Self-Assembled Fmoc-Ff Hydrogels

• US 20090175785A1
• Filed: 10/15/2006
• Published: 07/09/2009
• Est. Priority Date: 10/11/2005
• Status: Active Grant

• Current Assignee: Ramot at Tel Aviv University Limited (Tel Aviv University)
• Original Assignee: Ramot at Tel Aviv University Limited (Tel Aviv University)
• Inventors: Mahler, Assaf, Reches, Meital, Gazit, Ehud
• Granted Patent: US 10,004,828 B2
• Time in Patent Office: Days
• US Class Current: 424/1.290
• CPC Class Codes: A61L 27/227 Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06086 with the first amino acid being basic
• CPC Class Codes: C07K 5/06139 with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N

Abstract

Novel peptide-based hydrogels, composed of short aromatic peptides (e.g., homodipeptides of aromatic amino acid residues) are disclosed. The hydrogels are characterized by remarkable rigidity and biocompatibility. Further disclosed are uses of these hydrogels in applications such as tissue engineering, drug delivery, cosmetics, implantation, packaging and the like. Further disclosed are processes and kits for preparing these hydrogels.

Claims

1. A hydrogel comprising a fibrous network of a plurality of peptides, wherein each peptide in said plurality of peptides has an amino acid sequence not exceeding 6 amino acids in length, whereas said amino acid sequence comprises at least one aromatic amino acid residue.

2. The hydrogel of claim 1, wherein at least one peptide in said plurality of peptides is an end-capping modified peptide.

3. The hydrogel of claim 1, wherein each peptide in said plurality of peptides is an end-capping modified peptide.

4. The hydrogel of claim 2, wherein said end capping modified peptide comprises at least one end capping moiety, said end capping moiety being selected from the group consisting of an aromatic end capping moiety and a non-aromatic end-capping moiety.

5. The hydrogel of claim 4, wherein said aromatic end capping moiety is selected from the group consisting of 9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz).

6. The hydrogel of claim 1, wherein at least one peptide in said plurality of peptides consists essentially of aromatic amino acid residues.

7. The hydrogel of claim 1, wherein each peptide in said plurality of peptides consists essentially of aromatic amino acid residues.

8. The hydrogel of claim 1, wherein at least one peptide in said plurality of peptides is a dipeptide.

9. The hydrogel of claim 1, wherein each peptide in said plurality of peptides is a dipeptide.

10. The hydrogel of claim 8, wherein at least one of said dipeptides is a homodipeptide.

11. The hydrogel of claim 8, wherein each of said dipeptides is a homopeptide.

12. The hydrogel of claim 1, wherein said aromatic amino acid residue comprises an aromatic moiety selected from the group consisting of substituted or unsubstituted naphthalenyl, substituted or unsubstituted phenanthrenyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted[1,10]phenanthrolinyl, substituted or unsubstituted [2,2′

]bipyridinyl, substituted or unsubstituted biphenyl and substituted or unsubstituted phenyl.

13. The hydrogel of claim 12, wherein said substituted phenyl is selected from the group consisting of halophenyl, pentahalophenyl, aminophenyl, dialkylaminophenyl, alkoxyphenyl, trihalomethylphenyl, biphenyl and nitrophenyl.

14. The hydrogel of claim 10, wherein said homodipeptide is selected from the group consisting of naphthylalanine-naphthylalanine dipeptide, phenanthrenylalanine-phenanthrenylalanine dipeptide, anthracenylalanine-anthracenylalanine dipeptide, [1,10]phenanthrolinylalanine-[1,10]phenanthrolinylalanine dipeptide, [2,2′

]bipyridinylalanine-[2,2′

]bipyridinylalanine dipeptide, (pentahalo-phenylalanine)-(pentahalo-phenylalanine) dipeptide, phenylalanine-phenylalanine dipeptide, (amino-phenylalanine)-(amino-phenylalanine) dipeptide, (dialkylamino-phenylalanine)-(dialkylamino-phenylalanine) dipeptide, (halophenylalanine)-(halophenylalanine) dipeptide, (alkoxy-phenylalanine)-(alkoxy-phenylalanine) dipeptide, (trihalomethyl-phenylalanine)-(trihalomethyl-phenylalanine) dipeptide, (4-phenyl-phenylalanine)-(4-phenyl-phenylalanine) dipeptide and (nitro-phenylalanine)-(nitro-phenylalanine) dipeptide.

