WO2012144716A1 - Système d'administration de vaccin à base de nanoparticules ayant des fonctions doubles d'imagerie et d'administration - Google Patents

Système d'administration de vaccin à base de nanoparticules ayant des fonctions doubles d'imagerie et d'administration Download PDF

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WO2012144716A1
WO2012144716A1 PCT/KR2011/009553 KR2011009553W WO2012144716A1 WO 2012144716 A1 WO2012144716 A1 WO 2012144716A1 KR 2011009553 W KR2011009553 W KR 2011009553W WO 2012144716 A1 WO2012144716 A1 WO 2012144716A1
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antigen
rfp
gnp
imaging
vaccine
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Korean (ko)
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전상용
이인현
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Gwangju Institute of Science and Technology
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Gwangju Institute of Science and Technology
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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/646—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6923—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0476—Particles, beads, capsules, spheres
    • A61K49/0485—Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer
    • A61K49/049—Surface-modified nanoparticles, e.g. immune-nanoparticles
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1866—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds

Definitions

  • the present invention relates to nanoparticle-based vaccine carriers capable of imaging and delivery.
  • Vaccines are the most cost-effective medicines that can prevent and reduce the incidence of up to 99% of diseases, as well as therapeutic effects.
  • the use of vaccines is not limited to infectious diseases, but has been widened to various intractable diseases including cancer and autoimmune diseases, and vaccine development is recognized as very important as therapeutic vaccines are introduced.
  • cancer vaccines are a novel therapeutic vaccine that destroys cancer cells by inducing a powerful immune response by artificially activating an immune mechanism that specifically acts on cancer cells (eg, introducing cells into antigens).
  • APCs antigen-presenting cells
  • DC dendritic cells
  • the vaccine is useful for immunizing an individual against a target antigen, such as a pathogen antigen or an antigen associated with a cell involved in human disease.
  • a target antigen such as a pathogen antigen or an antigen associated with a cell involved in human disease.
  • Cell-associated antigens involved in human disease include cancer-associated tumor antigens and antigens associated with autoimmune disease-related cells.
  • vaccines that produce target antigens in the cells of vaccinated individuals are effective in inducing cellular arms of the immune system.
  • attenuated live vaccines, recombinant vaccines using non-toxic vectors, and DNA vaccines both induce antigen production in cells of vaccinated individuals, leading to cellular mineralization of the immune system.
  • subunit vaccines containing only proteins and dead or inactivated vaccines, which induce humoral responses do not induce a good cellular immune response.
  • the inventors have sought to develop a vaccine carrier capable of performing both imaging and vaccine delivery.
  • a vaccine carrier capable of performing both imaging and vaccine delivery.
  • antigens capable of inducing an immune response to gold nanoparticles or magnetic nanoparticles they show excellent performance as vaccine carriers, enable selective transport to lymph nodes, and also provide computed tomography (CT) imaging.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • the present invention has been completed by finding that vaccines based on gold nanoparticles or magnetic nanoparticles successfully achieve immune activation by antigen in lymph nodes and therapeutic effects by immune activity.
  • Another object of the present invention is to provide a vaccine pharmaceutical composition for anticancer.
  • the present invention provides a composition comprising: (a) gold nanoparticles or magnetic nanoparticles as imaging-carrying bifunctional particles having an imaging and transporting action; And (b) a vaccine delivery system comprising an antigen bound to the surface of the imaging-carrying bifunctional particle, wherein the vaccine delivery system is capable of delivering the antigen and tracing the antigen delivery. It provides a vaccine delivery, characterized in that to enable.
  • the inventors have sought to develop a vaccine carrier capable of performing both imaging and vaccine delivery.
  • a vaccine carrier capable of performing both imaging and vaccine delivery.
  • antigens capable of inducing an immune response to gold nanoparticles or magnetic nanoparticles
  • they show excellent performance as vaccine carriers, enable selective transport to lymph nodes, and also provide computed tomography (CT) imaging.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • vaccines based on gold nanoparticles or magnetic nanoparticles successfully achieve immune activation by antigen in lymph nodes and therapeutic effects by immune activity.
  • the present invention is to induce as a vaccine delivery system that combines the antigen on the surface of the gold nanoparticles, or magnetic nanoparticles, in vitro (in virto) as well, not just in vivo (in vivo) highly effective immune response in a (e. G., Antibody production) Vaccine carriers.
  • vaccine used to describe a vaccine carrier in the present invention means a substance used for automatically immunizing a human or animal, and typically, there is a dead virus vaccine, an attenuated vaccine, an autologous vaccine and a multivalent vaccine.
