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WO2009046950A1 - Dispositif pour le transfert d'acides nucléiques dans des cellules, et son procédé de fabrication - Google Patents

Dispositif pour le transfert d'acides nucléiques dans des cellules, et son procédé de fabrication Download PDF

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Publication number
WO2009046950A1
WO2009046950A1 PCT/EP2008/008416 EP2008008416W WO2009046950A1 WO 2009046950 A1 WO2009046950 A1 WO 2009046950A1 EP 2008008416 W EP2008008416 W EP 2008008416W WO 2009046950 A1 WO2009046950 A1 WO 2009046950A1
Authority
WO
WIPO (PCT)
Prior art keywords
nucleic acid
calcium phosphate
nanoparticles
carrier
functionalized
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2008/008416
Other languages
German (de)
English (en)
Inventor
Matthias Epple
Viktoriya Sokolova
Anna Kovtun
Henning Urch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of WO2009046950A1 publication Critical patent/WO2009046950A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/02—Animal zootechnically ameliorated
    • 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
    • A61L2300/258—Genetic materials, DNA, RNA, genes, vectors, e.g. plasmids
    • 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

  • the invention relates to a device for the transfer of nucleic acids into cells and to a method for producing the device.
  • the non-viral transfer of nucleic acids into cells can be carried out using nucleic acid-functionalized calcium phosphate nanoparticles, where the nucleic acid-functionalized calcium phosphate nanoparticles can control, for example, the formation of therapeutically active proteins targeted stimulation of the production of proteins possible, while through the introduction of small interfering RNA (siRNA) the targeted shutdown of the production of proteins possible (“antisense” or "gene silencing”) .
  • siRNA small interfering RNA
  • nanoparticles For the introduction of nanoparticles in the body, the injection or infusion offers.
  • a disadvantage here is that the nanoparticles are distributed uncontrollably in the body, so that control of protein production would be difficult and the success of the therapy would be called into question.
  • the object of the invention is to provide a technique for a controlled transfer of nucleic acids into cells.
  • a controlled delivery of nucleic acid-functionalized calcium phosphate nanoparticles to an organ to be treated is to be made available.
  • the object is achieved by a device for the transfer of nucleic acids into cells, which has nucleic acid-functionalized calcium phosphate nanoparticles on a carrier.
  • the device according to the invention can be introduced as an implant targeted into the body of a human or animal.
  • the nucleic acid-functionalized calcium phosphate nanoparticles (“nanoparticles”) can be derived from the Carriers migrate into cells in the vicinity of the implant. Thus, these cells are targeted to the nucleic acid-functionalized calcium phosphate nanoparticles. Furthermore, it is possible to remove the device in order to interrupt the supply. However, it is also possible to provide the carrier with nucleic acid-functionalized calcium phosphate nanoparticles in such a way that they migrate only after a certain time and / or migrate over a defined period of time and / or that different nucleic acid-functionalized calcium phosphate nanoparticles occur at different time intervals migrate.
  • the device can serve exclusively as a depot for the targeted delivery of the nanoparticles to the body of the patient.
  • the device supports or replaces further body functions that are added to the production of the proteins encoded by the nucleic acid.
  • the device may be an osteoarthritis treatment implant, a dental implant, a pacemaker, or a stent. The effect of these implants can be supported by the nanoparticles.
  • the nucleic acid-functionalized nanoparticles based on calcium phosphate have the advantage of being excellently biocompatible in the human or animal organism. This distinguishes them from viral, liposomal and cationic transfection agents. Furthermore, when several therapeutic doses are administered, no immune response is expected, as in viral transfection.
  • the nucleic acid attaches to the calcium phosphate nanoparticle and is immobilized without being degraded.
  • the device can be used molecular biologically for transfection in vitro.
  • stem cells can be genetically programmed by means of the device, so that they differentiate, for example, as bone cells or skin cells.
  • a possible further field of application of the device according to the invention is "the transfection of cell types which are difficult to transfect by means of other methods (eg neuronal cells).
  • the nanoparticle is additionally functionalized with cationic polymers.
  • cationic polymers are preferably nitrogen-containing polymers such as polyethyleneimine (PEI).
  • PEI polyethyleneimine
  • the device has means for holding the nucleic acid-functionalized calcium phosphate nanoparticles, which allow migration of the nanoparticles into adjacent cells, in particular when the device is inserted into the body of a patient.
  • the means for holding can be designed differently.
  • the carrier has at least one cavity in which the nanoparticles are arranged.
  • the at least one cavity may be permanently opened to the outside by at least one opening permeable to the nanoparticles and / or may have a wall which may be opened shortly before insertion into the body of the patient or at least partially opens in the human or animal body, for example because it is absorbed by the body.
  • the carrier is a capsule with a cavity which is partially closed by a porous or resorbable membrane.
  • the carrier is a porous body whose cavities are at least partially filled with the nanoparticles.
  • nucleic acid-functionalized calcium phosphate nanoparticles are immobilized on a surface of the support.
  • the immobilization is such that the nanoparticles are able to migrate from the patient's body away from the wearer's surface into adjacent cells.
  • the immobilization is given, for example, by adsorption of the nanoparticles on the surface of the support.
  • the nanoparticles can be applied to the surface in various ways.
  • the carrier may have been immersed in a solution of nanoparticles, so that they occupy the surface of the carrier after evaporation of the solvent.
  • An additional binder can cause this adhesion.
  • the carrier consists of an electrically conductive material at least on the surface and nucleic acid-functionalized calcium phosphate nanoparticles were electrophoretically deposited on the surface.
  • electrophoretic deposition surfaces of carriers can be coated with nanoparticles targeted.
  • the nanoparticles adhere better to the substrates than when coated Immersion in solution and evaporation of the solvent.
  • more uniform layers are achieved and the layer thickness is better controllable.
  • porous supports can also be coated, in particular the surfaces of their cavities.
  • the electrophoresis can also be carried out in alcoholic dispersion.
  • the nucleic acid is not denatured in the electrophoretic coating.
  • the nanoparticles can be immobilized by adsorption on the surface. The transfection is not prevented by this.
  • the nanoparticles can migrate directly into the surrounding cells.
