Claims for Patent: 10,117,946

Summary for Patent: 10,117,946

Title:	Self-assembling ultrashort peptides modified with bioactive agents by click chemistry
Abstract:	The present invention relates to hydrogels comprising a first peptide with a covalently linked bioactive agent and optionally a second peptide. The present invention further relates to uses of the hydrogel for delivery of the bioactive agent or as an implant. The present invention further relates to drug delivery devices, implant, pharmaceutical or cosmetic compositions comprising the hydrogel. The present invention further relates to methods of local treatment of diseases and to methods for preparing the first peptide and the hydrogels.
Inventor(s):	Reithofer; Michael R. (Singapore, SG), Hauser; Charlotte A. E. (Singapore, SG), Chan; Kiat Hwa (Singapore, SG), Mishra; Archana (Singapore, SG)
Assignee:	Agency for Science, Technology and Research (Singapore, SG)
Application Number:	14/655,223
Patent Claims:	1. A hydrogel comprising a first peptide having the general formula B*-Z.sub.p-(X).sub.m-(Y).sub.n-Z'.sub.q or Z.sub.p-(X).sub.m-(Y).sub.n-Z'.sub.q-B* or B*-Z.sub.p-(X).sub.m-(Y).sub.n-Z'.sub.q-B* wherein B* is a bioactive agent comprising anti-cancer therapeutic; X is, at each occurrence, independently selected from an aliphatic amino acid, an aliphatic amino acid derivative and a glycine; Y is, at each occurrence, independently selected from a polar amino acid and a polar amino acid derivative; Z is an N-terminal protecting group; Z' is a C-terminal protecting group; m is an integer selected from 2 to 6; n is selected from 1 or 2; and p and q are independently selected from 0 or 1, wherein said hydrogel further comprises a second peptide having the general formula Z-(X).sub.m-(Y).sub.n-Z'.sub.q, wherein said bioactive agent is covalently linked to the N-terminus and/or the C-terminus of said first peptide by means of a click chemistry reaction and the release of the bioactive agent is triggered via hydrolysis of the hydrogel, and wherein the covalent attachment of the bioactive agent to the first peptide and the release of the bioactive agent via hydrolysis are capable of achieving sustained or controlled release delivery of said bioactive agent wherein said second peptide is used as a matrix, and wherein the hydrogel comprises 10 wt % of the first peptide and 90 wt % of the second peptide. 2. The hydrogel of claim 1, wherein said first peptide has the general formula B*-(X).sub.m-(Y).sub.n-Z'.sub.q. 3. The hydrogel of claim 1, wherein said anti-cancer therapeutic is selected from the group consisting of nucleic acids, DNA, RNA, small RNAs, miRNA, mRNA, siRNA, rRNA, snRNA, snoRNA and analogs thereof, (poly)peptides, peptidomimetics, neutral or anionic or cationic polymers, virus particles, (poly)saccharides, oligosaccharides, glycans, vitamins, hormones, steroids, growth factors, sialic acids, antigens, antibiotics, anti-inflammatory molecules, vaccines, drugs, prodrugs, catechols, biotin, lipids and lipid analogs, antibodies, nanoparticles, organometallic compounds and other organic or inorganic compounds, complexes, composites and nanomaterials. 4. The hydrogel of claim 1, wherein said anti-cancer therapeutic is selected from the group consisting of oxaliplatin, cisplatin, carboplatin, doxorubicin, daunorubicin, clyclophosphamide, 5-fluorouracile, chlorambucil, vincristine, methotrexate, hydroxyurea, bleomecyn, topotecan, irinotecan, dactinomycin, docetaxel, vinblastine, paclitaxel, imatinib, herceptin and other monoclonal or polyclonal antibodies. 