  • nanoparticle means a particle having a size of 1-800 nm, preferably 1-100 nm.
  • the nanoparticles used in the present invention have a diameter in nano units, preferably 5-100 nm, more preferably 5-50 nm, and most preferably 12-14 nm.
  • Eggplant means nanoparticles.
  • This small size facilitates the penetration of the nanoparticles of the invention into cells of interest (eg, immune cells) or immune cell tissue, allowing the penetration of vaccine carriers into cells.
  • the present invention comprising such a configuration contributes to the accurate delivery of antigen and induction of immune activation (eg, antibody production) upon antigen delivery in a vaccine delivery vehicle.
  • Nanoparticles used in the present invention are gold nanoparticles or magnetic nanoparticles.
  • Gold nanoparticles are easy to manufacture in the form of stable particles, are easy to adjust in size, and unlike other heavy metals such as manganese, aluminum, cadmium, lead, mercury, cobalt, nickel and beryllium, they are highly biocompatible. .
  • the gold nanoparticles used in the present invention can be prepared, for example, as follows: HAuCl 4 is used as a gold source, and sodium citrate is used as a reducing agent to reduce HAuCl 4 to prepare gold nanoparticles.
  • the size of the gold nanoparticles can be adjusted by varying the citrate added. That is, the size of the gold nanoparticles decreases as the amount of citrate increases, so that nucleation increases.
  • the gold nanoparticles are larger than 100 nm in diameter, their properties as nanoparticles are greatly reduced, and the binding of functional groups such as the thiol group and the gold surface without the nanomaterial properties is weak. This bound particle is difficult to manufacture.
  • Magnetic nanoparticles used in the present invention include any magnetic nanoparticles known in the art.
  • the magnetic nanoparticles usable in the present invention are paramagnetic nanoparticles or superparamagnetic nanoparticles, most preferably superparamagnetic signal generating cores.
  • Exemplary paramagnetic nanoparticles suitable for the present invention include stable free radicals (eg, stable nitroxides), transition elements, lanthanides, and actinides. Preferred elements are Gd (III), Mn (II), Cu (II), Cr (III), Fe (II), Fe (III), Co (II), Er (II), Ni (II), Eu (III) and Dy (III).
  • Exemplary supercrystalline nanoparticles suitable for the present invention include ferro- or ferrimagnetic compounds, such as pure iron, magnetic iron oxides (eg magnetite, Fe 3 O 4 ), ⁇ -Fe 2 O 3 , Manganese ferrite, cobalt ferrite and nickel ferrite.
  • ferro- or ferrimagnetic compounds such as pure iron, magnetic iron oxides (eg magnetite, Fe 3 O 4 ), ⁇ -Fe 2 O 3 , Manganese ferrite, cobalt ferrite and nickel ferrite.
  • antigens There are many different types of antigens, and if they are foreign to the individual, in principle everyone recognizes them as antigens. Proteins, polysaccharides, nucleic acids, lipids, and complexes thereof are called natural antigens.
  • hapten as hapten (adhesive) or phosphorus airport agent. Molecules vary in size, ranging from peptide chains of amino acids to hundreds of thousands of molecules, and viruses, bacteria, and animal cells.
  • the antigen may be covalently or non-covalently bound to the nanoparticle surface, preferably covalently bound.
  • the antigen can be bound directly or indirectly (eg, via a linker) to the nanoparticles.
  • the antigen included in the vaccine carrier of the present invention comprises a microorganism-derived antigen, a virus-derived antigen, a parasite-derived antigen, a plant-derived antigen, an animal-derived antigen, an endogenous antigen and a synthetic antigen.
  • a microorganism-derived antigen e.g., a virus-derived antigen, a parasite-derived antigen, a plant-derived antigen, an animal-derived antigen, an endogenous antigen and a synthetic antigen.
  • One or more antigens selected from the group a microorganism-derived antigen, a virus-derived antigen, a parasite-derived antigen, a plant-derived antigen, an animal-derived antigen, an endogenous antigen and a synthetic antigen.
  • the present invention not only facilitates the production and secretion of antibodies and cytokines involved in the immune response from lymphocytes when the antigen is bound to the surface of an imaging-carrying bifunctional particle and administered to a subject (eg, mammalian oil). It is a vaccine carrier that can exert excellent anticancer efficacy by significantly reducing the size of cancer cells.
  • the antigen bound to the imaging-carrying bifunctional particle in the vaccine delivery vehicle of the present invention is a microbe-derived antigen, it preferably comprises a bacterial bacteria-derived antigen, a fungi-derived antigen or a mold-derived antigen.
