WO2022126004A1 - Hydrogels encapsulant des enzymes qui déphosphorylent l'adénosine et utilisations dans des applications médicales - Google Patents

Hydrogels encapsulant des enzymes qui déphosphorylent l'adénosine et utilisations dans des applications médicales Download PDF

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WO2022126004A1
WO2022126004A1 PCT/US2021/063006 US2021063006W WO2022126004A1 WO 2022126004 A1 WO2022126004 A1 WO 2022126004A1 US 2021063006 W US2021063006 W US 2021063006W WO 2022126004 A1 WO2022126004 A1 WO 2022126004A1
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hydrogel
certain embodiments
adenosine
seq
protease
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PCT/US2021/063006
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English (en)
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Rebecca D. LEVIT
Andres J. Garcia
Michael Sayegh
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Emory University
Georgia Tech Research Corporation
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Publication of WO2022126004A1 publication Critical patent/WO2022126004A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/008—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A61L2300/254—Enzymes, proenzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents

Definitions

  • PID peripheral arterial disease
  • skeletal muscle ischemia due to blockage of arterial blood flow results in tissue damage and myocyte loss, especially at the vulnerable, relatively under-perfused tissue of the extremities.
  • Treatment for PAD is typically limited to symptomatic relief, reduction of risk factors (hypertension and diabetes, antithrombotic), and ultimately highly invasive surgical intervention.
  • risk factors hypertension and diabetes, antithrombotic
  • Xu et al. report adenosine from a biologic source regulates neutrophil extracellular traps (NETs), J Leukoc Biol. 2019, 105(6): 1225-1234.
  • Wu et al. report a partial agonist of the Al-adenosine receptor selectively slows AV conduction in guinea pig hearts, Am J Physiol Heart Circ Physiol, 2001, 280:H334-343.
  • Ponnoth et al. report involvement of adenosine receptors in altered vascular responses and inflammation in an allergic mouse model of asthma. Am J Physiol heart Circ Physiol, 2009, 297:H1655-H1660. lyu et al. report adenosine derived from ADP can contribute to inhibition of platelet aggregation in the presence of a P2Y12 antagonist. Arterioscler Thromb Vase Biol, 2011, 31 :416- 422).
  • hydrogel materials comprising enzymes that dephosphorylate adenosine phosphates.
  • the hydrogel contains a hydrophilic polymer crosslinked with protease-degradable peptides.
  • this disclosure relates to methods of treating or preventing ischemic or cardiovascular diseases or conditions comprising contacting hydrogel materials disclosed herein with a tissue of a subject.
  • this disclosure relates to hydrogel materials that carry enzymes capable of adenosine generation in vivo.
  • this disclosure relates to methods of augmenting tissue adenosine levels for therapeutic purpose using a hydrogel to deliver ecto-nucleotidase enzymes such as CD39 and CD73.
  • compositions comprising enzymes that convert adenosine monophosphate to adenosine, dispersed in a hydrogel matrix, wherein the hydrogel matrix comprises a crosslinked hydrophilic polymer network covalently bonded to adhesion peptides.
  • enzyme that convert adenosine monophosphate to adenosine is CD73.
  • the compositions further comprise enzymes that convert adenosine triphosphate and/or adenosine diphosphate to adenosine monophosphate.
  • an enzyme that converts adenosine triphosphate and/or adenosine diphosphate to adenosine monophosphate is CD39.
  • the composition or hydrogel further comprises or encapsulates adenosine, adenosine monophosphate, adenosine diphosphate, adenosine triphosphate, or combinations thereof.
  • the hydrogel matrix comprises multi-armed polyethylene glycol).
  • the crosslinker comprises a valine-proline-methionine (VPM) peptide, a protease-degradable crosslinker.
  • VPM valine-proline-methionine
  • the crosslinked hydrophilic polymer comprises a protease cleavable peptide.
  • the protease cleavable peptide comprises GCRDVPMSMRGGDRCG (SEQ ID NO: 1) and optionally other peptide sequences disclosed herein or combinations thereof.
  • the crosslinkers of hydrogels disclosed herein are the following crosslinkers or optionally mixtures of these crosslinkers are protease-dependent crosslinkers comprising VPM, GPQXW (SEQ ID NO: 3, wherein X is any amino acid), GPQXXW (SEQ ID NO: 4, wherein X is individually at each occurrence any amino acid), GCRDGPQGIWGQDRCG (SEQ ID NO: 5), IPES (SEQ ID NO: 6), GCRDIPESLRAGDRCG (SEQ ID NO: 7), or combinations thereof.
  • the crosslinkers and mixtures of these crosslinkers are non-protease degradable such as dithiothreitol (DTT), polyethylene-dithiothreitol, PEG3-DTT, PEG6-DTT.
  • the crosslinkers or mixtures of these crosslinkers are hydrolytic such as an ethylene glycol bis-mercaptoacetate crosslinker.
  • the adhesion peptide comprises an arginine-glycine-aspartate (RGD) sequence and optionally mixtures of other adhesion peptides.
  • the adhesion peptide comprises GRGDSPC (SEQ ID NO: 2).
