WO2006095936A1 - Particules nanohybrides pour diagnostic et traitement de tumeurs - Google Patents

Particules nanohybrides pour diagnostic et traitement de tumeurs Download PDF

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Publication number
WO2006095936A1
WO2006095936A1 PCT/KR2005/000758 KR2005000758W WO2006095936A1 WO 2006095936 A1 WO2006095936 A1 WO 2006095936A1 KR 2005000758 W KR2005000758 W KR 2005000758W WO 2006095936 A1 WO2006095936 A1 WO 2006095936A1
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diagnosing
nanohybrid
treating tumors
particle
region
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PCT/KR2005/000758
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English (en)
Inventor
Yong Min Huh
Jin Suck Suh
Jin Woo Cheon
Ho Taek Song
Young Wook Jun
Jae Hyun Lee
Jin Sil Choi
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Yonsei University
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Publication of WO2006095936A1 publication Critical patent/WO2006095936A1/fr

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    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F01—MACHINES OR ENGINES IN GENERAL; ENGINE PLANTS IN GENERAL; STEAM ENGINES
    • F01N—GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR MACHINES OR ENGINES IN GENERAL; GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR INTERNAL COMBUSTION ENGINES
    • F01N3/00—Exhaust or silencing apparatus having means for purifying, rendering innocuous, or otherwise treating exhaust
    • F01N3/02—Exhaust or silencing apparatus having means for purifying, rendering innocuous, or otherwise treating exhaust for cooling, or for removing solid constituents of, exhaust
    • F01N3/04—Exhaust or silencing apparatus having means for purifying, rendering innocuous, or otherwise treating exhaust for cooling, or for removing solid constituents of, exhaust using liquids
    • 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
    • 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
    • A61K49/10—Organic compounds
    • A61K49/14—Peptides, e.g. proteins
    • A61K49/16—Antibodies; Immunoglobulins; Fragments thereof
    • 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
    • A61K49/1833—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 having a (super)(para)magnetic core coated or functionalised with a small organic molecule
    • 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
    • A61K49/1851—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 having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
    • A61K49/1857—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 having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA
    • A61K49/186—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 having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA the organic macromolecular compound being polyethyleneglycol [PEG]
    • 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
    • A61K49/1875—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 coated or functionalised with an antibody
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D47/00—Separating dispersed particles from gases, air or vapours by liquid as separating agent
    • B01D47/02—Separating dispersed particles from gases, air or vapours by liquid as separating agent by passing the gas or air or vapour over or through a liquid bath
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F01—MACHINES OR ENGINES IN GENERAL; ENGINE PLANTS IN GENERAL; STEAM ENGINES
    • F01N—GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR MACHINES OR ENGINES IN GENERAL; GAS-FLOW SILENCERS OR EXHAUST APPARATUS FOR INTERNAL COMBUSTION ENGINES
    • F01N13/00—Exhaust or silencing apparatus characterised by constructional features ; Exhaust or silencing apparatus, or parts thereof, having pertinent characteristics not provided for in, or of interest apart from, groups F01N1/00 - F01N5/00, F01N9/00, F01N11/00
    • F01N13/12—Exhaust or silencing apparatus characterised by constructional features ; Exhaust or silencing apparatus, or parts thereof, having pertinent characteristics not provided for in, or of interest apart from, groups F01N1/00 - F01N5/00, F01N9/00, F01N11/00 specially adapted for submerged exhausting

Definitions

  • the present invention relates to nanohybrid particles. More particularly, the present invention relates to nanohybrid particles for diagnosing or treating tumors, in which nanoparticles are surrounded by a multifunctional ligand comprising an attachment region, a cross-linking region, and an active ingredient-binding region, wherein the cross-linking region of the multifunctional ligand is cross- linked with a cross-linking region of another multifunctional ligand, and the active ingredient-binding region is bound to a substance capable of specifically binding to a tumor marker, a diagnostic or therapeutic composition comprising the nanohybrid particles, and a diagnostic or therapeutic method using the composition.
