Hydrogels for delivery of therapeutic compounds

Patent metadata

Field	Value
Publication number	US-9937256-B2
Application number	US-201614994704-A
Country	US
Kind code	B2
Filing date	Jan 13, 2016
Priority date	Jan 14, 2015
Publication date	Apr 10, 2018
Grant date	Apr 10, 2018

Abstract

In some aspects, methacrylate co-polymers crosslinked with an enzymatically cleavable peptide linker are provided and may be used for the oral delivery of a therapeutic. The peptide linker may be cleavable by an enzyme in the small intestine and may allow for the delivery of a therapeutic protein or nucleic acid to the small intestine. Also provided are methods of using the polymers for the treatment of a disease.

First claim

What is claimed is:

1. A hydrogel composed of a polymer, wherein the polymer comprises a poly(methacrylic acid-co-N-vinylpyrrolidone) (P(MAA-co-NVP)) copolymer that is crosslinked with an enzymatically cleavable peptide linker, wherein the peptide linker consists of 3-25 amino acid residues and contains at least one lysine amino acid, wherein the hydrogel further comprises a therapeutic agent.

2. The hydrogel of claim 1 , wherein the peptide linker is cleavable by a serine protease, carboxypeptidase, or aminopeptidase.

3. The hydrogel of claim 2 , wherein the serine protease is trypsin, chymotrypsin, or elastase.

4. The hydrogel of claim 3 , wherein the peptide linker is cleavable by trypsin, wherein the trypsin is trypsin 1, trypsin 2, or mesotrypsin.

5. The hydrogel of claim 1 , wherein the peptide is 4-20 amino acid residues in length.

6. The hydrogel of claim 5 , wherein the peptide is 5-15 amino acid residues in length.

7. The hydrogel of claim 6 , wherein the peptide is 5-10 amino acid residues in length.

8. The hydrogel of claim 7 , wherein the peptide comprises or consists of GRRRGK (SEQ ID NO: 1).

9. The hydrogel of claim 8 , wherein the peptide comprises the structure:

10. The hydrogel of claim 8 , wherein the polymer comprises the structure:

11. The hydrogel of claim 1 , wherein the polymer has been crosslinked with the peptide through the use of a coupling reagent.

12. The hydrogel of claim 11 , wherein the coupling reagent is a carbodiimide.

13. The hydrogel of claim 11 , wherein the polymer has been crosslinked with the peptide via an EDC-NHS reaction.

14. The hydrogel of claim 1 , wherein the hydrogel further comprises a polycationic nanoparticle.

15. The hydrogel of claim 14 , wherein the polycationic nanoparticle is substantially comprised within the hydrogel.

16. The hydrogel of claim 14 , wherein the polycationic nanoparticle comprises or consists of poly(2-methoxyethylacrylate) (PMEA), poly(2-(diethylaminoethyl) methacrylate) (PDEAEMA), chitosan, poly(ethyleneimine) (PEI), poly(amidoamine) (PAMAM), poly(dimethylaminopropyl methacrylate) (PDMAPMA), poly(2-aminoethyl methacrylate) (PAEMA), or poly(2-(dimethylaminoethyl) methacrylate) (PDMAEMA).

17. The hydrogel of claim 1 , wherein the therapeutic agent is a therapeutic protein.

18. The hydrogel of claim 1 , wherein the therapeutic agent is a nucleic acid.

19. The hydrogel of claim 18 , wherein the nucleic acid is a small interfering RNA (siRNA), a micro RNA (miRNA), a short hairpin RNA (shRNA), or an antisense oligonucleotide.

20. The hydrogel of claim 19 , wherein the nucleic acid is an siRNA.

21. A method of treating a disease comprising administering the hydrogel of claim 1 to a mammalian subject in need of such treatment.

22. The method of claim 21 , wherein the administration is oral.

Assignees

• Univ Texas

Inventors

• Knipe Jennifer M
• Strong Laura E
• Peppas Nicholas A

Classifications

• C08L33/02

  Homopolymers or copolymers of acids; Metal or ammonium salts thereof · CPC title

• C12N2320/32

  Special delivery means, e.g. tissue-specific · CPC title

• A61K38/10

  Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• C12N15/111

  General methods applicable to biologically active non-coding nucleic acids · CPC title

• A61K9/5138

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title