  • the adhesive peptide comprises one or more of following adhesion peptides: RGD, cyclic RGD, GFXGER (SEQ ID NO: 8, when X is O/pyrrolysine or any amino acid), AGQWHRVSVRWG (SEQ ID NO: 9, A5G81), TWSQKALHHRVP (SEQ ID NO: 10, A5G84) WHRVSVC (SEQ ID NO: 11), ATLQLQEGRLHFXFDLGKGR (SEQ ID NO: 12, "EF Izz" when X: Nle, or X is any amino acid), IKVAV (SEQ ID NO: 13), RKRLQVQLSIRT (SEQ ID NO: 14, AG73), and HAVDI (SEQ ID NO: 15) or combinations thereof.
  • the hydrogel does not include any cell adhesion sequence, e.g., does not include a cell adhesion sequence disclosed herein.
  • this disclosure relates to methods of treating or preventing conditions or diseases associated with cardiovascular dysregulation comprising administering or implanting an effective amount of a hydrogel matrix disclosed herein, to a subject in need thereof.
  • the administering or implanting the hydrogel may be in combination with administering or implanting phosphorylated adenosine or prodrugs thereof.
  • the condition or disease associated with cardiovascular dysregulation is peripheral arterial disease (PAD), coronary heart disease, myocardial infarction, arrhythmia, stroke, transient ischemic attack, paroxysmal supraventricular tachycardia, Wolff- Parkinson-White Syndrome, supraventricular tachycardia, thrombosis, aortic disease, high blood pressure, high cholesterol, diabetes, and obesity.
  • PID peripheral arterial disease
  • coronary heart disease myocardial infarction
  • arrhythmia stroke
  • transient ischemic attack paroxysmal supraventricular tachycardia
  • Wolff- Parkinson-White Syndrome supraventricular tachycardia
  • thrombosis thrombosis
  • aortic disease high blood pressure, high cholesterol, diabetes, and obesity.
  • this disclosure relates to a hydrogel comprising a protease- degradable peptide crosslinked to polyethylene glycol and an RGD peptide sequence, wherein the hydrogel encapsulates CD73.
  • the hydrogel encapsulates CD73 and CD39.
  • the protease-degradable peptide is VPM protease-degradable peptide.
  • polyethene glycol is about 10 kDa, e.g., between 5-15 kDa. In certain embodiments, polyethene glycol is about 4% or 6% w/v, e.g. between 3-5% or 3-7% w/v.
  • this disclosure relates to methods of treating ischemia after myocardial infarction, coronary heart disease, plaque buildup in coronary arteries, or preventing reperfusion injury using a hydrogel disclosed herein.
  • the hydrogel material or material comprising or coated with hydrogel material is placed on the epicardium, heart, or other muscle.
  • FIG 1 A illustrates the polyethylene glycol 4-maleimide (PEG-4MAL) hydrogel design.
  • PEG-4MAL is cross-linked using protease-degradable VPM (Vai-Pro-Met) (protease cleavable peptide GCRDVPMSMRGGDRCG (SEQ ID NO: 1)) and incorporates the adhesive peptide RGD (Arg-Gly-Asp) and the ecto-enzyme CD73.
  • RGD is tethered to the hydrogel skeleton using a cysteine residue with a maleimide-reactive thiol (SH, sulfhydryl), while CD73 is encapsulated as a freely diffusible protein.
  • Figure IB shows data on storage moduli measured and compared in 4% and 6% (w/v) PEG content gels showing high storage modulus compared with loss modulus at both densities and an increase in storage modulus with higher PEG density.
  • FIG. 2 shows data indicating VPM (protease cleavable peptide) crosslinking achieves controlled release from hydrogel.
  • VPM protease sensitive tripeptide
  • the function of the protein crosslinker containing the protease sensitive tripeptide VPM was tested by incubating gels with encapsulated fluorescein isothiocyanate (FITC)-dextran (70 kDa) in media containing collagenase I (39 U/mL).
  • FITC-dextran 70 kDa
  • the release of FITC-dextran into the media was measured using fluorescence imaging of on a microplate reader of serially sampled media from gels incubated with or without collagenase.
  • the gel integrity was also visually assessed at different time points.
  • Figure 3 A shows data on high-performance liquid chromatography (HPLC) measurements of AMP to ADO (adenosine) conversion by CD73 hydrogels.
  • HPLC high-performance liquid chromatography
  • Figure 3B shows data where the media was supplemented with AMP as a substrate for CD73 at the start of the experiment.
  • Figure 4A shows data indicating H2O2 production by neutrophils cultured with CD73 hydrogel is inhibited. Hydrogen peroxide was quantified with an AmplexTM Red assay in neutrophils stimulated with TNFa (tumor necrosis factor alpha)/N-formylmethionyl-leucyl- phenylalanine (fMLP) in the presence and absence of adenosine, and with AMP added to the media.
  • TNFa tumor necrosis factor alpha
  • fMLP N-formylmethionyl-leucyl- phenylalanine
  • Figure 4B shows data indicating hydrogen peroxide production increased over 150 min in neutrophils stimulated with TNFa-fMLP, an increase that was blunted by with the presence of CD73 -containing hydrogels. RGD presence in the gel had no measurable effect on neutrophil H2O2 production in stimulated or resting cells.