  • the antigen bound to the imaging-carrying bifunctional particle in the vaccine delivery system of the present invention is a virus-derived antigen, an antigen derived from human immunodeficiency virus (HIV), an antigen derived from human Papilloma viruses (HPV), an influenza virus derived Antigens, herpes virus derived antigens, hepatitis virus derived antigens or encephalitis virus derived antigens.
  • HIV human immunodeficiency virus
  • HPV human Papilloma viruses
  • influenza virus derived Antigens derived from human immunodeficiency virus
  • herpes virus derived antigens herpes virus derived antigens
  • hepatitis virus derived antigens or encephalitis virus derived antigens.
  • the antigen bound to the imaging-carrying bifunctional particle in the vaccine delivery vehicle of the present invention is a plant-derived antigen or an animal-derived antigen, it preferably includes an antigen that causes allergy.
  • the antigen bound to the imaging-carrying bifunctional particle in the vaccine delivery agent of the present invention is an endogenous antigen, it preferably includes a cancer cell antigen, a cancer causing antigen or an autoimmune disease causing antigen.
  • the antigen bound to the imaging-carrying bifunctional particle in the vaccine delivery agent of the present invention is a synthetic (artificial) antigen, it preferably includes a drug antigen.
  • the antigen bound to the surface of the imaging-carrying bifunctional particle in the vaccine carrier of the present invention may be bound to molecules of various forms and properties.
  • the antigen bound to the surface of the imaging-carrying bifunctional particle in the vaccine carrier of the invention is a single stranded oligonucleotide or polynucleotide, a double stranded oligonucleotide or At least one antigen selected from the group consisting of polynucleotides, proteins, polypeptides, oligopeptides, lipids, lipoproteins, glycolipids, glycoproteins, proteoglycans, polysaccharides and lipopolysaccharides, more preferably polypeptides, One or more antigens selected from the group consisting of oligopeptides, proteins, lipoproteins and glycoproteins, even more preferably polypeptides or proteins.
  • adjuvant used in expressing a vaccine carrier in the present invention refers to a substance called an adjuvant or an adjuvant, and more specifically, a lot of antibodies can be generated by the immune system by increasing the response to the vaccine. It means a substance to make.
  • the adjuvant is primarily involved in innate immune, but dendritic cells and macrophages that are involved in endogenous immunity secrete chemokines and only cells involved in endogenous immunity. Rather, even the cells involved in adaptive immune are called into the infected area, so the adjuvant also engages in acquired immunity, leading to memory immunity. In addition, by adding an adjuvant to recognize that the immune system is infected with bacteria, dendritic cells, lymphocytes and macrophages recognize the components of the bacteria and are activated to activate the innate immunity.
  • the present invention may further comprise an adjuvant or an immunomodulator to effectively enhance immune activity.
  • the present invention further comprises an adjuvants.
  • the adjuvant is preferably bound to the surface of the antigen or imaging-carrying bifunctional particle, more preferably, is covalently bound to the surface of the antigen or imaging-carrying bifunctional particle, even more preferred. Preferably it is covalently bonded to the surface of the imaging-carrying bifunctional particle.
  • the immunoadjuvant additionally included in the vaccine carrier of the present invention in the present invention may be combined molecules of various forms and properties.
  • the adjuvant in the present invention CpG oligodeoxynucleotide, unmethylated cystein-phosphate-guanine DNA (DCP), double-stranded RNA, microorganism-derived DNA or RNA, nucleic acid derivatives, Lipids, lipopolysaccharides, lipoproteins, lipopeptides, glycolipids, peptidoglycans, glycopeptides, proteins, recombinant proteins, flagellin, virosomes, Ribi (monophosphoryl-lipid A / trehalose dicorynomycolate) And one or more immunoadjuvant selected from the group consisting of saponins and squalene squalene, nucleic acid derivatives, aluminum salts, calcium salts, complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA), more preferably Preferably CpG oligodeoxynucleotides, unmethylated cystein-phosphate-guanine
  • the vaccine carrier of the present invention selectively delivers antigen to lymph nodes.
  • Lymph nodes are a major defense against infection and also act as a pathway in the metastasis of malignant tumors. Therefore, the selective delivery of the antigen to the lymph nodes by the vaccine carrier of the present invention shows that the vaccine carrier of the present invention can induce an immune response very effectively in vivo.
  • the delivery vehicle of the vaccine of the present invention can be traced by CT imaging or MRI imaging.