5. The hydrogel of claim 1, wherein said bioactive agent is covalently linked to the N-terminus and/or the C-terminus of said first peptide via a linking group comprising a moiety selected from the group consisting of a triazole group, a cyclohexene group, a thioether group, a succinimide group, an isoxazole group and analogs thereof, a isoxazolidine group and analogs thereof, and a pyrazoline group. 6. The hydrogel of claim 1, wherein said click chemistry reaction is a [3+2] cycloaddition reaction, a Diels-Alder reaction, a thiol-ene reaction, a thiol-Michael addition reaction, a thiol-vinylsulfone reaction, a Staudinger reaction. 7. The hydrogel of claim 1, wherein the hydrophobicity decreases from the N-terminus to the C-terminus of said peptide. 8. The hydrogel of claim 1, wherein said aliphatic amino acid and aliphatic amino acid derivative are selected from the group consisting of alanine (Ala, A), homoallylglycine, homopropargylglycine, isoleucine (Ile, I), norleucine, leucine (Leu, L) and valine (Val, V). 9. The hydrogel of claim 1, wherein said polar amino acid and polar amino acid derivative are selected from the group consisting of aspartic acid (Asp, D), asparagine (Asn, N), glutamic acid (Glu, E), glutamine (Gln, Q), 5-N-ethyl-glutamine (theanine), citrulline, thio-citrulline, cysteine (Cys, C), homocysteine, methionine (Met, M), ethionine, selenomethionine, telluromethionine, serine (Ser, S), homoserine, arginine (Arg, R), homoarginine, threonine (Thr, T), allo-threonine, lysine (Lys, K), hydroxylysine, N(6)-carboxymethyllysine, ornithine (Orn), 2,4-diaminobutyric acid (Dab), 2,4-diaminopropionic acid (Dap), histidine (His, H), azido-alanine, azido-homoalanine, azido-ornithine and azido-lysine. 10. The hydrogel of claim 1, wherein m is selected from 2 to 5. 11. The hydrogel of claim 1, wherein m+n is <7 or m+n is <6. 12. The hydrogel of claim 1, wherein (X).sub.m-(Y).sub.n is selected from the group consisting of TABLE-US-00013 SEQ ID NO: 1 LIVAGDD SEQ ID NO: 2 LIVAGDE SEQ ID NO: 3 LIVAGED SEQ ID NO: 4 LIVAGEE SEQ ID NO: 5 LIVAGKC SEQ ID NO: 6 LIVAGSC SEQ ID NO: 7 AIVAGKC SEQ ID NO: 8 AIVAGSC SEQ ID NO: 9 LIVAGC SEQ ID NO: 10 LIVAGD SEQ ID NO: 11 ILVAGD SEQ ID NO: 12 LIVAAD SEQ ID NO: 13 LAVAGD SEQ ID NO: 14 AIVAGD SEQ ID NO: 15 LIVAGE SEQ ID NO: 16 LIVAGK SEQ ID NO: 17 LIVAGS SEQ ID NO: 18 ILVAGS SEQ ID NO: 19 AIVAGS SEQ ID NO: 20 LIVAGT SEQ ID NO: 21 AIVAGT SEQ ID NO: 22 LIVAD SEQ ID NO: 23 LIVGD SEQ ID NO: 24 IVAD SEQ ID NO: 25 IIID SEQ ID NO: 26 IIIK SEQ ID NO: 43 IVD SEQ ID NO: 44 IID SEQ ID NO: 45 LVE SEQ ID NO: 46 IVE SEQ ID NO: 47 LVD SEQ ID NO: 48 VIE SEQ ID NO: 49 VID SEQ ID NO: 50 VLD SEQ ID NO: 51 VLE SEQ ID NO: 52 LLE SEQ ID NO: 53 LLD SEQ ID NO: 54 IIE SEQ ID NO: 55 IVK SEQ ID NO: 56 IV(Orn) SEQ ID NO: 57 IV(Dab) SEQ ID NO: 58 IV(Dap) SEQ ID NO: 59 IVS SEQ ID NO: 60 LVS SEQ ID NO: 61 LVK SEQ ID NO: 62 LV(Orn) SEQ ID NO: 63 LV(Dab) SEQ ID NO: 64 LV(Dap) SEQ ID NO: 27 ILVAGK SEQ ID NO: 28 ILVAG(Orn) SEQ ID NO: 29 ILVAG(Dab) SEQ ID NO: 30 ILVAG(Dap) SEQ ID NO: 31 ILVAGS SEQ ID NO: 32 ILVAGKC SEQ ID NO: 33 AIVAGK SEQ ID NO: 34 AIVAG(Orn) SEQ ID NO: 35 AIVAG(Dab) SEQ ID NO: 36 AIVAG(Dap) SEQ ID NO: 37 LIVAG(Orn) SEQ ID NO: 38 LIVAG(Dab) SEQ ID NO: 39 LIVAG(Dap) SEQ ID NO: 40 III(Orn) SEQ ID NO: 41 III(Dab) and SEQ ID NO: 42 III(Dap). 13. The hydrogel of claim 1, wherein said N-terminal protecting group is an acetyl group. 