  • Figure 5 shows data indicating CD73 -containing hydrogel increases muscle ADO (adenosine) levels after hindlimb ischemia.
  • a hydrogel consisting of 4% PEG (w/v), 1 mmol/L RGD (Arg-Gly-Asp) and crosslinked with VPM was used to encapsulate CD73 or an empty gel control and placed on the medial thigh skeletal muscles of mice having undergone hindlimb ischemia surgery by ligation and excision of the femoral artery and vein.
  • CD73 hydrogel treatment increased tissue adenosine levels at 24 h.
  • AMP levels also increased while there was no detectable difference between ADP and ATP levels.
  • Figure 6 shows data indicating CD73 hydrogel increases hindlimb perfusion in healthy mice.
  • a hydrogel consisting of 4% PEG (w/v), 1 mmol/L RGD (Arg-Gly-Asp) and crosslinked with a VPM (Vai-Pro-Met) peptide was loaded with CD73 or PBS as a control.
  • Laser Doppler perfusion imaging showed a significant increase in perfusion in the CD73 gel limb (right) relative to the control gel limb at 3 h post gel placement, with no difference detected at earlier timepoints of 15 min and 1 h.
  • Figure 7 shows data indicating purinergic hydrogel improves cardiac function.
  • MI/R MI/R injury
  • Echocardiography was used to assess cardiac function longitudinally after MI/R and treatment with CD39 and CD73 loaded hydrogels compared to empty hydrogel or PBS controls. Speckle tracking in B-mode was used to measures global longitudinal strain (GLS). At 7-37 days post-MI/R and hydrogel treatment, controls were significantly worse compared to the loaded hydrogel group.
  • Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, immunology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) have the meaning ascribed to them in U.S. Patent law in that they are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • Consisting essentially of' or “consists of' or the like when applied to methods and compositions encompassed by the present disclosure refers to the idea of excluding certain prior art element(s) as an inventive feature of a claim, but which may contain additional composition components or method steps, etc., that do not materially affect the basic and novel characteristic(s) of the compositions or methods, compared to those of the corresponding compositions or methods disclosed herein.
  • CD39 refers to an enzyme that converts ATP and ADP into AMP and is also referred to as apyrase, nucleoside triphosphate diphosphohydrolase, or ectonucleoside triphosphate diphosphohydrolase 1.
  • the human isoform 2 has NCBI Reference Sequence: NP_001091645.1.
  • CD73 refers to an enzyme that converts AMP into adenosine (ADO) by de-phosphorylation and is also referred to as ecto-5’ -nucleotidase.
  • ADO adenosine
  • ecto-5 adenosine
  • the human isoform 2 preproprotein has NCBI Reference Sequence: NP_001191742.1.
  • subject refers to any animal, preferably a human patient, livestock, rodent, monkey, or domestic pet.
  • the terms “prevent” and “preventing” include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.
  • the terms “treat” and “treating” are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.
  • the term "effective amount” refers to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as illustrated below.
  • the therapeutically effective amount can vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the specific dose will vary depending on, for example, the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • biodegradable in reference to a material refers to a molecular arrangement in the material that when implanted to a subject, e.g., human, will be broken down by biological mechanism such that a decomposition of the molecular arrangement will occur and the molecular arrangement will not persist for over a long period of time, e.g., the molecular arrangement will be broken down by the body after a several hours or days.
  • the disclosure contemplates that the biodegradable material will not exist after a week or a month.
  • pharmaceutical agent pharmaceutical agent
  • pharmaceutical agent pharmaceutical agent
  • agent agent
  • active agent drug
  • drug composition pharmaceutically acceptable composition
  • statins examples include statins, antibiotics, anti-viral agents, analgesics, steroidal anti-inflammatories, non-steroidal antiinflammatories, anti -neoplasties, anti-spasmodics, modulators of cell-extracellular matrix interactions, proteins, hormones, enzymes and enzyme inhibitors, anticoagulants and/or antithrombic agents, DNA, RNA, modified DNA and RNA, NSAIDs, inhibitors of DNA, RNA or protein synthesis, polypeptides, oligonucleotides, polynucleotides, nucleoproteins, compounds that modulate cell migration, compounds that modulate proliferation and growth of tissue, and vasodilating agents.
  • anti-inflammatory and anti-inflammatory agent are also used interchangeably herein and mean and include a “pharmacological agent” and/or “active agent formulation”, which, when a therapeutically effective amount is administered to a subject, prevents or treats bodily tissue inflammation i.e., the protective tissue response to injury or destruction of tissues, which serves to destroy, dilute, or wall off both the injurious agent and the injured tissues.