  • Nanoparticles have been used in the biotechnology field for tumor cell-specific killing, immune response boosting, cell fusion, gene or drug delivery, diagnosis, and the like.
  • nanoparticles should possess a region providing an attachment site to an active ingredient, as well as being well transported and dispersed in vivo, that is, in an aqueous environment.
  • a variety of techniques have been developed in the art in order to satisfy such requirements.
  • U.S. Pat. No. 6,274,121 discloses superparamagnetic particles, which consist of superparamagnetic one-domain particles and aggregates of superparamagnetic one-domain particles to whose surfaces are bound inorganic and organic substances including binding sites for coupling to tissue-specific binding substances, diagnostic or pharmacologically active substances.
  • U.S. Pat No. 6,649,138 discloses a method of preparing nanoparticles having enhanced water-solubility by forming a coating of multiple amphipathic dispersants on the surface of a nanoparticle being composed of a semiconductive or metallic material.
  • the amphipathic dispersants include (1) a hydrophobic backbone having hydrophilic branches, (2) a hydrophilic backbone having hydrophobic branches, or (3) a hydrophobic or hydrophilic backbone having both hydrophilic and hydrophobic branches.
  • U.S. Pat. Application No. 2003/0092029 discloses nanoparticles containing a binding moiety, which is an oligonucleotide, polypeptide or polysaccharide.
  • the nanoparticles may be used for detecting target molecules, such as nucleic acids or proteins, in vitro, or as magnetic resonance (MR) contrast agents to diagnose diseases in vivo.
  • target molecules such as nucleic acids or proteins
  • MR magnetic resonance
  • the nanoparticles described in U.S. Pat. No. 6,274,121 and U.S. Pat. Application No. 2003/0092029, are synthesized in an aqueous solution. In this case, however, it is difficult to control the size of the nanoparticles, and the nanoparticles thus synthesized have non-uniform size distribution. Also, since the nanoparticles are synthesized at low temperature, they have poor crystallizability and tend to form non-stoichiometric compounds. Further, since the surface of the nanoparticles is coated with a single surface stabilizer having a low binding affinity for the nanoparticles, the nanoparticles have low stability in an aqueous solution.
  • nanoparticles unstable in aqueous media as described above, do not diffuse or disperse well in vivo, it takes a long time to diagnose diseases, and when such nanoparticles form aggregates, they cannot penetrate deeply enough into tissues but may remain in sites other than diseased sites, leading to misdiagnosis.
  • International Pat. Publication No. WO01/56546 relates to a composition comprising magnetoliposome for treating a target site of a biological tissue, and a treatment method using the composition.
  • the treatment method includes administering the composition containing magnetoliposome to a target site, chosen through a separate diagnosis, and applying an electromagnetic field to the target site to concentrate the magnetoliposomes in the target site, thereby selectively treating only target sites.
  • this prior art is inconvenient in practice because the diagnosis and treatment are performed separately.
  • the present inventors prepared nanohybrid particles for tumor diagnosis by binding a substance capable of binding to a tumor marker to an active ingredient-binding region of water-soluble nanoparticles, which are stable in aqueous media and thus disperse and difiuse well, and found that the nanohybrid particles are capable of accurately and effectively diagnosing tumors and also selectively treating only tumor sites, thereby leading to the present invention.
  • the present invention provides nanohybrid particles for diagnosing or treating tumors, in which nanoparticles are surrounded by a multifunctional ligand comprising an attachment region, a cross-linking region and an active ingredient-binding region, wherein the cross-linking region of the multifunctional ligand is cross-linked with a cross-linking region of another multifunctional ligand, and the active ingredient-binding region is bound to a substance capable of specifically binding to a tumor marker.
  • the present invention provides a composition for diagnosing or treating tumors, comprising the nanohybrid particles and a pharmaceutically acceptable carrier.
