# US 2013/0281602 A1 · Thermo-responsive polymer covalently bound with a peptide

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- Number: US 2013/0281602 A1
- Document ID: US20130281602A1
- Status: Published application
- Kind: A1
- Application number: 13/877,910
- Filed: 2011-10-06
- Published: 2013-10-24
- Earliest claimed: 2010-10-08
- Assignees: Solvay SA
- Inventors: Alberto Saiani; Aline Miller; Roland Callens; Laurent Jeannin; Wafa Moussa
- Web page: https://patentgrep.com/patent/US20130281602A1

## CPC

- C08F 122/38: Amides
- A61K 47/58: obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 47/6903: {the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel}
- C07K 7/06: having 5 to 11 amino acids
- C08G 83/00: Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
- C08L 89/00: Compositions of proteins; Compositions of derivatives thereof
- C12N 5/0625: {Epidermal cells, skin cells; Cells of the oral mucosa}
- C08F: MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

A thermo-responsive polymer covalently bound with a peptide, wherein the peptide comprises a peptide moiety that is able to self-assemble and a functional peptide moiety comprising a bioactive sequence, and compositions comprising such thermo-responsive polymer covalently bound with a peptide. Methods for the preparation of such thermo-responsive polymers covalently bound with a peptide and the use thereof for the preparation of hydrogels.

## Claims

### Claim 1

A thermo-responsive polymer covalently bound with at least one peptide, wherein the peptide comprises a peptide moiety that is able to self-assemble and a functional peptide moiety comprising a bioactive sequence.

### Claim 2 (depends on 1)

The polymer according to claim 1, wherein the bioactive sequence of the functional peptide moiety is a cell adhesion providing amino acid sequence.

### Claim 3 (depends on 1)

The polymer according to claim 1, wherein the at least one peptide is covalently bound with the thermo-responsive polymer through a linkage selected from the group consisting of thioether linkage, amino linkage, amido linkage, ester linkage, and ether linkage.

### Claim 4 (depends on 3)

The polymer according to claim 3, wherein the linkage is
a thioether linkage, according to the formula:
—S—(CH2)x—[C(O)]y—
wherein x is 1-10; y is 0 or 1;
an amino linkage, according to the formula:
—NH—(CH2)x—[C(O)]y—
wherein x is 0-10; y is 0 or 1;
an amido linkage, according to the formula:
—C(O)—NH—(CH2)x—[C(O)]y—
wherein x is 0-10; y is 0 or 1;
an ester linkage, according to the formula:
—C(O)—O—(CH2)x—[C(O)]y—
wherein x is 1-10; y is 0 or 1;
an ether linkage, according to the formula:
—O—(CH2)x—[C(O)]y—
wherein x is 0-10; y is 0 or 1.

### Claim 5 (depends on 1)

The polymer according to claim 1, wherein said peptide moiety that is able to self-assemble is self-assembling in a β-sheet, a coiled coil a-helix structure, a peptide triple helix structure, or combinations thereof.

### Claim 6 (depends on 1)

The polymer according to claim 1, wherein said peptide moiety that is able to self-assemble into a β-sheet, and wherein said peptide moiety is an octapeptide moiety comprising alternating hydrophobic and charged amino acids.

### Claim 7 (depends on 19)

The polymer according to claim 19, wherein the peptide moiety that is able to self-assemble into a β-sheet is selected from the group consisting of FEFKFEFK, FEFEFKFK, FDFKFDFK, FDFDFKFK, FEFRFEFR, FEFEFRFR, YDYKYDYK, YDYDYKYK, YEYRYEYR, YEYKYEYK, YEYEYKYK, WEWKWEWK, WEWEWKWK, WDWKWDWK, and WDWDWKWK.

### Claim 8 (depends on 1)

The polymer according to claim 1, wherein the thermo-responsive polymer is covalently bound with the at least one peptide through a terminus of the functional peptide moiety.

### Claim 9 (depends on 1)

The polymer according to claim 1, wherein the thermo-responsive polymer is covalently bound with at least one peptide derivative selected from the group consisting of acrylate-GABA-hRGDWP-FEFEFKFK; acrylate-GABA-hRGDWP-FEFKFEFK, wherein GABA is γ-amino butyric acid; acrylate-Ava-hRGDWP-FEFEFKFK; acrylate-Ava-hRGDWP-FEFKFEFK, wherein Ava is 5-aminovaleric acid; acrylate-ε-Ahx-hRGDWP-FEFEFKFK; acrylate-ε-Ahx-hRGDWP-FEFKFEFK, wherein ε-Ahx is ε-amino caproic acid; acrylate-β-ala-hRGDWP-FEFEFKFK; acrylate-β-ala-hRGDWP-FEFKFEFK, wherein β-ala is 3-aminopropionic acid; Mpr-hRGDWP-FEFEFKFK; Mpr-hRGDWP-FEFKFEFK, wherein Mpr is mercapto propionic acid; and combinations thereof.

### Claim 10 (depends on 1)

The polymer according to claim 1, wherein the thermo-responsive polymer is poly-(N-isopropylacrylamide) or a copolymer thereof.

### Claim 11 (depends on 1)

A composition comprising the thermo-responsive polymer according to claim 1.