  • alclofenac alclometasone dipropionate, alpha amylase, amcinafal, amfenac sodium, anakinra, anirolac, balsalazide disodium, bendazac, benoxaprofen, bromelains, broperamole, budesonide, carprofen, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cortodoxone, decanoate, deflazacort, depo-testosterone, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate, dimethyl sulfoxide, enolicam sodium, etodolac, felbinac, fenamole, fenbufen, fen
  • a “conservative substitution” is an amino acid replacement in a protein that changes a given amino acid side chain to a different amino acid with similar biochemical properties such as charge, hydrophobicity, size which are often grouped into categories such as aliphatic side chain substitutions of glycine, alanine, valine, leucine, and isoleucine; hydroxyl or sulfur containing side chain substitutions of serine, cysteine, threonine, and methionine; aromatic side chain substitutions of phenylalanine, tyrosine, and tryptophan; basic side chains of histidine, lysine, and arginine; and acids or amides substitutions of aspartate, glutamate, asparagine, and glutamine.
  • this disclosure relates to hydrogel materials comprising enzymes that dephosphorylate adenosine phosphates.
  • the hydrogel contains a hydrophilic polymer crosslinked with protease-degradable peptides and envelops CD73 and optionally CD39 and optionally another pharmaceutical agent.
  • the hydrophilic polymer is biodegradable.
  • the hydrogel matrix comprises a multi-armed poly(ethylene glycol).
  • the crosslinker is a VPM protease-degradable crosslinker.
  • the crosslinked hydrophilic polymer comprises a protease cleavable peptide.
  • the protease cleavable peptide comprises GCRDVPMSMRGGDRCG (SEQ ID NO: 1) or variants thereof.
  • the variant comprises one or two amino acid substitutions.
  • the variant comprises three or four amino acid substitutions.
  • the substitutions are conservative substitutions or nonconservative substitutions.
  • the variant comprises one or two amino acid deletions.
  • the variant comprises one or two amino acid additions.
  • the adhesion peptide comprises an arginine-glycine-aspartate (RGD) sequence.
  • the adhesion peptide comprises GRGDSPC (SEQ ID NO: 2).
  • the crosslinkers of hydrogels disclosed herein are the following crosslinkers or optionally mixtures of these crosslinkers are protease-dependent crosslinkers comprising VPM, GPQXW (SEQ ID NO: 3, wherein X is any amino acid), GPQXXW (SEQ ID NO: 4, wherein X is individually at each occurrence any amino acid), GCRDGPQGIWGQDRCG (SEQ ID NO: 5), IPES (SEQ ID NO: 6), GCRDIPESLRAGDRCG (SEQ ID NO: 7), or combinations thereof.
  • the crosslinkers and mixtures of these crosslinkers are non-protease degradable such as dithiothreitol (DTT), polyethylene-dithiothreitol, PEG3-DTT, PEG6-DTT.
  • the crosslinkers or mixtures of these crosslinkers are hydrolytic such as an ethylene glycol bis-mercaptoacetate crosslinker.
  • the adhesion peptide comprises an arginine-glycine-aspartate (RGD) sequence and optionally mixtures of other adhesion peptides.
  • the adhesion peptide comprises GRGDSPC (SEQ ID NO: 2).
  • the adhesive peptide comprises one or more of following adhesion peptides: RGD, cyclic RGD, GFXGER (SEQ ID NO: 8, when X is O/Pyrrolysine), AGQWHRVSVRWG (SEQ ID NO: 9, A5G81), TWSQKALHHRVP (SEQ ID NO: 10, A5G84) WHRVSVC (SEQ ID NO: 11), ATLQLQEGRLHFXFDLGKGR (SEQ ID NO: 12, "EFizz" when X: Nle), IKVAV (SEQ ID NO: 13), RKRLQVQLSIRT (SEQ ID NO: 14, AG73), and HAVDI (SEQ ID NO: 15) or combinations thereof .
  • adhesion peptides RGD, cyclic RGD, GFXGER (SEQ ID NO: 8, when X is O/Pyrrolysine), AGQWHRVSVRWG (SEQ ID NO: 9, A5G81), TWSQKALHHR
  • the hydrogel material elutes a drug or growth factor.
  • the drug is an anti-inflammatory agent or an anti-coagulant.
  • the growth factor is vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and/or insulin-like growth factor- 1 (IGF-1).
  • the hydrogel material has an average thickness of between 10 pm to 5 cm. In certain embodiments, the hydrogel material has an average thickness of between 30 pm to 150 pm, 50 m to 150 pm, 50 pm to 200 pm, or 50 pm to 500 pm, 30 pm to 5 cm, 50 pm to 5 cm, 50 pm to 200 pm, or 50 pm to 5 cm.
  • the hydrogel materials disclosed herein are in any form, e.g., in the form of strips, strands, sheets, or tubes, and maintained in a lyophilized (e.g., freeze-dried) condition for storage. Before being used, the material may be rehydrated with aqueous solutions, e.g., sterile saline and/or pH buffered solutions.
  • aqueous solutions e.g., sterile saline and/or pH buffered solutions.
  • this disclosure relates to a material used for the repair or replacement of living tissue comprising or coated with a hydrogel material disclosed herein. In certain embodiments, this disclosure relates to a material colonized by the cells of a subject, providing a matrix or scaffold for growth of the cells.
  • this disclosure relates to a hydrogel material wherein living cells are attach to or become attached to the material comprising or coated with a hydrogel material disclosed herein.