  • the present invention provides a method of diagnosing or treating tumors, comprising (1) injecting the composition for diagnosing or treating tumors into a body or a specimen; (2) diagnosing the presence of tumors by sensing a signal emitted by the nanohybrid particles from the body or the specimen; and optionally (3) selectively killing identified tumor cells.
  • FIG. 1 is a schematic presentation of a process for preparing nanohybrid particles for diagnosing or treating tumors, according to the present invention, and of tumor diagnosis using the nanohybrid particles;
  • FIG. 2 illustrates various aspects of nanohybrid particles for diagnosing or treating tumors according to the present invention
  • FIG. 3 shows the results of dynamic laser light scattering (DLS) analysis for detecting nanohybrid particles formed by binding Herceptin to water-soluble iron oxide nanoparticles;
  • DLS dynamic laser light scattering
  • FIG. 4 shows the results of flow cytometry, indicating that nanohybrid particles according to the present invention selectively bind to cells expressing a breast cancer marker antigen in vitro (the expression of the breast cancer marker antigen increased in the following order: control ⁇ 1. Bx-PC3 cells ⁇ 2. MDA-MB-231 cells ⁇ 3. BT-474 cells ⁇ 4. MH3T6.7 cells);
  • FIG. 5 shows the results of magnetic resonance (MR) imaging, indicating that nanohybrid particles according to the present invention selectively bind to cells expressing a breast cancer marker antigen in vitro (the expression of the breast cancer marker antigen increased in the following order: control ⁇ 1. Bx-PC3 cells ⁇ 2. MDA-MB-231 cells ⁇ 3. BT-474 cells ⁇ 4. NIH3T6.7 cells);
  • FIG. 6 shows the results of MR imaging, indicating that nanohybrid particles according to the present invention selectively bind to cells expressing a breast cancer marker antigen in vivo;
  • FIG. 7 shows the results of immunohistological staining, indicating that nanohybrid particles according to the present invention selectively bind to cells expressing a breast cancer marker antigen in vivo
  • FIG. 8 shows the results of MR imaging, indicating that nanohybrid particles according to the present invention selectively bind to cells expressing an ovarian cancer marker receptor in vitro
  • FIG. 9 is a graph showing that nanohybrid particles according to the present invention selectively kill cells expressing a breast cancer marker antigen.
  • water-soluble nanoparticles refers to particles in which nanoparticles are surrounded by a multifunctional ligand comprising an attachment region, a cross- linking region and an active ingredient-binding region, the cross-linking region of the multifunctional ligand being cross-linked with a cross-linking region of another multifunctional ligand.
  • the water- soluble nanoparticles are stable, particularly in an aqueous environment.
  • nanoparticles refers to particles that comprise a magnetic material, a magnetic alloy material, or a multicomponent hybrid construct containing the magnetic material and the magnetic alloy material, and that are 1 nm to 1 ,000 ran, and preferably 2 ran to 100 nm, in diameter.
  • magnetic materials include Co, Mn, Fe, Ni, Gd, MM 2 O 4 , and M x O y (M or
  • M Co, Fe, Ni, Mn, Zn, Gd, Cr, 0 ⁇ x ⁇ 3, 0 ⁇ y ⁇ 5).
  • magnetic alloy materials include
  • the multicomponent hybrid construct indicates a particle containing two or more components selected from the magnetic materials and the magnetic alloy materials.
  • Multifunctional ligand refers to a substance that comprises (a) an attachment region, (b) a cross-linking region and (c) an active ingredient-binding region.
  • an attachment region a substance that comprises (a) an attachment region, (b) a cross-linking region and (c) an active ingredient-binding region.
  • attachment region means a portion, preferably a terminus, of the multifunctional ligand, which includes a functional group capable of attaching to nanoparticles.
  • the attachment region preferably includes a functional group having high affinity to a substance of the nanoparticles, and may be selected depending on the substance of the nanopaticles.