  • Conductive substances smooth, rough or porous, can be electrophoretically coated with nanoparticles.
  • Suitable electrically conductive materials are, in particular, metals, semiconductors and alloys.
  • the carrier as a whole consists of electrically conductive material.
  • the carrier is made of titanium, for example.
  • Correspondingly designed titanium implants can additionally serve to treat broken bones.
  • the carrier consists of a ceramic material with an electrically conductive layer on the surface.
  • This device can be configured, for example, as a dental implant.
  • the device has at least one layer comprising nucleic acid-functionalized calcium phosphate nanoparticles on the surface of the carrier. In the layer, a large number of nanoparticles can be provided.
  • the layer may also comprise other substances which, for example, control the immobilization and / or release of the nanoparticles in the body of the patient.
  • the layer may contain electrically conductive substances to promote the deposition of another layer by electrophoretic deposition.
  • the device has various nucleic acid-functionalized calcium phosphate nanoparticles.
  • this device can z. B. when used as an implant, the production of various proteins are controlled, which are needed for the treatment of one or more diseases.
  • the device according to a further embodiment comprises a mixture comprising different nucleic acid-functionalized calcium phosphate nanoparticles.
  • the use of this device can cause the simultaneous production of various proteins.
  • the device has multiple layers on the surface of the support, which differ in that they comprise different nucleic acid-functionalized calcium phosphate nanoparticles.
  • the multiple layers may comprise nucleic acid encoding different proteins. After the particles have migrated from an overlying layer, the particles of the underlying layer can migrate. In this way, for example, a step therapy is possible.
  • the device has at least one calcium phosphate nanoparticle-comprising layer on the surface of the carrier which is not nucleic acid-functionalized.
  • a layer containing nucleic acid-functionalized calcium phosphate nanoparticles is covered with a layer containing non-nucleic acid-functionalized nanoparticles.
  • the nanoparticles of the "buried layer" can migrate only when the non-nucleic acid-functionalized nanoparticles have migrated away.
  • the device can be designed such that in the case of an inflammation the pH rising in the tissue causes the uppermost layer to migrate, so that thereafter Nucleic acid-functionalized nanoparticles can migrate.
  • the nucleic acid of the nucleic acid-functionalized calcium phosphate nanoparticles encodes proteins which promote the wound healing process or bone growth and / or impair cells and / or cell growth and / or the provision of which is the goal of gene therapy.
  • the promotion of the wound healing process or bone growth is particularly advantageous in the case of an implant which additionally serves to supply bone fractures.
  • Impairment of cells and / or cell growth may be considered as a stent when the implant is implemented, in order to prevent unwanted coalescence of the connective tissue around the stent ("restenosis") prevent.
  • An implant for gene therapy can be designed, for example, as a chip ("chip").
  • a device is prepared by electrophoretically depositing nucleic acid-functionalized nanoparticles on a surface of a carrier.
  • At least one mixture of different nucleic acid-functionalized calcium phosphate nanoparticles is deposited on the surface of the carrier.
  • nucleic acid-functionalized calcium phosphate nanoparticles and / or mixtures of different nucleic acid-functionalized calcium phosphate nanoparticles are deposited on the surface of the carrier in several steps.
  • a layer of non-nucleic acid-functionalized nanoparticles is deposited electrophoretically on the surface of the carrier.
  • the nucleic acid-functionalized calcium phosphate nanoparticles are electrophoretically deposited on the support from a dispersion in a polar solvent (eg, an alcohol or acetone).
  • a polar solvent eg, an alcohol or acetone.
  • the prerequisite for successful gene therapy is the identification of the gene that has the therapeutic effect for the disease to be treated.
  • an orthopedic (pathological) disease such as osteoarthritis
  • the nucleic acid which encodes factors that slow down the degeneration of the hyaline cartilage, could be loaded onto the particles and then brought into the organism via an implant. It would also be possible to code for a matrix protein which stimulates the rebuilding of the cartilage.
  • nucleic acid nanoparticle layer which codes for a vector which prevents the formation of the cellular pseudomembrane in the space between implant and bone.
  • a coated implant could be used directly on the bone.
  • the nucleic acid could encode a bone growth factor (e.g., BMP-2) that stimulates bone growth and, thus, the healing process.
  • the same principle applies to a permanent implant (eg hip prosthesis, dental implant, knee joint).
  • the lifetime of such implants could be improved by the expression of bone growth factors.
  • the following is an exemplary embodiment relating to the preparation and the electrophoretic deposition of the nanoparticles on the support and the detection of the transfection of cells by means of the coated support.
  • DNA-functionalized calcium phosphate nanoparticles were prepared according to the method described in the two publications by Sokolova et al. (2006). The two publications are incorporated in this patent application with regard to the manufacturing process of the nanoparticles.
  • the DNA encoded the formation of Enhanced Green Fluorescent Protein (EGFP).
  • EGFP Enhanced Green Fluorescent Protein
  • the application on a 1 cm 2 -large titanium plate is carried out by electrophoresis from isopropanol in the form of a few microns thick layer. These platelets were air dried and placed in cell culture with T-HUVEC cells. After a transfection period of 48 hours, the formation of the green fluorescent protein EGFP was clearly evident in the cells that had colonized the platelet. This demonstrated that the cells had taken up the DNA-functionalized calcium phosphate nanoparticles.
  • a control experiment in which DNA was added directly to a plasma-deposited calcium phosphate layer on plasma followed by cell colonization revealed no transfection of the cells.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Public Health (AREA)
  • Transplantation (AREA)
  • General Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Plant Pathology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Inorganic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Materials For Medical Uses (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dispositif pour le transfert d'acides nucléiques dans des cellules avec des nanoparticules de phosphate de calcium fonctionnalisées acide nucléique sur un substrat.
PCT/EP2008/008416 2007-10-05 2008-10-06 Dispositif pour le transfert d'acides nucléiques dans des cellules, et son procédé de fabrication Ceased WO2009046950A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007048591.5 2007-10-05
DE200710048591 DE102007048591A1 (de) 2007-10-05 2007-10-05 Implantat und Verfahren zu seiner Herstellung