  • a hydrogel material for example, cardiac stem/stromal cells, stem cell antigen-l+ (Scal+) and lslet- 1 - (Isl-H-) cells, mesenchymal stem cells, bone marrow-derived stem/progenitor cells, human fetal skeletal progenitor cells or human articular chondrocytes, or induced pluripotent stem cells.
  • this disclosure relates to a material comprising or coated with a hydrogel material disclosed herein incubated with suitable cells, in vitro, prior to use, to provide a material comprising tissue, which may be natural tissue or modified or genetically engineered tissue.
  • this disclosure relates to a hydrogel material disclosed herein comprising DNA, RNA, proteins, peptides, or therapeutic agents for uses reported herein.
  • the RNA is mircroRNA (miR), miR-24, miR-199a, or miR-590.
  • protein is a growth factor, collagen, proteoglycan, glycosaminoglycan (GAG) chain, glycoprotein, cytokine, cell-surface associated protein, cell adhesion molecule (CAM), angiogenic growth factor, endothelial ligand, matrix metalloprotease, cadherin, immunoglobin, fibril collagen, non-fibrillar collagen, basement membrane collagen, small-leucine rich proteoglycan, decorin, fibromodulin, keratocan, lumican, epiphycan, heparan sulfate proteoglycan, perlecan, agrin, testican, syndecan, glypican, serglycin, selectin, lectican, aggrecan, versican, neurocan, brevican, cytoplasmic domain-44 (CD44), macrophage stimulating factor, amyloid precursor protein, heparin, chondroitin sulfate B (dermatan sulfate), chon
  • this disclosure relates to a hydrogel material disclosed herein used for creating a stent comprising or coated with a hydrogel material disclosed herein.
  • this disclosure relates to methods of treating or preventing ischemic or cardiovascular diseases or conditions comprising contacting hydrogel materials disclosed herein with a tissue of a subject.
  • this disclosure relates to methods of treating or preventing conditions or diseases associated with cardiovascular dysregulation comprising administering or implanting an effective amount the hydrogel matrix disclosed herein, to a subject in need thereof.
  • administering or implanting the hydrogel may be in combination with administering or implanting phosphorylated adenosine or prodrugs thereof.
  • the condition or disease associated with cardiovascular dysregulation is peripheral arterial disease (PAD), coronary heart disease, myocardial infarction, arrhythmia, stroke, transient ischemic attack, paroxysmal supraventricular tachycardia, Wolff- Parkinson-White Syndrome, supraventricular tachycardia, aortic disease, high blood pressure, high cholesterol, diabetes, and obesity.
  • PID peripheral arterial disease
  • coronary heart disease myocardial infarction
  • arrhythmia CAD
  • stroke transient ischemic attack
  • paroxysmal supraventricular tachycardia achycardia
  • Wolff- Parkinson-White Syndrome supraventricular tachycardia
  • aortic disease high blood pressure
  • high cholesterol high cholesterol
  • diabetes diabetes
  • obesity obesity
  • this disclosure relates to methods of repairing a tissue comprising implanting an effective amount of a hydrogel material disclosed herein into a subject at a location of desired tissue growth in a subject in need thereof and optionally suturing the hydrogel materials disclosed herein to the surrounding tissue or fascia.
  • this disclosure relates to methods of repairing the heart following open-heart surgery such as intracardiac defects, septal defects and annulus repairs, cardiac and vascular reconstruction and repairs, peripheral vascular reconstruction and repairs, great vessel reconstruction and repairs, and suture-line buttressing.
  • the location of implantation is in or on the heart of a subject diagnosed with heart defect.
  • the subject is less than one, two, or three years old or at risk of, exhibiting symptoms of, or diagnosed with congenital heart disease regardless of age.
  • a material comprising or coated with a hydrogel material disclosed herein is used in an atrial septal defect repair by implanting a material comprising or coated with a hydrogel material disclosed herein in, on, or around the atrial septum, i.e., the wall between the left and right atria (upper chambers) of the heart.
  • a material comprising or coated with a hydrogel material disclosed herein is used in a ventricular septal defect repair by implanting a material comprising or coated with a hydrogel material disclosed herein on, or around the ventricular septum.
  • a material comprising or coated with a hydrogel material disclosed herein are used in a tetralogy of Fallot repair by placing a material comprising or coated with a hydrogel material disclosed herein in, on, or around the right ventricle and main pulmonary artery to improve blood flow to the lungs.
  • a material comprising or coated with a hydrogel material disclosed herein is used in coarctation of the aorta repair by cutting the narrow section of the aorta and widening it by inserting/implanting a tube made of a material comprising or coated with a hydrogel material disclosed herein disclosed herein.
  • a material comprising or coated with a hydrogel material disclosed herein is used in coarctation of the aorta repair by implanting a stent comprising a material comprising or coated with a hydrogel material disclosed herein into the narrow section of the aorta.
  • this disclosure relates to methods of repairing, treating, or preventing cardiovascular disease or condition using a material comprising or coated with a hydrogel material disclosed herein comprising implanting a heart valve, artificial heart valve, comprising or coated with a hydrogel material disclosed herein.