14. The hydrogel of claim 1, wherein said N-terminal protecting group is a peptidomimetic molecule, including natural and synthetic amino acid derivatives, wherein the N-terminus of said peptidomimetic molecule may be modified with a functional group selected from the group consisting of carboxylic acid, amide, alcohol, aldehyde, amine, imine, nitrile, an urea analog, thiol, phosphate, carbonate, sulfate, nitrate, maleimide, vinyl sulfone, azide, alkyne, alkene, carbohydrate, imide, peroxide, ester, thioester, aryl, ketone, sulphite, nitrite, phosphonate and silane. 15. The hydrogel of claim 1, wherein the C-terminal protecting group is an amide group comprising the formula --CONHR or --CONRR', with R and R' being selected from the group consisting of H, unsubstituted or substituted alkyls, and unsubstituted or substituted aryls. 16. The hydrogel of claim 1, wherein the C-terminal protecting group is an ester group comprising the formula --CO.sub.2R, with R being selected from the group consisting of H, unsubstituted or substituted alkyls, and unsubstituted or substituted aryls. 17. The hydrogel of claim 1, wherein said C-terminal protecting group is a peptidomimetic molecule, including natural and synthetic amino acid derivatives, wherein the C-terminus of said peptidomimetic molecule may be modified with a functional group selected from the group consisting of carboxylic acid, amide, alcohol, aldehyde, amine, imine, nitrile, an urea analog, thiol, phosphate, carbonate, sulfate, nitrate, maleimide, vinyl sulfone, azide, alkyne, alkene, carbohydrate, imide, peroxide, ester, thioester, aryl, ketone, sulphite, nitrite, phosphonate and silane. 18. The hydrogel of claim 1, wherein said second peptide is capable of forming said hydrogel via self-assembly. 19. The hydrogel of claim 1, wherein said first peptide is capable of forming said hydrogel via self-assembly. 20. The hydrogel of claim 1, wherein the hydrogel is characterized by a storage modulus G' to loss modulus G'' ratio that is greater than 2. 21. The hydrogel of claim 1, wherein the hydrogel is characterized by a storage modulus G' in the range of from 100 Pa to 100,000 Pa at a frequency in the range of from 0.001 Hz to 16 Hz. 22. The hydrogel of claim 1, wherein the hydrogel is injectable and gels in situ. 23. A device for drug delivery comprising a hydrogel of claim 1. 24. An implant comprising a hydrogel of claim 1. 25. A pharmaceutical or cosmetic composition comprising a hydrogel of claim 1. 26. A kit comprising a first container with a first peptide as defined in claim 1 and a second container with an aqueous solution, wherein said first container further contains a second peptide as defined in claim 1, or wherein said kit further comprises a third container with a second peptide as defined in claim 1. 27. The hydrogel according to claim 1, wherein p is 0. 28. The hydrogel according to claim 6, wherein said click chemistry reaction further comprises 1,3-dipolar cycloaddition reaction. 29. The hydrogel according to claim 28, wherein said 1,3-dipolar cycloaddition reaction is selected from the group comprising Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction and strained promoted 1,3-dipolar cycloaddition reaction. 30. The hydrogel according claim 18, wherein the self-assembly is an antiparallel self-assembly. 31. The hydrogel according to claim 19, wherein the self-assembly is an antiparallel self-assembly. 32. The hydrogel according to claim 21, wherein the frequency is in the range of from 0.01 Hz to 0.2 Hz. 33. The hydrogel according to claim 23, wherein the drug delivery is sustained or controlled release drug delivery.

Details for Patent 10,117,946

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2032-12-24
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2032-12-24