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WO2018187184A1 - Substance angiogénique injectable à visée thérapeutique pour la réparation du cerveau - Google Patents

Substance angiogénique injectable à visée thérapeutique pour la réparation du cerveau Download PDF

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Publication number
WO2018187184A1
WO2018187184A1 PCT/US2018/025554 US2018025554W WO2018187184A1 WO 2018187184 A1 WO2018187184 A1 WO 2018187184A1 US 2018025554 W US2018025554 W US 2018025554W WO 2018187184 A1 WO2018187184 A1 WO 2018187184A1
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Prior art keywords
vegf
heparin
stroke
gel
nanoparticles
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Ceased
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PCT/US2018/025554
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English (en)
Inventor
Tatiana Segura
Stanley Thomas CARMICHAEL
Lina R. NIH
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University of California Berkeley
University of California San Diego UCSD
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University of California Berkeley
University of California San Diego UCSD
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Publication of WO2018187184A1 publication Critical patent/WO2018187184A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1858—Platelet-derived growth factor [PDGF]
    • A61K38/1866—Vascular endothelial growth factor [VEGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • 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
    • A61K9/0085—Brain, e.g. brain implants; Spinal cord
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • A61L2300/23—Carbohydrates
    • A61L2300/236—Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
    • 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
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces

Definitions

  • a successful strategy for brain repair after stroke would deliver a molecule that stimulates angiogenesis and neural regeneration, reduces local inflammation, removes the barrier to cellular infiltration in the stroke site, and introduces a scaffold that can serve as a physical support onto which a new neuronal network can grow.
  • biopolymer hydrogels have developed materials with extracellular matrix motifs that directly support survival and cell infiltration. The problem remains, however of the adverse effects of incorporating VEGF into the brain.
  • Each dot in the plots represents one animal and p values were determined by One-way ANOVA with a Tukey's post-hoc test, with *, ** and **** indicating p ⁇ 0.05, p ⁇ 0.01 and p ⁇ 0.0001, respectively.
  • FIG. 13F illustrates graphs showing infiltration distance and penetration angle in the stroke site at 2 weeks after stroke (10 days after gel transplantation).
  • FIG. 13G illustrates fluorescent images of axonal neurofilaments (NF200) in and around the stroke site (*) at 16 weeks after gel transplantation. Scale bar: 100 ⁇ .
  • FIG. 18C illustrates a graph illustrating the NF200 positive area a distance of 50 ⁇ from vessels.
  • FIG. 18D illustrates fluorescent images of the peri-infarct astrocytic scar (GFAP) and BDA-traced neurons in the ipsilateral hemisphere of gel + hcV injected mice 16 weeks after gel transplantation.
  • GFAP peri-infarct astrocytic scar
  • FIG. 22A illustrates fluorescent images of vessels (Glut-1), astrocytic scar (GFAP), microglia (Iba-1) and axonal neurofilaments (NF200) in and around the stroke site (*) of gel + (hcV - nH) and LcV + nH) conditions, 16 weeks post-stroke. Scale bar: 100 ⁇ .
  • FIG. 22D illustrates graphs showing the percentage NF200 area for the infarct and peri-infarct areas at 16 weeks after gel transplantation.
  • FIG. 1 illustrates a cross-sectional view of a mammalian brain 10 that includes stroke cavity 12 formed therein.
  • the delivery site is a stroke cavity 12 such as that illustrated in FIG. 1 that naturally forms after stroke.
  • the clearance of debris in the lesion leaves a compartmentalized cavity 12 that can accept a large volume of the injectable therapeutic angiogenic material 20 described herein without further damaging the surrounding healthy parenchyma.