  • this disclosure relates to methods of surgically implanting a heart valve comprising a material comprising or coated with a hydrogel material disclosed herein.
  • the heart valve leaflets comprise a material comprising or coated with a hydrogel material disclosed herein.
  • this disclosure relates to methods of surgically implanting a transcatheter heart valve (e.g., transcatheter aortic valve) comprising a material comprising or coated with a hydrogel material disclosed herein.
  • the transcatheter aortic valve (TAV) leaflets comprise a material comprising or coated with a hydrogel material disclosed herein.
  • this disclosure relates to methods of slowing down AV node function/ conduct! on on or in a heart of a subject comprising implanting a material comprising or coated with a hydrogel material disclosed herein on or in the heart of the subject to slowing down AV node function/conduction.
  • the method may include removing a defective AV valve from the heart of the subject.
  • this disclosure relates to methods of regenerating an atrioventricular (AV) valve to replace a defective AV valve within a heart of a subject comprising removing a defective AV valve from the heart of the subject and implanting a material comprising or coated with a hydrogel material disclosed herein within the heart of the subject to regenerate a functional AV valve.
  • AV atrioventricular
  • this disclosure relates to methods of treating or preventing cardiovascular disease or condition using a material comprising or coated with a hydrogel material disclosed herein comprising implanting a vascular patch comprising or coated with a hydrogel material disclosed herein for uses in vascular reconstruction and repairs, peripheral vascular reconstruction, and repairs, and suture-line buttressing.
  • a material comprising or coated with a hydrogel material disclosed herein may be used in/as or coating on a wound dressings, dura repair, fistula plugs, myocardial patches, myocardial injections, heart valve repair, tympanoplasty grafts, nasal septal defect repair, hernia or body wall repair, hemostasis grafts, urology slings, tracheal grafts, esophageal grafts, lung patches, small bowel grafts, staple bolsters, nerve grafts, spinal cord repair, nerve cuff, nerve guide, pelvic floor grafts, amniotic sac patches, cornea repair, cartilage repair, bone repair, tendon/ligament repair, muscle repair, plastic and reconstructive surgery applications, lip augmentation, facial augmentation, nipple reconstruction, hair growth augmentation, bile duct repair, ureter repair, urethra repair, and vascular access graft.
  • this disclosure relates to methods of improving hernia repair or hernia reinforcement using a material comprising or coated with a hydrogel material disclosed herein.
  • methods of treating or preventing a hernia comprise implanting a material comprising or coated with a hydrogel material disclosed herein to fill a gap between fascial edges of the abdominal wall.
  • the material is laid over the peritoneal sac and sutured to surrounding tissue or fascia.
  • this disclosure relates to uses of materials comprising or coated with hydrogel material disclosed herein in bariatric surgery wherein methods comprise contacting a material comprising or coated with a hydrogel material disclosed herein in an area of the stomach and suturing to the surrounding tissue or fascia.
  • a material comprising or coated with a hydrogel material disclosed herein prevents or reduces chronic inflammation, tissue deposition, and/or fibrosis, e.g., a fibrotic valve. In certain embodiments, it is contemplated that the material comprising or coated with a hydrogel material disclosed herein prevents or reduces calcification.
  • this disclosure relates to a hydrogel material disclosed herein placed within a subject when a tissue or an internal tissue or organ is being repaired. In certain embodiments, this disclosure relates to a hydrogel material disclosed herein placed on the body of a subject when a cut, wound, or skin tissue is being repaired.
  • this disclosure relates to methods of implanting a hydrogel material disclosed herein in a subject and administering an anticoagulant or immune suppressive agent to the subject.
  • the nucleotide, adenosine is a vasodilatory, anti-inflammatory, and antithrombotic agent; however, directly administering adenosine for the treatment of cardiovascular diseases is challenging due to short half-life and dose-limiting side effects.
  • Peripheral artery disease one of the most prevalent atherosclerotic diseases of the cardiovascular system, remains without adequate nonsurgical treatments, resulting in significant morbidity due to ischemia and inflammation.
  • This disclosure contemplates the use of an enzyme-loaded synthetic hydrogel for local adenosine production.
  • a protease-sensitive poly(ethylene glycol)-maleimide-based hydrogel is disclosed. One can modulate the poly(ethylene glycol) density and tethering a peptide to a gel backbone.
  • the gel was loaded with (encapsulated) an ecto-nucleotidase, CD73, which catalyzes adenosine production from phosphorylated substrates.
  • CD73 ecto-nucleotidase
  • the CD73-loaded gel is useful to generate adenosine in vitro and in vivo and inhibit harmful oxidative bursts typical of neutrophils.
  • the CD73 hydrogel augments adenosine levels in hindlimb skeletal muscles 24 hours after induction of peripheral arterial ischemia and increases lower limb perfusion compared with control gel in healthy mice on laser Doppler imaging.
  • This enzyme-delivering hydrogel provides a strategy for local and sustained adenosine generation to improve perfusion and useful for disease modulation.
  • Adenosine 6-amino-9-beta-D-ribofuranosyl-9-H-purine, may be used for atrioventricular nodal blocking in the diagnosis and treatment of supraventricular tachycardias and in cardiac perfusion testing.
