Self-assembly of peptide-amphiphile nanofibers under physiological conditions

• US 20040001893A1
• Filed: 02/18/2003
• Published: 01/01/2004
• Est. Priority Date: 02/15/2002
• Status: Active Grant

• Current Assignee: Northwestern University
• Original Assignee: Northwestern University
• Inventors: Stupp, Samuel I., Hartgerink, Jeffrey D., Beniash, Elia
• Granted Patent: US 7,371,719 B2
• Time in Patent Office: Days
• US Class Current: 424/488
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/78 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
• CPC Class Codes: Y10S 977/705 Protein or peptide
• CPC Class Codes: Y10T 428/12014 having metal particles
• CPC Class Codes: Y10T 428/24413 Metal or metal compound

Abstract

Peptide amphiphile compounds, compositions and methods for self-assembly or nanofibrous network formation under neutral or physiological conditions.

Claims

1. A sol-gel system comprising a peptide amphiphile compound having a bioactive epitope sequence, a hydrophobic component, and a net charge at substantially physiological pH;

and a reagent to induce gelation of said amphiphile compound.

2. The system of claim 1 wherein said reagent comprises a metal ion and said system is a gel of supramolecular nanofibers of said amphiphile compound.

3. The system of claim 2 wherein said ion is selected from the group consisting of Ca, Mg, Cd, Fe and Zn divalent ions, Al, Fe and Gd trivalent ions, and combinations of said ions.

4. The system of claim 3 wherein said metal ion is in stoichiometric excess of said amphiphile compound.

5. The system of claim 1 wherein said peptide component of said amphiphile compound comprises a residue with a functional moiety capable of intermolecular covalent bond formation.

6. The system of claim 5 wherein said residue is cysteine.

7. The system of claim 6 further comprising an oxidizing agent to form a disulfide bond between amphiphile compounds.

8. The system of claim 7 further comprising a subsequent reducing agent to cleave said disulfide bond.

9. The system of claim 1 wherein said peptide amphiphile compound has a net charge, and said reagent comprises an aqueous solution of another peptide amphiphile compound with an opposite net charge at substantially physiological pH, and said system is a network of nanofibers of said amphiphile compounds.

10. The system of claim 9 wherein said peptide components of said amphiphile compounds comprise a residue with a functional moiety capable of intermolecular covalent bond formation.

11. The system of claim 10 wherein said residue is cysteine.

12. The system of claim 11 further comprising an oxidizing agent to form a disulfide bond between amphiphile compounds.

13. The system of claim 12 further comprising a subsequent reducing agent to cleave said disulfide bond.

14. The system of claim 1 wherein said bioactive epitope sequence is selected from RGD, IKVAV and YIGSR.

15. The system of claim 1 wherein said peptide amphiphile compound has a net positive charge, and said reagent provides said system a basic pH, and said system comprises a network of nanofibers of said amphiphile compounds.

16. The system of claim 15 wherein said reagent comprises hydroxide ion.

21. The composition of claim 14 wherein said bioactive sequence is IKVAV.

17. A method of peptide amphiphile nanofiber formation, said method comprising:

providing an aqueous medium including a peptide amphiphile compound having a peptide component with a bioactive epitope sequence, and a hydrophobic component, said hydrophobic component sufficient to afford nanofiber formation of said compound;

placing said medium on a surface; and

removing said aqueous component from said medium.

18. The method of claim 17 wherein said removal is passive drying.

19. The method of claim 17 wherein said amphiphile compound has a net charge at a physiological pH.

20. The method of claim 17 wherein said bioactive sequence is RGD.

22. The method of claim 17 wherein said peptide component further comprises at least one phosphorylated residue.

23. The method of claim 17 wherein said hydrophobic component comprises an alkyl moiety of at least six carbon units.

24. A method of peptide amphiphile nanofiber formation, said method comprising:

providing an aqueous medium comprising a peptide amphiphile compound having a bioactive epitope sequence, a hydrophobic component, and a net charge at substantially physiological pH; and

introducing a reagent to said medium to induce nanofiber formation.

25. The method of claim 24 wherein said reagent comprises a metal ion.

26. The method of claim 24 wherein said peptide amphiphile compound has a net charge, and said reagent comprises an aqueous medium of another peptide amphiphile compound with an opposite net charge at substantially physiological pH.

27. The method of claim 24 wherein said peptide amphiphile compound has a net positive charge and said reagent provides said medium a basic pH.

28. A peptide amphiphile composition comprising a first peptide component comprising a hydrophobic moiety and a first amino acid sequence, said sequence further comprising a first bioactive epitope sequence;

and a second peptide component comprising a hydrophobic moiety and a second amino acid sequence, said sequence further comprising a second bioactive epitope sequence, said first amino acid sequence having a net charge at a physiological pH, and said second amino acid sequence having a net charge at a physiological pH opposite said net charge of said first amino acid sequence.

29. The composition of claim 28 wherein each of said first and second bioactive epitope sequences is selected from RGD, IKVAV and YIGSR.

30. The composition of claim 28 wherein each of said first and second peptide components comprise a residue with a functional moiety capable of intermolecular covalent bond formation.

31. The composition of claim 30 wherein said residue is cysteine.

32. The composition of claim 28 wherein at least one of said first and second peptide components further comprises at least one phosphorylated residue.

33. The composition of claim 28 having a nanofibrous structured assembly.