  • CT imaging or MRI imaging is performed after a predetermined time, it is possible to confirm whether the vaccine delivery agent of the present invention is properly transferred to the lymph nodes. This feature also greatly increases the usefulness of the vaccine carrier of the present invention.
  • the invention provides a composition comprising: (a) gold nanoparticles or magnetic nanoparticles as imaging-carrying bifunctional particles for imaging and conveying action; And (b) provides a vaccine pharmaceutical composition for cancer comprising a cancer antigen bound to the surface of the imaging-carrying bifunctional particles.
  • the vaccine pharmaceutical composition for anticancer in the present invention is a composition comprising the vaccine carrier, the common content between the two is omitted in order to avoid excessive complexity of the present specification.
  • Cancer antigens used in the pharmaceutical compositions of the present invention are P91A, p53, p21 ras , P210, BTA, P198, P1A, gp100, TAG-72, PSMA, G250, Her-2 / neu, CTKA-4, hTERT, VEGF, VEGF-A, MART-1-4, BAGE 1-3, melan-A (MART-1 (Melanoma Antigen Recognized by T cells)), SSX-2, SSX-4, mucin, MAGE-1, MAGE-2, MAGE-3, NY-ESO-1, LAGE, carcinoembryonic antigen (CEA), PRAME, mesothelin, PLK1, GP100 (PMel17), GAGE-1, PSA, PSCA, SAGE and SCP-1 It is not.
  • the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like It doesn't happen.
  • the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
  • a lubricant e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, a kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mann
  • the pharmaceutical composition of the present invention may be administered orally or parenterally, and is preferably applied by parenteral administration.
  • Suitable dosages of the pharmaceutical compositions of the present invention may vary depending on factors such as the formulation method, mode of administration, age, weight, sex, morbidity, condition of food, time of administration, route of administration, rate of excretion and response to response of the patient. Can be. Typical dosages of the pharmaceutical compositions of the invention are in the range of 0.001-100 mg / kg on an adult basis.
  • compositions of the present invention may be prepared in unit dose form by formulating with a pharmaceutically acceptable carrier and / or excipient according to methods which can be easily carried out by those skilled in the art. Or may be prepared by incorporation into a multi-dose container.
  • the formulation may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of extracts, powders, powders, granules, tablets or capsules, and may further comprise dispersants or stabilizers.
  • the vaccine carrier of the present invention effectively induces an immune response because it selectively transports antigens to the lymph nodes, and moreover, since the lymph nodes play a role in the metastasis of malignant tumors, the anticancer vaccine composition of the present invention is a cancer Very effective in the treatment of
  • the present invention provides a vaccine carrier comprising a gold nanoparticle and an antigen, and a vaccine pharmaceutical composition for anticancer.
  • the present invention shows little toxicity and side effects on in vivo and can induce high antibody production even when used with antigens with low antigenicity.
  • the present invention can significantly induce and enhance humoral mediated immune responses (Th1) and cell mediated immune responses (Th2) in vivo by effectively delivering and presenting antigens to immune cells and enhancing these effects. Through this, it is possible to prevent and treat immunity to antigens causing various diseases and diseases.
  • the vaccine carrier of the present invention selectively delivers antigen to lymph nodes. Due to this property, the vaccine carrier of the present invention can induce an immune response very effectively in vivo.
  • Figure 1a-1c is a result of measuring the size of the GNP, GNP-RFP and GNP-CpG-RFP in the present invention using an ELS 8000 device.
  • the size of nanoparticles after GNP, GNP-RFP, and GNP-CpG-RFP administration was confirmed to be 7.3 nm, 13.7 nm, and 24.3 nm, respectively.
  • Figure 2 is a result of measuring the content of gold nanoparticles in the local leaf nodes after administration of GNP-RFP prepared in the present invention to C57BL / 6 mice. Over time, it was found that the content of GNP-RFP increased in local lymph nodes (superficial groin lymph nodes and popliteal lymph nodes).
  • Figures 3a-3b was confirmed by silver staining after the administration of GNP-RFP to C57BL / 6 mice by silver staining and also by immunostaining which immune cells capture gold nanoparticles.
  • cytokines are markedly expressed in C57BL / 6 mouse immune cells mixed with GNP-RFP or GNP-CpG-RFP.
  • Figure 6 in the present invention administered negative control (PBS), RFP, positive control (Alum-RFP), GNP-RFP and GNP-CpG-RFP three times a week intervals (12 ⁇ g antigen / mouse) to C57BL / 6 mice
  • the expression pattern of RFP-specific antibody in mouse serum was confirmed by ELISA. It was confirmed that RFP-specific antibodies were highly generated in the mouse serum administered with GNP-RFP and GNP-CpG-RFP.
