptides of claim 1 , wherein the hydrophilic region comprises charged amino acid residues.
3. The self-assembling glucose binding peptides of claim 1 , wherein the hydrophobic region comprises side chains or amino acids forming a beta sheet structure.
4. The self-assembling glucose binding peptides of claim 1 , wherein the organic borate is a phenyl borate.
5. The self-assembling glucose binding peptides of claim 1 , wherein the glucose binding moiety is attached to the hydrophobic region.
6. The self-assembling glucose binding peptides of claim 1 , wherein the beta-sheet forming regions of individual self-assembling peptides associate to form nanofibers.
7. The self-assembling glucose binding peptides of claim 1 , wherein the beta-sheet forming region has about four to ten amino acid residues.
8. The self-assembling glucose binding peptides of claim 7 , wherein the hydrophilic region has about two to seven amino acid residues.
9. The self-assembling glucose binding peptides of claim 8 , the self-assembling peptide comprising between eight and about twenty-four α-amino acid residues.
10. A self-assembling glucose binding peptide having the chemical structure:
11. A hydrogel composition for delivering insulin or an insulin analog, comprising
Insulin or an insulin analog; and
self-assembling peptides comprising
(a) a hydrophilic region comprising a charged segment which enhances solubility of the self-assembling peptide in an aqueous environment,
(b) a hydrophobic region,
(c) a beta-sheet forming region,
(d) an organic borate glucose binding moiety,
wherein the hydrophilic and hydrophobic regions, present in distinct regions, sequentially along the backbone of the self-assembling peptide, are covalently linked via the beta-sheet forming region,
wherein the self-assembling peptides are between six and about 200 α-amino acid residues and
wherein the self-assembling peptides self-assemble under physiological conditions, of pH of approximately 7-7.5, forming a hydrogel,
wherein binding of glucose to the glucose binding moiety increases the permeability of the hydrogel, and
wherein the insulin or insulin analog is released.
12. The composition of claim 11 , wherein the composition comprises insulin.
13. The composition of claim 11 , wherein the insulin is selected from the group consisting of insulin lispro, insulin glulisine, insulin aspart, and insulin detemir.
14. The composition of claim 11 , wherein the permeability of the hydrogel to insulin is increased when tissue glucose levels at physiological pH are increased.
15. The composition of claim 11 , wherein the insulin or insulin analog is entrapped within the hydrogel.
16. A method for making a formulation for delivering insulin comprising self-assembling glucose binding peptides, wherein the self-assembling peptides each comprise:
(a) a hydrophilic region comprising a charged segment which enhances solubility of the self-assembling peptide in an aqueous environment,
(b) a hydrophobic region,
(c) a beta-sheet forming region, and
(d) an organic borate glucose binding moiety,
wherein the hydrophilic and hydrophobic regions, present in distinct regions, sequentially along the backbone of the self-assembling peptide, are covalently linked via the beta-sheet forming region,
wherein the self-assembling peptide comprises between six and about 200 α-amino acid residues, and
wherein the self-assembling peptides self-assemble under physiological conditions, of pH of approximately 7-7.5, to form a hydrogel, and
wherein binding of glucose to the glucose binding moiety increases the permeability of the hydrogel,
comprising adding insulin or insulin analog to a solution of the self-assembling peptides and
adding ions or changing pH to cause the self-assembling peptides to form a hydrogel entrapping the insulin or insulin analog in the hydrogel.
17. The method of claim 16 , wherein the hydrophilic region has about two to seven amino acid residues.
18. The method of claim 17 , the self-assembling peptide comprising between eight and about twenty-four α-amino acid residues.
19. A method of alleviating one or more symptoms of diabetes comprising administering to a diabetic individual an effective amount of the formulation of claim 11 .
20. The method of claim 19 wherein the formulation is administered by subcutaneous injection.
21. The method of claim 16 , wherein the insulin or insulin analog is entrapped within the hydrogel.
22. The method of claim 16 , wherein the beta-sheet forming regions of individual self-assembling peptides associate to form nanofibers.