  • the attachment region may include a functional group, for example, -COOH, -NH 2 , -SH, -CONH 2 , -PO 3 H, -PO 4 H, -SO 3 H, -SO 4 H or -OH.
  • cross-linking region means a portion, preferably a central portion, of the multifunctional ligand, which includes a functional group capable of cross-linking with another adjacent multifunctional ligand.
  • Cross linking indicates the binding of a multifunctional ligand to another adjacent multifunctional ligand through intermolecular interaction.
  • the type of intermolecular interaction e.g., hydrophobic interaction, hydrogen bond, covalent bond (e.g., disulfide bond), van der Waals force, ionic bond, etc.
  • the cross-linking region may include a functional group, for example, -SH, -NH 2 , -COOH, -OH, -epoxy, -ethylene or - acetylene.
  • the "active ingredient-binding region” means a portion of the multifunctional ligand, preferably a terminus located at the opposite side from the attachment region, which includes a functional group capable of binding to an active ingredient.
  • the functional group of the active ingredient-binding region may vary depending on the type and chemical formula of the active ingredient (see, Table 1).
  • the active ingredient-binding region may include - SH, -COOH, -NH 2 , -OH, -NR 4 4 X, -sulfonate, -nitrate, or -phosphonate, but the present invention is not limited to these examples.
  • Such water-soluble nanoparticles may be prepared according to the method described in Korean Pat Application No. 10-2004-0070303. The preparation method is incorporated herein by reference.
  • the present invention provides nanohybrid particles, which are prepared by binding a substance capable of diagnosing and/or treating tumors to the active ingredient-binding region of the water-soluble nanoparticles.
  • hybrid particles refers to particles in which nanoparticles are surrounded by a multifunctional ligand comprising an attachment region, a cross-linking region and an active ingredient-binding region, the cross-linking region of the multifunctional ligand being cross-linked with a cross-linking region of another multifunctional ligand, and the active ingredient-binding region being bound to a substance capable of specifically binding to a tumor marker.
  • the nanohybrid particles of the present invention may be usful for diagnosing and/or treating various types of cancer, for example, gastric cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchogenic cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, and cervical cancer.
  • cancer for example, gastric cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchogenic cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, and cervical cancer.
  • Such tumor cells express and/or secrete a specific substance, which is seldom or never produced in normal cells, and such a substance is generally called "a tumor marker".
  • a tumor marker Such tumor cells express and/or secrete a specific substance, which is seldom or never produced in normal cells, and such a substance is generally called "a tumor marker".
  • the nanohybrid particles which are prepared by binding a substance capable of specifically binding to such a tumor marker to the active ingredient-binding region of the water-soluble nanoparticles, may be useful for tumor diagnosis.
  • a variety of tumor markers and substances capable of specifically binding thereto are known in the art.
  • the substance capable of specifically binding to a tumor marker has identical meaning to the term "active ingredient”, and thus may be used interchangeably with the term "active ingredient”.
  • tumor markers may be classified into ligands, antigens, receptors, and encoding nucleic acids thereof according to action mechanisms (see, Table 2). TABLE 2
  • a substance capable of specifically binding to the ligand may be introduced as an active ingredient into the nanohybrid particles of the present invention.
  • a suitable substance is a receptor or an antibody capable of specifically binding to the ligand.
  • ligands and receptors capable of specifically binding thereto include, but are not limited to, C2 of synaptotagmin and phosphatidylserine, annexin V and phosphatidylserine, integrin and its receptor, vascular endothelial growth factor (VEGF) and its receptor, angiopoietin and Tie2 receptor, somatostatin and its receptor, and vasointestinal peptide and its receptor.
  • C2 of synaptotagmin and phosphatidylserine include, but are not limited to, C2 of synaptotagmin and phosphatidylserine, annexin V and phosphatidylserine, integrin and its receptor, vascular endothelial growth factor (VEGF) and its receptor, angiopoietin and Tie2 receptor, somatostatin and its receptor, and vasointestinal peptide and its receptor.