  • Figure 7 is a negative control group (PBS), RFP, GNP-RFP and GNP-CpG-RFP in the present invention administered to C57BL / 6 mice three times a week intervals (12 ⁇ g antigen / mouse), the immune cells in local lymph nodes (CD8 T-cell memory) were isolated and stimulated to measure the amount of interferon gamma (IFN- ⁇ ) expressed from immune cells.
  • PBS negative control group
  • RFP RFP
  • GNP-RFP GNP-RFP
  • GNP-CpG-RFP GNP-CpG-RFP in the present invention administered to C57BL / 6 mice three times a week intervals (12 ⁇ g antigen / mouse), the immune cells in local lymph nodes (CD8 T-cell memory) were isolated and stimulated to measure the amount of interferon gamma (IFN- ⁇ ) expressed from immune cells.
  • IFN- ⁇ interferon gamma
  • FIG. 8 shows immune cells (CD8 T-cell memory) in local lymph nodes after administration of C57BL / 6 mice (12 ⁇ g antigen / mouse) of negative control (PBS), RFP, GNP-RFP and GNP-CpG-RFP in the present invention. ) Were isolated and stimulated with RFP to immune cells, and IFN- ⁇ -expressing immune cells were examined by FACS. In the GNP-RFP-administered group, 22.66% and 28.92% in the GNP-CpG-RFP-administered group were identified as immune cells expressing IFN- ⁇ .
  • naive T cells by separating immune cells from local lymph nodes after administration of C57BL / 6 mice (12 ⁇ g antigen / mouse) of negative control group (PBS), RFP, GNP-RFP and GNP-CpG-RFP in the present invention. This is the result of the FACS investigation. GNP-RFP and GNP-CpG-RFP administration group showed lower naive T cell count (distribution) than the negative control group.
  • Figure 10 after the administration of the negative control group (PBS), RFP, GNP-RFP and GNP-CpG-RFP in C57BL / 6 mice, isolating immune cells from local lymph nodes regulatory T cells (Treg) This is the result of checking the number of. As a result of confirming the number of regulatory T cells (Treg) expressing Foxp3 using the Foxp3 antibody, the number of regulatory T cells in the GNP-RFP and GNP-CpG-RFP-administered groups was compared with those of the negative control group. Little difference was found.
  • FIG. 11 is a negative control group (PBS), GNP-RFP and GNP-CpG-RFP in the present invention, after administration of C57BL / 6 mice, isolating immune cells from local lymph nodes, separating only T cells and stimulating with RFP. This is the result of confirming the proliferation of cells. Unlike the negative control group in the GNP-RFP and GNP-CpG-RFP administration group, it was confirmed that T cells proliferate depending on the RFP concentration.
  • FIG. 12 shows B16F10-RFP cancer after one week (0 day) after immunizing negative control group (PBS), GNP, RFP, GNP-RFP, and GNP-CpG-RFP three times a week at C57BL / 6 mice The result of observing the growth of cancer after administration of the cells. In the group immunized with GNP-RFP, cancer growth was delayed for about a month.
  • PBS negative control group
  • FIG. 13 shows B16F10-RFP cancer after one week (0 day) after immunizing negative control group (PBS), GNP, RFP, GNP-RFP and GNP-CpG-RFP to C57BL / 6 mice three times a week apart This is a result of comparing the survival rate of mice after administration of the cells.
  • the group that immunized with GNP-RFP was found to have a 60-day longer survival compared to the negative control group.
  • Figure 14 in the present invention after immunizing the control group (PBS), GNP, RFP, GNP-RFP and GNP-CpG-RFP three times a week at C57BL / 6 mice, do not express RFP after a week (0 day) Cancer growth after administration of B16F10 cancer cells. As a result, it was confirmed that the size of the cancer grows similarly in all experimental groups. These results confirm that GNP conjugates induce RFP specific immune responses.
  • Figure 15 shows the negative control group (PBS), GNP, RFP, GNP-RFP and GNP-CpG-RFP when the size of the cancer after administration of B16F10-RFP cancer cells to C57BL / 6 mice in the present invention
  • PBS negative control group
  • FIG. 16 is a mucin peptide specific in mouse serum after immunizing negative control group (PBS), CGG Mucin peptide, CAL Mucin peptide, GNP- CGG MUC and GNP- CAL MUC three times a week at C57BL / 6 mice This is a comparison result confirming the expression pattern of the antibody by ELISA. As a result, it was confirmed that many mucin-specific antibodies covalently bound to mucin peptides were produced.