  • This stroke cavity 12 is situated directly adjacent to the peri-infarct tissue area 14, the region of the brain that undergoes the most substantial repair and recovery, meaning that any therapeutic delivered to the cavity 12 will have direct access to the tissue target for repair.
  • the injectable therapeutic angiogenic material 20 may also be transplanted in the peri-infarct area 14, or the brain surface 16.
  • the therapeutic angiogenic material 20 is preferably s injected within fifteen (15) days of stroke onset, after day three (3) post-stroke to avoid the severe post-stroke inflammation and edema in the damaged brain.
  • the specific localization of both the infarct (stroke cavity 12) and the peri-infarct areas are determined with three-dimensional intra-cerebral coordinates (x, y and z). While a syringe is illustrated as the delivery device 22 the therapeutic angiogenic material 20 may also be delivered using a catheter-based device or the like to deliver the injectable therapeutic angiogenic material 20 from a location outside the subject's brain to the stroke cavity 12.
  • FIG. 4 illustrates one preferred embodiment of injectable therapeutic angiogenic material that was used in mouse brain studies.
  • the injectable therapeutic angiogenic material illustrated in FIG. 4 is a hyaluronic acid hydrogel based on thiol-acrylamide Michael-type addition as described herein with a MMP labile peptide used as the crosslinker which resulted in a hydrogel that is both hyaluronidase degradable and MMP degradable, designed with a stiffness corresponding to the brain to reduce the local inflammatory response.
  • FIG. 4 illustrates one preferred embodiment of injectable therapeutic angiogenic material that was used in mouse brain studies. The injectable therapeutic angiogenic material illustrated in FIG.
  • Angiopoietin-2 (FIGS. 14A-14C) showed a significant increase in the peri-infarct area compared with the No gel and gel + Vs conditions. Angiopoietin-2 was significantly increased in the close vicinity of vessels (10 ⁇ ) in the gel + hcV condition compared with any other group, except of gel + nH.
  • the nanoparticles were then dialyzed in 100 kD MWCO dialysis units for 12 hours and stored at +4C.
  • the amount of heparin in the solution was determined by lyophilizing a small aliquot of the solution.
  • a total concentration of 20 ⁇ g/ml VEGF was mixed with different concentrations of heparin nanoparticles ranging from 0.1 to 0.001 mg/mL to form different packing densities of VEGF onto the nanoparticle's surface, incubated overnight and exposed to a 365 nm wavelength UV light for 10 minutes to lock VEGF covalently to the surface.
  • VEGF nanoparticles were then washed from excess with 0.05% Tween-20 in PBS, then with PBS, using a 100 kD MWCO dialysis units. The washes were collected and an Elisa and Dot blot were performed to estimate the amount of VEGF bound to nanoparticles by subtracting the washes to the total amount of VEGF mixed. [00143] Heparin nanoparticle characterization
  • Hyaluronic acid (60,000 Da, Genzyme, Cambridge, MA) was functionalized with an acrylamide groups using a two-step synthesis as previously described in Lei, S. et al, The spreading, migration and proliferation of mouse mesenchymal stem cells cultured inside hyaluronic acid hydrogels, Biomaterials 32, 39-47 (2011) and P. Moshayedi et al, Systematic optimization of an engineered hydrogel allows for selective control of human neural stem cell survival and differentiation after transplantation in the stroke brain, Biomaterials 105, 145- 155 (2016), which are incorporated herein by reference.
  • an aliquot of the desired crosslinker (Ac-GCREGPQGIWGQERCG-NH2 [SEQ ID NO: 1], MMP-degradable or Ac-GCREGDQGIAGFERCG-NH2 [SEQ ID NO: 2], MMP- nondegradable) was dissolved in 0.3 M HEPES and added to the gel precursor solution.
  • the precursor was loaded into the Hamilton syringe directly after mixing in the desired crosslinking peptide.
  • mice were videotaped during walking and exploratory behavior in the cylinder, grid-walking, and pasta-handling tasks, two weeks before surgery to establish baseline performance levels. For all of the studies, animals were tested every four weeks after stroke at approximately the same time each day at the end of their dark cycle. Behavioral tests were scored by observers, who were masked to the treatment group in the study.