  • VEGF vascular endothelial growth factor
  • a substance capable of specifically binding to the antigen may be introduced as an active ingredient into the nanohybrid particles of the present invention.
  • a suitable substance is an antibody capable of specifically binding to the antigen.
  • antigens and antibodies capable of specifically binding thereto, useful in the present invention include, but are not limited to, carcinoembryonic antigen (large intestine marker antigen) and Herceptin (Genentech, USA), HER2/neu antigen (breast cancer marker antigen) and Herceptin, and prostate-specific membrane antigen (prostate cancer marker antigen) and Rituxan (TDCE/Genentech, USA).
  • a representative example of suitable receptors for use as the tumor marker is folic acid receptor, which is expressed in ovarian carcinoma cells.
  • a substance capable of specifically binding to the receptor may be introduced as an active ingredient into the nanohybrid particles of the present invention.
  • a suitable substance is a ligand or an antibody capable of specifically binding to the receptor.
  • antibodies are particularly preferred active ingredients in the present invention.
  • antibodies have the ability to selectively and stably bind only to specific subjects, and -NH 2 of lysine, -SH of cysteine, and -COOH of aspartate and glutamate, which are present in the Fc region of antibodies, may be useful for binding to a functional group at the active ingredient-binding region of the water-soluble nanoparticles.
  • Such antibodies may be commercially available or may be prepared by any method known in the art. Generally, a mammal (e.g., mice, rats, goats, rabbits, horses or sheep) is immunized with a suitable amount of an antigen once more. When the antibody titer has reached a suitable level after a given period of time, sera are collected from the mammal. The recovered antibodies may be, if desired, purified using a known process, and may be stored in a freezing buffer solution until use. The details of such a method are well known in the art.
  • the nucleic acids include RNA and DNA encoding the aforementioned ligands, antigens, receptors, or portions thereof. Nucleic acids, as known in the art, form base-pairing between complementary sequences. Thus, a nucleic acid having a specific nucleotide sequence may be detected using another nucleic acid having a nucleotide sequence complementary to the nucleotide sequence. Nucleic acids having nucleotide sequences complementary to nucleic acids encoding the aforementioned enzymes, ligands, antigens and receptors may be used as active ingredients of the nanohybrid particles according to the present invention.
  • nucleic acids may be useful for binding to a functional group of the active ingredient-binding region because they have functional groups, such as -NH 2 , -SH and -COOH, at their 5'-end and 3'-end.
  • nucleotide acids may be synthesized by any standard method known in the art, for example using an automated DNA synthesizer (such as commercially available from Biosearch, Applied Biosystems, etc.).
  • phosphorothioate oligonucleotides may be synthesized using the method described in tie literature: Stein et al., Nucl. Acids Res. 1988, vol.16, p.3209.
  • Methylphosphonate oligonucleotides may be prepared using controlled glass polymer supports (Sarin et al., Proc. Natl. Acad. Sci. U.S.A. 1988, vol.85, p.7448).
  • the present invention provides a composition for diagnosing or treating tumors, comprising the nanohybrid particles according to the present invention and a pharmaceutically acceptable carrier.
  • the composition for diagnosing or treating tumors according to the present invention may be administered via any route commonly used in the medical field.
  • the present composition may be preferably administered parenterally, for example, via intravenous, intraperitoneal, intramuscular, subcutaneous, or topical routes.
  • the carrier used in the composition for diagnosing or treating tumors according to the present invention includes carriers and vehicles commonly used in the medical field.
  • Suitable pharmaceutically acceptable carriers for use in the present composition for diagnosing or treating tumors include, but are not limited to, ion exchange resin, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering agents (e.g., sodium phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of vegetable saturated fatty acids), water, salts or electrolytes (e.g., protamine sulfate, disodium hydrophosphate, potassium hydrophosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substrates, polyethylene glycol, sodium carboxymethylcellulose, polyarylate, waxes, polyethylene glycol, and wool fat.
