INJECTABLE DRUG-RELEASING MICROPOROUS ANNEALED PARTICLE SCAFFOLDS FOR TREATING MYOCARDIAL INFARCTION

Abstract

A therapeutic microporous hydrogel scaffold for use in an animal is disclosed that releases one or more therapeutic agents or drugs. The scaffold uses a drug-releasing microporous annealed particle system that encapsulates drug-loaded nanoparticles into particle building blocks. By modulating nanoparticle hydrophilicity and pre-gel solution viscosity, the particle building blocks were generated with consistent and homogeneous encapsulation of nanoparticles. The scaffold may be used to treat myocardial infarction (MI) using, for example, the drugs forskolin (F) and Repsox (R). The intramyocardial injection of the pre-annealed hydrogel slurry of particles that formed the resultant scaffold improved left ventricular functions, which were further enhanced with increased angiogenesis and reduced fibrosis and inflammatory response. This therapeutic microporous hydrogel scaffold platform represents a new generation of microgel particles for MI therapy and will have broad applications in regenerative medicine and disease therapy.

Description

Claims

1. A therapeutic hydrogel system for use in an animal comprising: a plurality of spherical hydrogel particles decorated with K peptides and Q peptides and having distributed therein a plurality of nanoparticles loaded with one or more therapeutic agents or drugs, wherein the plurality of spherical hydrogel particles when exposed to an annealing agent, induces surface binding between the spherical hydrogel particles via the K peptides and Q peptides and forms a porous scaffold.

2. The therapeutic hydrogel system of claim 1, wherein the one or more therapeutic agents or drugs comprises one of: a small molecule, a cytokine, a protein or fragment thereof, a peptide, a vaccine, a nucleic acid, a gene or a genetic sequence, and a biomolecule.

3. The therapeutic hydrogel system of claim 1, wherein the one or more therapeutic agents or drugs comprises a cAMP agonist and/or a TGF-β inhibitor.

4. The therapeutic hydrogel system of claim 1, wherein the one or more therapeutic agents or drugs comprises Forskolin and 2-(3-(6-Methylpyridine-2-yl)-1H-pyrazol-4-yl)-1,5-naphthyridine (RepSox).

5. The therapeutic hydrogel system of claim 1, wherein the plurality of nanoparticles comprise poly(lactic-co-glycolic acid) (PLGA) nanoparticles.

6. The therapeutic hydrogel system of claim 1, wherein the plurality of nanoparticles comprise poly(lactic-co-glycolic acid) (PLGA)-polyethlyene glycol (PEG) nanoparticles.

7. The therapeutic hydrogel system of claim 6, wherein the plurality of nanoparticles comprise PLGA55k-b-PEG5k.

8. The therapeutic hydrogel system of claim 1, wherein the plurality of spherical hydrogel particles are decorated with RGD peptide.

9. The therapeutic hydrogel system of claim 1, wherein the spherical hydrogel particles are biodegradable via a MMP-sensitive crosslinker.

10. The therapeutic hydrogel system of claim 1, wherein the nanoparticles comprise PLGA35k/PLGA55k-PEG5k in a weight ratio of substantially 1:1.

11. A therapeutic hydrogel system for use in an animal comprising: a plurality of spherical hydrogel particles having distributed therein a plurality of nanoparticles loaded with one or more therapeutic agents or drugs, wherein the plurality of spherical hydrogel particles when exposed to an annealing agent, induces surface binding between the spherical hydrogel particles and forms a porous scaffold.

12. The therapeutic hydrogel system of claim 11, wherein the system further comprises an exogenous annealing agent.

13. The therapeutic hydrogel system of claim 11, wherein an annealing moiety on the surface of the hydrogel particles links adjacent hydrogel particles.

14. A method of manufacturing a therapeutic hydrogel comprising: providing a microfluidic device configured to generate aqueous emulsions in an oil phase, the microfluidic device having a first aqueous phase microfluidic channel and a second aqueous phase microfluidic channel interfacing in an emulsion generating region, the emulsion generating region interfacing with a first oil phase microfluidic channel and a second oil phase microfluidic channel;flowing a first aqueous solution into the first aqueous phase microfluidic channel comprising PEG vinyl sulfone pre-reacted with K-peptide, Q-peptide, RGD peptide, and a plurality of nanoparticles loaded with one or more therapeutic agents or drugs;flowing a second aqueous solution into the second aqueous phase microfluidic channel comprising a MMP-sensitive crosslinker;flowing oil into the first and second oil phase microfluidic channels to generate emulsions of the mixed first and second aqueous solutions in the oil; andallowing the emulsions to crosslink to form spherical hydrogel particles.

15. The method of claim 14, wherein the first aqueous solution further comprises a cell adhesive moiety.

16. The method of claim 15, wherein the cell adhesive moiety comprises RGD peptide.

17. The method of claim 14, wherein the first aqueous solution contains less than about 1% v/v% hyaluronic acid (HA).

18. The method of claim 14, wherein the plurality of nanoparticles comprise poly(lactic-co-glycolic acid) (PLGA) nanoparticles.

19. The method of claim 14, wherein the plurality of nanoparticles comprise poly(lactic-co-glycolic acid) (PLGA)-polyethlyene glycol (PEG) nanoparticles.

20. The method of claim 19, wherein the plurality of nanoparticles comprise PLGA55k-b-PEG5k.

21. The method of claim 14, wherein the one or more therapeutic agents or drugs comprises a cAMP agonist and/or a TGF-β inhibitor.

22. The method of claim 14, wherein the one or more therapeutic agents or drugs comprises Forskolin and 2-(3-(6-Methylpyridine-2-yl)-1 H-pyrazol-4-yl)-1,5-naphthyridine RepSox.

23. A method of treating myocardial infarction in an animal comprising: injecting a therapeutic hydrogel system into heart tissue of the animal, the therapeutic hydrogel system comprising a plurality of spherical hydrogel particles decorated with K peptides and Q peptides and having distributed therein a plurality of nanoparticles loaded with one or more therapeutic agents or drugs, wherein the plurality of spherical hydrogel particles when exposed to an annealing agent, induces surface binding between the spherical hydrogel particles via the K peptides and Q peptides and forms a porous scaffold.

24. The method of claim 23, wherein the one or more therapeutic agents or drugs comprises a cAMP agonist and/or a TGF-β inhibitor.

25. The method of claim 23, wherein the one or more therapeutic agents or drugs comprises Forskolin and 2-(3-(6-Methylpyridine-2-yl)-1H-pyrazol-4-yl)-1,5-naphthyridine RepSox.

26. The method of claim 23, wherein the plurality of nanoparticles comprise poly(lactic-co-glycolic acid) (PLGA) nanoparticles.

27. The method of claim 23, wherein the plurality of nanoparticles comprise poly(lactic-co-glycolic acid) (PLGA)-polyethlyene glycol (PEG) nanoparticles.

28. The method of claim 23, wherein the plurality of nanoparticles comprise PLGA55k-b-PEG5k.

29. The method of claim 23, wherein the therapeutic hydrogel is injected into an interior or exterior surface of heart tissue.

30. (canceled)