  • adenosine acts as a platelet inhibitor and antithrombotic agent via the A2a receptor, and in opposition to phosphorylated adenosine species like ADP that activate platelets.
  • PAD a chronic ischemic state in peripheral skeletal muscle and connective tissue.
  • Intravenous administration of adenosine causes dose-limiting hypotensive and bradycardic side effects.
  • the half-life of adenosine in circulation is short ( ⁇ 10 seconds), requiring continuous intravenous administration that is not practical for long-term applications and exacerbates its off-target actions.
  • Randomized clinical trials of direct adenosine administration in ischemic cardiovascular disease have had conflicting results, with significant variability in dosage, duration, and delivery route.
  • improvement in ischemic post-MI scar size in certain subgroups with systemic adenosine delivery required prolonged infusion for 3 hours and resulted in systemic side effects such as hypotension.
  • adenosine is physiological sources of extracellular adenosine and act by dephosphorylation of ATP and ADP into AMP in the case of the membrane bound, widely expressed CD39 (also called apyrase or nucleoside triphosphate diphosphohydrolase), while CD73 (also called ecto-5’ -nucleotidase) converts AMP into adenosine reported to be the rate-limiting final step in ATP de-phosphorylation.
  • Adenine nucleotides are released from cells actively (e.g., via pannexins or by exocytosis) or passively during cell death and/or cell membrane compromise.
  • AMP is released from ischemic, energy-rich musculoskeletal, cardiac, and nervous tissues. Once generated, adenosine is metabolized by deamination into inosine and eventually converted into renally excreted uric acid. Some adenosine is also rephosphorylated into ATP.
  • a synthetic hydrogel -based delivery vehicle incorporating the adenosine-generating CD73 enzyme with the goal of local and continuous tissue adenosine augmentation.
  • Locally released adenosine precursors phosphorylated adenine nucleotides
  • the hydrogel water-swollen, crosslinked polymer network
  • 4-armed polyethylene glycol macromers end-functionalized with polyethylene glycol 4-maleimide.
  • RGD and CD73 solutions in HEPES buffer were individually adjusted to achieve pH of 6.5 to 7.0 before mixing into the PEG solution.
  • the protease- cleavable crosslinking peptide VPM, GCRDVPMSMRGGDRCG SEQ ID NO: 1 was dissolved in HEPES buffer, and its pH adjusted to 6.5 to 7, then mixed into the rest of the premixed hydrogel components by pipetting once up and down. The gel was left to polymerize at room temperature for 5 minutes before the start of in vitro experiments.
  • the hydrogel was swollen in PBS for 12 hours at 4 °C to achieve equilibrium.
  • Dynamic oscillatory strain of 1% amplitude and a frequency sweep of 0.1 to 100 rad/s was applied to the hydrogel on a 37 °C heated platform using an MCR 302 rheometer (Anton Paar) to measure loss and storage moduli.
  • G’ (storage modulus) and G” (loss modulus) were obtained by averaging data points obtained in the 0.5 to 32 rad/s interval.
  • a hydrogel was designed based on 20 kDa, 4-armed PEG macromers with a terminal maleimide on each arm (PEG-4MAL) ( Figure 1 A).
  • a hydrogel was developed that uses the VPM peptide crosslinker containing a protease-cleavable sequence in order to enhance on-target delivery to inflamed, MMP (matrix metalloproteinase)-rich tissue, and allows the gel matrix to degrade over time.
  • MMP matrix metalloproteinase
  • the cell adhesive peptide RGD promotes host cell infiltration and remodeling.
  • Diffusion of cargo of the hydrogel through the mesh structure of the gel and its release can be modulated by adjusting the polymer density, crosslink density, and degradation rate.
  • Rheological analysis was performed to assess the elastic (storage modulus) and viscous (loss modulus) properties of the hydrogel, as well as the impact of modulating PEG macromer density (%w/v).
  • %w/v the impact of modulating PEG macromer density
  • For both 4% and 6% (w/v) VPM-crosslinked PEG hydrogels a >20-fold ratio of storage to loss moduli was observed, indicating that these hydrogels behave as elastic materials.
  • Six percentage PEG hydrogels exhibited significantly increased storage modulus compared with 4% hydrogels ( Figure IB), indicating one can control elasticity by modulating macromer density.
  • RGD peptides were incorporated into 4% hydrogels at E0 mmol/L concentration. The magnitude ratio of storage to loss modulus was still elevated, indicating maintenance of the elastic properties of the gel
  • the hydrogels were incubated at 37 °C in 10x times their volume of PBS with or without collagenase I (39 U/mL), and media was sampled at 10 seconds, 1, 5, 15, 30, 60, and 720 minutes, and imaged for fluorescence using a microplate reader. Free media (PBS) with and without collagenase, and FITC-dextran directly dissolved into PBS were also assayed to account for background and maximum possible release (input). Controlled gel degradation and cargo release using VPM crosslink
  • the function of the protease degradable peptide containing the MMP target sequence VPM was tested.