  • the present composition for diagnosing or treating tumors may include, but are
  • the present composition for diagnosing or treating tumors may be formulated as aqueous solutions for parenteral administration.
  • a suitable buffer solution such as Hank's solution, Ringer's solution or physiologically buffered saline, may be employed.
  • Aqueous injection suspensions may be supplemented with substances capable of increasing viscosity of the suspensions, which are exemplified by sodium carboxymethylcellulose, sorbitol and dextran.
  • the present composition for diagnosing or treating tumors is preferably in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • a suspension may be formulated according to the methods known in the art, using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents.
  • the sterile injectable preparations may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents include mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • the present invention provides a method of diagnosing or treating tumors, comprising (1) injecting the composition for diagnosing or treating tumors according to the present invention into a body or a specimen; (2) diagnosing the presence of tumors by sensing a signal emitted by the nanohybrid particles from the body or the specimen; and optionally (3) selectively killing identified tumor cells.
  • the term "specimen” refers to a tissue or a cell which is isolated from a subject to be diagnosed. With such a diagnostic method for tumors, tumor diagnosis may be possible both in vivo and in vitro.
  • the signal emitted by the nanohybrid particles may be sensed using various equipment using a magnetic field, and such equipment may include magnetic resonance imaging (MRT) equipment.
  • MRT magnetic resonance imaging
  • MRI is a diagnostic device that produces images of body tissues.
  • MRI reading are as follows. First, the body is placed in a strong magnetic field, and electric waves of a specific frequency are then irradiated to the body, causing the atomic nuclei of certain atoms, such as hydrogen, in body tissues to absorb energy and enter a state of high energy. When the radiofrequency radiation is turned off, the atomic nuclei of atoms, such as hydrogen, release energy unique to the nuclei.
  • MRI magnetic or electric waves are not interrupted by the bone, MRI can construct clear three-dimensional cross-sectional images of areas surrounding the hard bone, or of tumors in the brain or bone marrow in certain angular positions with respect to longitudinal or transverse axes in the body.
  • therapy including a step of selectively killing only tumor cells, may be subsequently performed.
  • Hyperthermia is a treatment method which involves externally applying an alternating magnetic field in the radio frequency range to magnetic nanoparticles.
  • the magnetic nanoparticles generate heat through Neel relaxation of the spin of magnetic electrons, and the generated heat affects the surrounding temperature of the magnetic nanoparticles, such that the body temperature increases from 37 ° C up to a range from 40 to 45 ° C, thereby killing cells.
  • a magnetic field is applied to the tumorous region to generate heat, thereby selectively killing only tumor cells.
  • Another aspect of the therapy is a treatment method that is available when the substance capable of specifically binding to a tumor marker has a cell-killing effect in itself.
  • the aforementioned antibodies such as Herceptin and Rituxan, are able to specifically bind to tumor cells, and are also able to kill tumor cells by themselves.
  • the substance capable of specifically binding to a tumor marker is an antibody such as Herceptin and Rituxan, a tumor of interest may be diagnosed, and the tumor may also be treated by killing tumor cells.
  • a further aspect of the therapy is based on using the nanohybrid particles according to the present invention as an anticancer drug carrier.
  • An anticancer drug is bound to the nanohybrid particles, and preferably to the substance capable of specifically binding to a tumor marker.
  • Such nanohybrid particles are concentrated in tumor cells and thus enable tumor diagnosis, and also accumulate an anticancer drug in a tumorous area, thereby selectively killing only tumor cells while not affecting normal cells.
  • the anticancer drugs useful in the therapy according to the present invention include, but are not limited to, cisplatin, carboplatin, taxol, procarbazine, cyclophosphamide, dactinomycin, daunorubicin, etoposide, tamoxifen, doxorubicin, mitomycin, bleomycin, pliconiycin, transplatinum, vinblastin, and methotrexate.
