Hydrogels for delivery of therapeutic compounds
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.
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.