Publications (1)

Publication Number Publication Date
WO2009046950A1 true WO2009046950A1 (fr) 2009-04-16

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PCT/EP2008/008416 Ceased WO2009046950A1 (fr) 2007-10-05 2008-10-06 Dispositif pour le transfert d'acides nucléiques dans des cellules, et son procédé de fabrication

Country Status (2)

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DE (2) DE102007048591A1 (fr)
WO (1) WO2009046950A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102011051692A1 (de) * 2011-07-08 2013-01-10 Peter Brehm Chirurgie-Mechanik e.K. Verfahren zur Sterilisation von funktionalisierten, Nukleotide und/oder Nukleotidderivate enthaltenden, beschichteten Oberflächen

Citations (2)

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US20080057105A1 (en) * 2006-09-06 2008-03-06 Boston Scientific Scimed, Inc. Medical devices having nanostructured coating for macromolecule delivery
DE102007020302A1 (de) * 2007-04-20 2008-10-30 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Verbesserte dreidimensionale biokompatible Gerüststruktur, die Nanopartikel beinhaltet

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DE10113108B4 (de) * 2001-03-15 2007-07-26 Dot Gmbh Wirkstoffhaltige Calciumphosphat-Materialien
US7247288B2 (en) * 2002-04-18 2007-07-24 Carnegie Mellon University Method of manufacturing hydroxyapatite and uses therefor in delivery of nucleic acids

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
US20080057105A1 (en) * 2006-09-06 2008-03-06 Boston Scientific Scimed, Inc. Medical devices having nanostructured coating for macromolecule delivery
WO2008030383A2 (fr) * 2006-09-06 2008-03-13 Boston Scientific Scimed, Inc. Dispositifs médicaux ayant un revêtement nanostructuré pour une administration de macromolécules
DE102007020302A1 (de) * 2007-04-20 2008-10-30 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Verbesserte dreidimensionale biokompatible Gerüststruktur, die Nanopartikel beinhaltet
WO2008128717A1 (fr) * 2007-04-20 2008-10-30 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Structure charpentée biocompatible tridimensionnelle améliorée contenant des nanoparticules

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Title
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SHEN HONG ET AL: "Surface-mediated gene transfer from nanocomposites of controlled texture", NATURE MATERIALS, vol. 3, no. 8, August 2004 (2004-08-01), pages 569 - 574, XP002510856, ISSN: 1476-1122 *
SOKOLOVA V V ET AL: "Effective transfection of cells with multi-shell calcium phosphate-DNA nanoparticles", BIOMATERIALS, ELSEVIER SCIENCE PUBLISHERS BV., BARKING, GB, vol. 27, no. 16, 1 June 2006 (2006-06-01), pages 3147 - 3153, XP025097257, ISSN: 0142-9612, [retrieved on 20060601] *
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Also Published As

Publication number Publication date
DE202007015205U1 (de) 2008-02-28
DE102007048591A1 (de) 2009-04-09

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