  • EXAMPLE 1 Preparation of iron oxide-Herceptin nanohybrid particles for diagnosis of breast cancer 100 ⁇ Jt of Herceptin (10 mg/ml, in 10 mM phosphate buffer (pH 7.2), Genentech, Inc., South San Francisco, CA, USA) was placed in an Eppendorf tube, and 0.2 mg of sulfo-SMCC (40(N- Maleimidomethyl) cyclohexane-1-carboxylic acid 3-sulfo-N-hydroxy-su ⁇ mide ester) was added to the tube. The mixture was allowed to react at room temperature for 30 min in order to replace a lysine residue of Herceptin with a maleimide group.
  • Herceptin 10 mg/ml, in 10 mM phosphate buffer (pH 7.2), Genentech, Inc., South San Francisco, CA, USA
  • sulfo-SMCC 40(N- Maleimidomethyl) cyclohexane-1-carboxylic acid 3-sul
  • the iron oxide-Herceptin nanohybrid particles prepared in Example 1 were assessed for binding specificity and efficiency for a breast cancer marker antigen, HER2/neu antigen, using in vitro magnetic resonance imaging and flow cytometry.
  • Cell lines not expressing, expressing and overexpressing HER2/neu antigen were treated with the iron oxide-Herceptin nanohybrid particles, as follows. First, each cell line was grown in culture dishes, and harvested from the dishes by treatment with 0.25% trypsin/EDTA at room temperature. The iron oxide-Herceptin nanohybrid particles were added to 50 ⁇ i of PBS buffer containing 10 7 cells in 20 ⁇ g'ml based on the antibody, followed by incubation on ice for about 30 min.
  • control nanohybrid particles containing anti-HMEN-B3 antibody were used as a control (hereinafter, referred to as "control nanohybrid particles").
  • the iron oxide-Herceptin nanohybrid particles were assessed for antigen specificity and its efficiency using a FACScan flow cytometer (Becton Dickinson, San Diego, CA). A total of ten thousand events were collected for each cell line. Fluorescence index was estimated using mean and median values of fluorescence intensity distribution.
  • the iron oxide-Herceptin nanohybrid particles and the control nanohybrid particles were individually applied to cell lines expressing the HER2/neu receptor, and allowed to react with an FITC-conjugated secondary antibody as described above. Fluorescence expression was analyzed using fluorescent microscopy, and the results are given in FIG. 4. As shown in FIG. 4, fluorescence intensity increased as the expression levels of HER2/neu receptor increased.
  • BX-PC-3 cells which express HER2/neu receptor at low levels, displayed a slight increase in fluorescence intensity when treated with the iron oxide-Herceptin nanohybrid particles (FIG. 4, 1), compared to the case of being treated with control nanohybrid particles (FIG. 4, control). Also, fluorescence intensity gradually increased as the expression levels of the receptor increased (BX-PC-3 cells ⁇ MDA-MB-231 cells ⁇ BT-474 cells ⁇ NIH3T6.7 cells). B. Magnetic resonance imaging
  • T2 mapping was performed.
  • Target imaging for tumors was performed to nude mice which in the proximal femur have tumors consisting of a cell line overexpressing HER2/neu antigen.
  • Control nanohybrid particles were administered to mice according to the same method as described above, and the resulting images of mice were used as controls.
  • In vivo imaging experiments were carried out as follows. Imaging was done with a 1.5 T imager (Intera; Philips Medical Systems, Best, The Netherlands) and micro ⁇ 7 coils.
  • Coronal images were obtained with fast field echo (FFE) pulse sequences (FIG. 6).
