Hydrogels for delivery of therapeutic compounds

Patent metadata

Field	Value
Publication number	US-10835609-B2
Application number	US-201815906881-A
Country	US
Kind code	B2
Filing date	Feb 27, 2018
Priority date	Jan 14, 2015
Publication date	Nov 17, 2020
Grant date	Nov 17, 2020

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 method for loading a nucleic acid into a copolymer, comprising:
(i) incubating a copolymer comprising an acrylic acid, an acrylate monomer, or methacrylic acid in a loading solution comprising the nucleic acid: and subsequently
(ii) crosslinking the copolymer with a crosslinker;
wherein the crosslinker comprises GRRRGK (SEQ ID NO: 1).

2. The method of claim 1 , wherein the crosslinker is an enzymatically cleavable peptide crosslinker.

3. The method of claim 2 , wherein the copolymer comprises methacrylic acid and N-vinylpyrrolidone.

4. The method of claim 1 , wherein the nucleic acid is a siRNA, an miRNA, or an shRNA.

5. The method of claim 1 , wherein the copolymer is a P(MAA-co-NVP) copolymer; and wherein the crosslinker is an enzymatically cleavable peptide linker, wherein the peptide linker is 6-25 amino acid residues in length and contains at least one lysine amino acid.

6. The method of claim 2 , wherein the peptide crosslinker is 6-20 amino acid residues in length.

7. The method of claim 1 , wherein the hydrogel polymer comprises the structure:

8. The method of claim 2 , wherein the polymer is crosslinked with the peptide through the use of a coupling reagent.

9. The method of claim 8 , wherein the coupling reagent is a carbodiimide.

10. The method of claim 2 , wherein the polymer is crosslinked with the peptide via an EDC-NHS reaction.

11. A method for loading a nucleic acid into a copolymer, comprising:
(i) incubating a copolymer comprising an acrylic acid, an acrylate monomer, or methacrylic acid in a loading solution comprising the nucleic acid; and subsequently
(ii) crosslinking the copolymer with a crosslinker;
wherein the crosslinker comprises the structure:

12. The method of claim 11 , wherein the crosslinker is an enzymatically cleavable peptide crosslinker.

13. The method of claim 12 , wherein the copolymer comprises methacrylic acid and N-vinylpyrrolidone.

14. The method of claim 11 , wherein the nucleic acid is a siRNA, an miRNA, or an shRNA.

15. The method of claim 11 , wherein the copolymer is a P(MAA-co-NVP) copolymer; and wherein the crosslinker is an enzymatically cleavable peptide linker, wherein the peptide linker is 6-25 amino acid residues in length and contains at least one lysine amino acid.

16. The method of claim 12 , wherein the peptide crosslinker is 6-20 amino acid residues in length.

17. The method of claim 11 , wherein the copolymer comprises the structure:

18. The method of claim 12 , wherein the copolymer is crosslinked with the peptide through the use of a coupling reagent.

19. The method of claim 18 , wherein the coupling reagent is a carbodiimide.

20. The method of claim 12 , wherein the copolymer is crosslinked with the peptide via an EDC-NHS reaction.

Assignees

• Univ Texas

Inventors

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

Classifications

• A61K38/08

  Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• C12N15/113

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• A61K9/1635

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

• A61K38/16

  Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)} · CPC title

• C12N15/111

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