  • PBS positive control group
  • Figure 17 is a negative control group (PBS), CGG Mucin peptide, CAL Mucin peptide, GNP- CGG MUC and GNP- CAL MUC immunized three times a week intervals in C57BL / 6 mice, a week later (0 day)
  • B16F1-mucin cancer cells expressing mucin protein were subcutaneously administered to the animals of each experimental group to observe the growth of cancer.
  • the experimental group administered gold nanoparticles significantly inhibited cancer growth compared to the negative control.
  • Figure 18 is a negative control group (PBS), CAL Mucin peptideGNP, and GNP- CAL MUC immunized three times a week to C57BL / 6 mice in the present invention, B16F1-mucin cancer cells were administered subcutaneously of experimental animals It is a result of comparing survival rate.
  • the group immunized with GNP- CAL MUC was found to have a longer survival rate compared to the negative control group.
  • 20A-20C show the results of measuring the size of ELS 8000 after the preparation of RFP-magnetic nanoparticles.
  • Figure 21 shows the antibody induced analysis by RFP-magnetic nanoparticles.
  • % used to refer to the concentration of a particular substance is (weight / weight)% solids / solid, (weight / volume)%, and liquid / Liquid is (volume / volume)%.
  • Gold nanoparticles were synthesized as follows: Milli-Q water (150 mL) solution containing 2.2 mM sodium citrate was placed in a 250 mL round-bottom flask and heated. The mixture was heated to reflux for 15 minutes with vigorous stirring using mantel. After boiling, 1 ml of HAuCl 4 at a concentration of 23.4 mM was injected. The prepared particles were stabilized with negatively charged citrate ions and the stabilized particles were suspended.
  • the gene encoding the RFP was amplified using a polymerase chain reaction (PCR) from a pDSRed2_C1 vector (clontech, Palo Alto, USA) containing all DNA sequences of DsRed. All molecular biology experiments were conducted following standard protocols (Molecular Cloning, Cold Spring Harbor, New York). Forward primer 5-ATAGAAA to bind two cysteines (marked codons in bold in reverse primer) at C-terminus CATATG GCCTCCTCCGAGAAC-3 and Reverse Primer 5-ATA CTCGAG TTA ACAACA CAGGAACAGGTG-3 was designed (Genotech, South Korea).
  • PCR polymerase chain reaction
  • PCR products were purified using a DNA purification kit (GeneAll, South Korea), and the restriction enzyme having an underlined site in the primer Nde I (NEB, Ipswich, MA) Xho Cuts were made using I (NEB, Ipswich, Mass.).
  • the cleaved DNA fragments were linked to the pET28b (Novagen, Northumberland, UK) vector. Plasmids prepared for expressing proteins Escherichia coli Strain (DE3; Novagen, Northumberland, UK) was transformed. 1 mM IPTG (isopropyl ⁇ -D-thiogalactopyranoside; Sigma, St. Louis, MO) was treated at 37 ° C. for 6 hours to induce transformants by the strain.
  • lysis buffer 50 mM sodium phosphate containing pH 8.0, 300 mM NaCl and 5 mM imidazole
  • Cell lysates were centrifuged at 1,550 g at 4 ° C. for 1 hour.
  • Suspension was placed in a gravity flow column (BioRad, Hercules, CA) filled with Ni-NTA affinity resin (Peptron, Daejeon, Korea) pre-equilibrated with Lysis buffer (3 ml bad volume per liter of medium). .
  • RFP was extracted using a 50 mM sodium phosphate (pH 8.0) solution containing 300 mM NaCl and 300 mM imidazole. Fractions containing RFP were collected using a Superdex 200 column (Amersham Pharmacia, Bucks, UK) pre-equilibrated with PBS (phosphate-buffered saline; pH 7.4) solution and the proteins were further purified.
  • PBS phosphate-buffered saline; pH 7.4
  • Gold particles stabilized with 10 nm citrate were synthesized as described above.
  • the synthesized gold particles were then modified with two cysteine modified RFP proteins or thiol modified A10-CpG1668 sequences. That is, in the case of RFP-GNP, a water-soluble protein solution (200 mL; 200 mg / mL) was added to a final concentration of 4 ⁇ M gold nanoparticle solution, followed by stirring at room temperature for 24 hours. In the case of RFP-CpG-GNP, a water-soluble protein solution (200 mL; 200 mg / mL) was added to a final concentration of 4 ⁇ M gold nanoparticle solution, followed by stirring at room temperature for 1 hour.