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Abstract

Cette invention concerne une substance angiogénique injectable à visée thérapeutique comprenant un hydrogel à base d'acide hyaluronique à gélification in situ contenant une première pluralité de nanoparticules d'héparine-VEGF en grappes, où le VEGF est immobilisé sur les nanoparticules d'héparine, et une seconde pluralité de nanoparticules d'héparine nues, sans VEGF immobilisé sur les nanoparticules d'héparine. Selon un aspect de l'invention, la substance angiogénique injectable à visée thérapeutique est utilisée pour réparer un tissu ischémique chez un sujet (p. ex., mammifère). Pour traiter le sujet ou le patient, la cavité ischémique dans le tissu cérébral est localisée et la substance angiogénique à visée thérapeutique est injectée dans ladite cavité conjointement avec un agent de réticulation.
PCT/US2018/025554 2017-04-04 2018-03-30 Substance angiogénique injectable à visée thérapeutique pour la réparation du cerveau Ceased WO2018187184A1 (fr)

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US201762481587P 2017-04-04 2017-04-04
US62/481,587 2017-04-04

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019217855A1 (fr) 2018-05-10 2019-11-14 The Regents Of The University Of California Matériau de type hydrogel thérapeutique et ses procédés d'utilisation
CN119185187A (zh) * 2024-10-09 2024-12-27 四川大学 一种炎症响应型仿生水凝胶及其制备方法和用途

Citations (5)

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Publication number Priority date Publication date Assignee Title
US20090118423A1 (en) * 2006-03-14 2009-05-07 Novozymes Biopolymer A/S Acrylated Hyaluronic Acid
WO2012162555A2 (fr) * 2011-05-24 2012-11-29 The Regents Of The University Of California Nano-amas d'héparine
US20140315805A1 (en) * 2011-03-04 2014-10-23 The Regents Of The University Of California Locally released growth factors to mediate motor recovery after stroke
US20150166962A1 (en) * 2009-11-10 2015-06-18 The Johns Hopkins University Hydrogel-based vascular lineage cell growth media and uses thereof
US20150359752A1 (en) * 2011-09-02 2015-12-17 Yunfeng Lu Enzyme responsive nanocapsules for protein delivery

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090118423A1 (en) * 2006-03-14 2009-05-07 Novozymes Biopolymer A/S Acrylated Hyaluronic Acid
US20150166962A1 (en) * 2009-11-10 2015-06-18 The Johns Hopkins University Hydrogel-based vascular lineage cell growth media and uses thereof
US20140315805A1 (en) * 2011-03-04 2014-10-23 The Regents Of The University Of California Locally released growth factors to mediate motor recovery after stroke
WO2012162555A2 (fr) * 2011-05-24 2012-11-29 The Regents Of The University Of California Nano-amas d'héparine
US20150359752A1 (en) * 2011-09-02 2015-12-17 Yunfeng Lu Enzyme responsive nanocapsules for protein delivery

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NIH ET AL.: "Hydrogels for brain repair after strode: an emerging treatment option", CURRENT OPINION IN BIOTECHNOLOGY, vol. 40, 7 May 2016 (2016-05-07), pages 155 - 163, XP029669923 *
WANG ET AL.: "Bioengineered sequential growth factor delivery stimulates brain tissue regeneration after stroke", JOURNAL OF CONTROLLED RELEASE, vol. 172, no. 1, 9 August 2013 (2013-08-09), pages 1 - 11, XP028772914 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019217855A1 (fr) 2018-05-10 2019-11-14 The Regents Of The University Of California Matériau de type hydrogel thérapeutique et ses procédés d'utilisation
EP3790603A4 (fr) * 2018-05-10 2021-06-30 The Regents of the University of California Matériau de type hydrogel thérapeutique et ses procédés d'utilisation
CN119185187A (zh) * 2024-10-09 2024-12-27 四川大学 一种炎症响应型仿生水凝胶及其制备方法和用途

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