15. The hydrogel of claim 1, wherein a concentration of said plurality of peptides is less than 1 weight percent of the total weight of the gel.

16. The hydrogel of claim 1, wherein said fibrous network comprises a plurality of fibrils, whereas an average diameter of said fibrils ranges from about 10 nm to about 100 nm.

17. The hydrogel of claim 1, characterized by a storage modulus G′

to loss modulus G″

ratio that is greater than 3.

18. The hydrogel of claim 1, being characterized by a storage modulus G′

higher than 1,000 Pa at 1 Hz frequency.

19. The hydrogel of claim 1, being characterized by a storage modulus G′

higher than 10,000 Pa at 1 Hz frequency.

20. The hydrogel of claim 1, being stable at a temperature range of from about 0°

C. to about 90°

C.

21. The hydrogel of claim 1, being stable upon contacting, for at least 24 hours, a medium selected from the group consisting of an acidic solution, a basic solution and an organic solvent.

22. The hydrogel of claim 1, wherein said fibrous network of peptides comprises microscopic hollow cavities capable of entrapping therein a biological or chemical agent.

23. A composition-of-matter comprising the hydrogel of claim 1 and at least one agent being attached thereto or encapsulated therein.

24. The composition-of-matter of claim 23, wherein said agent is selected from the group consisting of a therapeutically active agent, a diagnostic agent, a biological substance and a labeling moiety.

25. The composition-of-matter of claim 24, wherein said agent is selected from the group consisting of a drug, a cell, a nucleic acid, a fluorescence compound or moiety, a phosphorescence compound or moiety, a protein, an enzyme, a hormone, a growth factor, a bacterium and a radioactive compound or moiety.

26. A process of preparing the hydrogel of claim 1, the process comprising contacting said plurality of peptides with an aqueous solution.

27. The process of claim 26, wherein said contacting comprises dissolving said plurality of peptides in said aqueous solution.

28. The process of claim 27, wherein a concentration of said plurality of peptides in said aqueous solution ranges from about 0.1 mg/ml to about 50 mg/ml.

29. The process of claim 26, wherein said contacting is performed at room temperature.

30. The process of claim 26, further comprising, prior to said contacting, dissolving said plurality of peptides in a water-miscible organic solvent.

31. The process of claim 30, wherein said solvent is selected from the group consisting of acetone, dimethylsulfoxide and hexafluoroisopropanol.

32. The process of claim 26, wherein said contacting is effected ex-vivo.

33. The process of claim 26, wherein said contacting is effected in-vivo.

34. The process of claim 26, wherein said contacting is effected at a desired site of application of the hydrogel.

35. A pharmaceutical, cosmetic or cosmeceutical composition comprising the hydrogel of claim 1.

36. The pharmaceutical, cosmetic or cosmeceutical composition of claim 35, further comprising a pharmaceutically acceptable carrier.

37. A pharmaceutical, cosmetic or cosmeceutical composition comprising the composition-of-matter of claim 23.

38. An article-of-manufacture comprising the hydrogel of claim 1.

39. The article-of-manufacture of claim 38, being selected from the group consisting of a medicament, a drug delivery system, a cosmetic agent, a cosmeceutical agent, an implant, an artificial body part, a cell culture matrix, a protein microarray chip, a biosensor, a stent, a vibration damping device and a packaging material.

40. A kit for forming the hydrogel of claim 1, the kit comprising a plurality of peptides and an aqueous solution, each being individually packaged within the kit, wherein each peptide in said plurality of peptides has an amino acid sequence not exceeding 6 amino acids in length, whereas said amino acid sequence comprises at least one aromatic amino acid residue, and further wherein said plurality of peptides and said solution are selected such that upon contacting said plurality of peptides and said solution, the hydrogel or is formed.

41. A kit for forming the composition-of-matter of claim 23, the kit comprising a plurality of peptides and an aqueous solution each being individually packaged within the kit, wherein each peptide in said plurality of peptides has an amino acid sequence not exceeding 6 amino acids in length, whereas said amino acid sequence comprises at least one aromatic amino acid residue, and further wherein said plurality of peptides and said solution are selected such that upon contacting said plurality of peptides and said solution, the composition-of-matter is formed, the kit further comprising an active agent, wherein said plurality of peptides, said solution and said active agent are selected such that upon contacting said plurality of peptides, said active agent and said solution, the composition-of-matter is formed.

42. An article-of-manufacture comprising the composition-of-matter of claim 23.

43. An article-of-manufacture comprising the composition of claim 35.