  • thiol modified A10-CpG1668 sequence (5 nmole) was added to the RFP-GNP solution and stirred for 23 hours at room temperature. Centrifugation (20,000 x g, 30 minutes) was used to remove excess protein and DNA oligos from the nanoparticles.
  • the hydrodynamic particle size of GNP dispersed in distilled water was measured using ELS 8000 (Otsuka Electronics Korea, Seoul, Korea).
  • the morphology and dispersibility of GNP was measured by transmission electron microscopy (TEM) using Philips TECNAI F20 (Philips Electronic Instrument Corp., Mahwah, NJ) operating at 200 kV.
  • Plasmon uptake of GNP was measured by UV-vis spectrophotometry using NEOSYS-2000 (Sinco, Daejeon, Korea).
  • the size of the nanoparticles after GNP conjugation was found to be 7.3 nm for GNP, 13.7 nm for GNP-RFP, and 24.3 nm for GNP-RFP-CpG (FIGS. 1A-1C).
  • PET / SPECT / CT system (Inveon TM; Siemens Preclinical Solutions, Knoxville, TN) was used. Images were taken at 60 kVp X-ray voltage, 500 ⁇ A anodic current, and 500 millisecond exposure time for each 360 rotational step. One bed position was scanned for 7 minutes to get the whole body of C57BL / 6 mice. The second order slice of each bed position was reconstructed using the modified Feldkamp algorithm with a ramp filter.
  • the image was reconstructed on a 512 x 512 pixel grid with a 50 x 50 ⁇ m pixel size.
  • the system was calculated using 50-mL polypropylene tubes containing water as described in the Inveon TM Instruction Manual.
  • the resolution of the reconstructed image was 111 ⁇ m.
  • CT data for the target area were analyzed using HUs.
  • LPS Lipopolysaccharides; 10 ng / ml
  • a 10 CpG 1668 10 ⁇ M
  • GNP 8 nM
  • GNP-RFP 8 nM
  • GNP-CpG-RFP 8 nM
  • RNAs were extracted using Welprep TM (Jeil Biotechservices Inc., Daegu, Korea). 1 ⁇ g of total RNA was reverse transcribed with UmProm-II reverse transcriptase (Promega) and amplified with MJ Mini TM PCR system (Bio-Rad, Hercules, CA).
  • IL-6 5-TTCCTCTCTGCAAGAGACT-3, 5-TGTATCTCTCTGAAGGACT-3; Actin, 5'-TCATGAAGTGTGACGTTGACATCCGT-'3,5'-TTGCGGTGCACGATGGAGGGGCCGGA-'3; IL-12p40, 5'-GAAGTTCAACATCAAGAGCAGTAG-'3, 5'-AGGGAGAAGTAGGAATGGGG-30; IL-1 ⁇ , 5'-CCTGTGGCCTTGGGCCTCAA-'3, 5'-GAGGTGCTGATGTACCAGTTGG-'3; TNF- ⁇ , 5'-AAAATTCGAGTGACAAGCCTGTAG-'3, 5'-CCCTTGAAGAGAACCTGGGAGTAG-'3; iNOS2, 5'-GATGTTGAACTATGTCCTATCTCC-'3, 5'-AACACCACTTTCACCAAGAC-'3.
  • mice C57BL / 6 mice were immunized with boosters (PBS, RFP, GNP-RFP, and GNP-RFP-CpG) on the soles of boosters on days 1, 8 and 15.
  • boosters PBS, RFP, GNP-RFP, and GNP-RFP-CpG
  • T-cells were isolated from draininig lymph nodes and na ⁇ ve T-cell counts were examined using FACs analysis (using naive T-cell markers CD62L and CD45RB).
  • the GNP conjugate administration group showed less naT cell distribution compared with the negative control group (FIG. 9).
  • mice C57BL / 6 mice were immunized with boosters (PBS, RFP, GNP-RFP, and GNP-RFP-CpG) on the soles of boosters on days 1, 8 and 15.
  • boosters PBS, RFP, GNP-RFP, and GNP-RFP-CpG
  • T-cells were isolated from draining lymph nodes and exposed to various concentrations of trypsinized RFP, followed by heat-inactivated T-cell medium containing 10% (vol / vol) FBS (HyClone). T-cells were incubated for 5672 hours in 96-well plates with flat bottoms. After 5672 hours of T-cell incubation, 0.5 ⁇ Ci of NEN ([H 3 ] -thymidine) was added to each well and further incubated for 16 hours. After the cultured cells were recovered, [H 3 ] -thymidine uptake was measured using liquid scintillation counting.