### Claim 12

A peptide derivative selected from the group consisting of acrylate-GABA-hRGDWP-FEFEFKFK; acrylate-GABA-hRGDWP-FEFKFEFK, wherein GABA is γ-amino butyric acid; acrylate-Ava-hRGDWP-FEFEFKFK; acrylate-Ava-hRGDWP-FEFKFEFK, wherein Ava is 5-aminovaleric acid; acrylate-ε-Ahx-hRGDWP-FEFEFKFK; acrylate-ε-Ahx-hRGDWP-FEFKFEFK, wherein ε-Ahx is ε-amino caproic acid; acrylate-β-ala-hRGDWP-FEFEFKFK; acrylate-β-ala-hRGDWP-FEFKFEFK, wherein β-ala is 3-aminopropionic acid; Mpr-hRGDWP-FEFEFKFK; and Mpr-hRGDWP-FEFKFEFK, wherein Mpr is mercapto propionic acid.

### Claim 13 (depends on 1)

A method for preparing the thermo-responsive polymer according to claim 1, comprising the step of reacting a mixture comprising thermo-responsive polymer monomers or a thermo-responsive polymer, and peptides or peptide derivatives, under appropriate reaction conditions allowing covalent attachment of the peptides or peptide derivatives to the monomers or the polymer;
wherein the peptides comprise a peptide moiety that is able to self-assemble and a functional peptide moiety comprising a bioactive sequence; and
wherein the peptide derivatives are selected from the group consisting of acrylate-GABA-hRGDWP-FEFEFKFK; acrylate-GABA-hRGDWP-FEFKFEFK, wherein GABA is γ-amino butyric acid; acrylate-Ava-hRGDWP-FEFEFKFK; acrylate-Ava-hRGDWP-FEFKFEFK, wherein Ava is 5-aminovaleric acid; acrylate-ε-Ahx-hRGDWP-FEFEFKFK; acrylate-ε-Ahx-hRGDWP-FEFKFEFK, wherein ε-Ahx is ε-amino caproic acid; acrylate-β-ala-hRGDWP-FEFEFKFK; acrylate-β-ala-hRGDWP-FEFKFEFK, wherein β-ala is 3-aminopropionic acid; Mpr-hRGDWP-FEFEFKFK; and Mpr-hRGDWP-FEFKFEFK, wherein Mpr is mercapto propionic acid.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the mixture comprises thermo-responsive polymer monomers, and wherein the appropriate reaction conditions further allow polymerization of the thermo-responsive polymer monomers.

### Claim 15 (depends on 14)

The method according to claim 14, wherein the thermo-responsive polymer monomers are N-isopropylacrylamide, or the thermo-responsive polymers are poly(N-isopropylacrylamide) or copolymers thereof.

### Claim 16 (depends on 1)

A method for the preparation of hydrogels, comprising using the thermo-responsive polymer according to claim 1.

### Claim 17 (depends on 2)

The polymer according to claim 2, wherein the bioactive sequence of the functional peptide moiety comprises one or more sequences selected from the group consisting of Arg-Gly-Asp (RGD), Har-Gly-Asp (Har-GD or hRGD), RGDS, GRGDS, GRGDY, GRGDSY, GRGDF, YGRGD, GRGDSY, GRGDSP, GRGDSPK, YRGDS, GRGETP, GRGESP, GRGDTP, GRGDSPK, GRGDSP, GRGDK, GRADSPK, GGGGRGDS, GRGDSP, RGDYK, RGDFK,LDV, REDV, RGDV, LRGDN, IKVAV, YIGSR, PDSGR, RNAIEIIKDA, RGDT, DGEA, VTXG, GHK, QHREDGS, Arg-Gly-Asp-Trp-Pro (RGDWP), Har-Gly-Asp-Trp-Pro (Har-GDWP or hRGDWP), GRGDSY, QHREDGS, SDKP, (PPG)z, (PEG)z, (PDG)z, (PKG)z, (PRG)z where z is 1-50, analogues thereof, and combinations thereof.

### Claim 18 (depends on 17)

The polymer according to claim 17, wherein the bioactive sequence of the functional peptide moiety comprises RGDWP or hRGDWP sequences.

### Claim 19 (depends on 6)

The polymer according to claim 6, wherein the octapeptide moiety is formed by the combination of two sequences selected independently from the group consisting of FEFE, FEFK, FEFD, FEFR, FRFR, FRFK, FRFE, FRFD, FKFE, FDFK, FKFR, FKFD, FDFD, FDFE, FDFR, FDFK, WEWE, WEWK, WRWR, WEWK, WKWE, WEWR, WRWE, WKWR, WRWK, WDWD, WDWE, WEWD, WDWK, WKWD, WDWR, WRWD, IEIE, IEIK, IRIR, IEIK, IKIE, IEIR, IRIE, IKIR, IRIK, IDID, IDFE, IEID, IDIK, IKID, IDIR, IRID, YEYE, YEYK, YRYR, YEYK, YKYE, YEYR, YRYE, YKYR, YRYK, YDYD, YDYE, YEYD, YDYK, YKYD, YDYR, YRYD, Nle-E-Nle-E, Nle-K-Nle-K, Nle-R-Nle-R, Nle-E-Nle-K, Nle-K-Nle-E, Nle-E-Nle-R, Nle-R-Nle-E, Nle-K-Nle-R, Nle-R-Nle-K, Nle-D-Nle-D, Nle-D-Nle-E, Nle-E-Nle-D, Nle-D-Nle-K, Nle-K-Nle-D, Nle-D-Nle-R, and Nle-R-Nle-D.

### Claim 20 (depends on 7)

The polymer according to claim 7, wherein the peptide moiety that is able to self-assemble into a β-sheet is selected from the group consisting of FEFKFEFK and FEFEFKFK.