  • FITC-labeled dextran was encapsulated because it has a similar molecular weight (70 kDa) to CD73 (61 kDa).
  • the FITC-dextran containing hydrogels were incubated in media with or without collagenase I. The media was sampled at serial time points to assess release of the fluorescent cargo.
  • Collagenase treatment induced release of all cargo of the gel within 30 minutes ( Figure 2). In contrast, release in the absence of collagenase averaged 70% at 24 hours.
  • the release half-life values were 9 and 51 minutes for gels incubated in collagenase or control solutions, respectively.
  • Activated neutrophils undergo oxidative bursts generating reactive oxygen species such as hydrogen peroxide. These released proinflammatory species are useful in physiological signaling and digesting internalized and extracellular pathogens but can exacerbate sterile inflammation and cause collateral damage. Adenosine blunts the generation of hydrogen peroxide from stimulated neutrophils. The ability of gel-free CD73 to reduce hydrogen peroxide production was tested, which was only possible in the presence of its substrate AMP.
  • the CD73- containing hydrogel was tested using a mouse model of hindlimb ischemia.
  • Phosphorylated adenosine nucleotides released from damaged tissue at the site of ischemic injury serves as a substrate for CD73 encapsulated in the locally delivered, hydrogel.
  • Experiments were performed to determine whether the generated adenosine shifts the balance of purines from a proinflammatory to an anti-inflammatory state and contribute to vasodilation, improving perfusion and clearance.
  • the 4% (w/v) PEG, CD73-loaded gels versus empty control gels were in situ polymerized onto the medial thigh muscles of mice undergoing hindlimb ischemia surgery.
  • mice 6 to 8 weeks of age Male C57BL/6J mice 6 to 8 weeks of age were used. Experiments were blinded and animals randomized to treatment versus control groups. A 1.5-cm incision was performed unilaterally on the left limb to expose the medial thigh muscle and blood vessels. The femoral artery and vein were dissected away from the nerve and ligated using 6-0 sutures between the superficial epigastric artery and profunda femoris artery, and again proximal to the branching of the tibial arteries, and the section between the ligations was excised.
  • hydrogel solution was placed on the medial thigh muscles and held in place with a parafilm covered Eppendorf 1.5 mL tube for 60 seconds to ensure adhesion, and the skin was then closed using 6-0 nylon suture. Additional animals underwent treatment with hydrogel alone without hindlimb ischemia with a bilateral incision for control (empty) and experimental (CD73) hydrogel placement on opposite limbs. At the 24-hour time point, mice were euthanized by CO2 inhalation, and the adductor muscle between the femoral ligation sutures was excised and snap-frozen in liquid nitrogen for high- performance liquid chromatography (HPLC).
  • HPLC high- performance liquid chromatography
  • CD73-containing hydrogel increases hindlimb perfusion in vivo
  • a poly(ethylene) glycol hydrogel functionalized with the adenosine generating enzymes CD39 and CD73 was designed and tested. Availability of substrate for the enzymes was demonstrated in the myocardium during and post myocardial ischemia/reperfusion (MI/R) by LC/MS, and release kinetics were tested from the hydrogel. On echocardiography, global longitudinal strain (GLS) was preserved in MI/R hearts treated with the functionalized hydrogel (Fig. 7). The functionalized hydrogel resulted in lower innate immune infiltration into the myocardium post-MI/R, decreased markers of macrophage and neutrophil activation (NETosis), and decreased leukocyte-platelet complexes in circulation. In rats with MI/R, CD39 and CD73 delivered via a hydrogel preserve cardiac function.

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Abstract

La présente invention concerne des matériaux d'hydrogel comprenant des enzymes qui déphosphorylent des adénosine phosphates. Dans certains modes de réalisation, l'hydrogel contient un polymère hydrophile réticulé avec des peptides dégradables par protéase. Dans certains modes de réalisation, la présente invention concerne des matériaux d'hydrogel qui portent des enzymes capables de générer de l'adénosine in vivo et des procédés associés.
PCT/US2021/063006 2020-12-11 2021-12-13 Hydrogels encapsulant des enzymes qui déphosphorylent l'adénosine et utilisations dans des applications médicales WO2022126004A1 (fr)

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SAYEGH ET AL.: "Abstract 146: Investigating and Inhibiting Neutrophil Extracellular Trap Formation in the Heart", CIRCULATION RESEARCH, vol. 125, no. 1, 16 October 2019 (2019-10-16), Retrieved from the Internet <URL:https://www.ahajournals.org/doi/abs/10.1161/res.125.suppl_l.146> [retrieved on 20220221] *
SHIN ERIC Y., WANG LANFANG, ZEMSKOVA MARINA, DEPPEN JULINE, XU KAI, STROBEL FREDERICK, GARCÍA ANDRÉS J., TIROUVANZIAM RABINDRA, LE: "Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury", JOURNAL OF THE AMERICAN HEART ASSOCIATION, JOHN WILEY & SONS, vol. 7, no. 2, 23 January 2018 (2018-01-23), pages 1 - 18, XP009537688, ISSN: 2047-9980, DOI: 10.1161/JAHA.117.006949 *

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