  • C57BL / 6 mice were immunized by injecting PBS, RFP, GNP-RFP and GNP-RFP-CpG into the soles on days 1, 8 and 15.
  • PBS PBS
  • RFP GNP-RFP
  • GNP-RFP-CpG GNP-RFP-CpG
  • B16F10 cells 5 ⁇ 10 5 cells / mouse
  • wild type B16F10 cells 5 ⁇ 10 5 cells / mouse
  • GNP conjugates were immunized three times a week at mice and cancer growth was observed after administration of B16F10 cancer cells that did not express RFP. As a result, it was confirmed that the growth of cancer in all the experimental groups similarly (Fig. 14). From these results, it was concluded that GNP conjugates induce RFP specific immune responses.
  • mice 6-week-old female C57BL / 6 mice were injected subcutaneously with 5 ⁇ 10 5 transformed B16F10 cells delivered to the dorsal flank on day 0. On day 10, mice were randomly divided into groups when tumors became more than 30 mm 3 and PBS, RFP, GNP-RFP, and GNP-RFP-CpG at various concentrations in the dorsal region at 10, 13, 16, 21 and 26 days. Tumor size was observed after injection.
  • the group administered with the GNP conjugate showed a more delayed growth of cancer compared to the negative control (FIG. 15).
  • CAL-mucin CALNN PDTRPAPGSTAPPAHGVTSA PDTRPAPGST; CGG-mucin: CGGGG PDTRPAPGSTAPPAHGVTSA PDTRPAPGST. (Anigen, South Korea)
  • mucin antigen peptides were dissolved in distilled water at a concentration of 10 mM and mixed with 6 ⁇ M gold nanoparticles (GNP). Then, the mixture was covalently bonded to the gold nanoparticles with mucin peptides by reaction covalent bonding at room temperature for 24 hours, and then confirmed whether the covalent bonds with the gold nanoparticles by UV and visible spectroscopy. Mucin peptides were quantified.
  • mice were administered to the soles of mice three times at weekly intervals, and 7 days later, B16F1-mucin cancer cells expressing mucin protein to the animals of each experimental group were administered subcutaneously to the experimental animals. Observed.
  • GNP conjugates were immunized three times a week at mice, followed by cancer growth after administration of B16F1 cancer cells that did not express mucin. As a result, it was confirmed that the growth of cancer in all the experimental groups similarly (Fig. 19). These results led to the conclusion that GNP conjugates induce mucin specific immune responses.
  • FIG. 20a is for G1 of Table 5 below and 34.2 ⁇ 7.5 nm particle size
  • FIG. 20b is for G2 of Table 5 below and 32.4 ⁇ 6.4 nm particle size
  • FIG. 20c is for G3 of Table 5 below, 34 ⁇ 6.7 nm particle size.
  • Serum samples were obtained from C57BL / 6 mice immunized three times each at three weekly intervals using physiological saline, RFP (12 ⁇ g / mouse) and magnetic nanoparticle-RFP (12 ⁇ g / mouse).
  • Anti-RFP antibody in serum was analyzed using ELISA (anti-mouse IgG-HRP, San Cruz Biotechnology, Inc.). As a result, it was confirmed that high antibody was produced in the serum of the group treated with magnetic nanoparticle-RFP. (FIG. 21).

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Abstract

La présente invention porte sur une nanoparticule d'or ou sur une nanoparticule magnétique en tant que particule ayant une fonction double d'imagerie-administration pour des effets d'imagerie et d'administration, un système d'administration de vaccin contenant un antigène, un vaccin anticancéreux et une composition pharmaceutique à base de vaccin anticancéreux. La présente invention montre rarement de toxicité in vivo et d'effets secondaires, et peut induire un taux de génération d'antigène élevé même lorsqu'elle est utilisée avec un antigène ayant une faible antigénicité. En outre, la présente invention administre et présente efficacement l'antigène à un immunocyte, permettant ainsi d'induire et d'améliorer significativement une réponse immunitaire humorale (Th1) in vivo et une réponse immunitaire cellulaire (Th2), et par l'intermédiaire de tels effets, permet une immunoprophylaxie et une immunothérapie à l'encontre d'antigènes provoquant différentes pathologies et différentes maladies.
PCT/KR2011/009553 2011-04-19 2011-12-12 Système d'administration de vaccin à base de nanoparticules ayant des fonctions doubles d'imagerie et d'administration Ceased WO2012144716A1 (fr)

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KR102685034B1 (ko) * 2022-05-17 2024-07-16 주식회사 엔이에스바이오테크놀러지 금속 나노 입자-핵산 결합체를 기반으로 하는 유전자 운반체

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