  • EXAMPLE 4 Identification of in vivo tumor cell selectivity of the iron oxide-Herceptin nanohybrid particles by immunohistological staining
  • Tumors (N1H3T6.7) formed in nude mice were excised and fixed with 4% paraformaldehyde. Then, the tumors were embedded in OCT compound (Sakura, Tokyo, Japan), sectioned into about 10 ⁇ m-thick slices, and immunostained. Immunostaining was carried out using Herceptin as a primary antibody and fluorescein-conjugated goat IgG fraction (TCN Biomedicals, Inc. Aurora, OH 44202) against the Fc region of human immunoglobulins (IgG, IgA and IgM) as a secondary antibody.
  • Immunostaining for vascular endothelial cells was performed using purified anti- mouse CD31 (PECAM-I) (A Becton Dickinson Co.) as a primary antibody and Cy5 goat anti-rat IgG+IgM (Biomeda corp.) as a secondary antibody. Immunofluorescence was analyzed using a confocal microscope (Olympus Optical, Tokyo, Japan), and the results are given in FIG.7.
  • EXAMPLE 5 Preparation of iron oxide-PEG-folic acid nanohybrid particles for diagnosis of ovarian cancer 100 ⁇ JL of folic acid (10 mg/ml, in 1O mM phosphate buffer (pH 7.2), Genentech, Inc., South San Francisco, CA, USA) was placed in an Eppendorf tube, and 0.2 mg of PEG was added to the tube. The mixture was allowed to react at room temperature for 30 min in order to replace an amine group at one end of PEG, which has amine groups at both ends thereof, with folic acid.
  • reaction mixture was then passed through a Sephacryl S- 300 column to remove non-reacted PEG-folic acid and water-soluble iron oxide nanoparticles, and was concentrated to about 2 mg/ml using a Centricon filtration kit, thereby yielding iron oxide-PEG-folic acid nanohybrid particles.
  • EXAMPLE 6 In vitro diagnosis of ovarian cancer using the iron oxide-PEG-folic acid nanohybrid particles
  • the iron oxide-PEG-folic acid nanohybrid particles prepared in Example 5 were assessed for binding specificity and efficiency for folic acid receptor using in vitro magnetic resonance imaging.
  • Cell lines not expressing, expressing, and overexpressing folic acid receptor were treated with the iron oxide-PEG-folic acid nanohybrid particles, as follows. First, each cell line was grown in culture dishes, and harvested from the dishes by treatment with 0.25% trypsin/EDTA at room temperature. The iron oxide-PEG-folic acid nanohybrid particles were added to 50 ⁇ i of PBS buffer containing 10 7 cells in 20 ⁇ g/ml based on the iron, followed by incubation on ice for about 30 min. The cells were then washed three times. To evaluate the antigen specificity of the nanohybrid particles using magnetic resonance imaging, cells were transferred into PCR tubes and precipitated by centrifugation.
  • the MRI contrast effect of the nanohybrid particles according to the antigen specificity of each cell line was analyzed using a 1.5 T imager (bitera; Philips Medical Systems, Best, The Netherlands) and micro-47 coils. Coronal images were obtained with fast field echo (FFE) pulse sequences (FIG. 8).
  • the MR signal gradually changed to black as the expression levels of folic acid receptor increased (A431 cells ⁇ SKOV cells ⁇ OVCAR cells).
  • the gradual color change of the MR signal to black resulted from the selective binding of the iron oxide-PEG-folic acid nanohybrid particles to folic acid receptor-expressing cell lines.
  • EXAMPLE 7 Evaluation of ability of the iron oxide-Herceptin nanohybrid particles to kill breast carcinoma cells
  • a trypan blue exclusion assay was carried out to determine whether the iron oxide-Herceptin nanohybrid particles, prepared in Example 1 , selectively kill breast carcinoma cells.
  • Trypan blue staining was performed by adding the iron oxide-Herceptin nanohybrid particles to a culture medium containing 10 7 NIH3T6.7 cells, expressing HER2/neu antigen, or HeLa cells, not expressing the antigen, in concentrations of 12.5, 25, 50, 100 and 200 ⁇ gjv ⁇ . The results are given in FIG. 9.
  • the iron oxide-Herceptin nanohybrid particles never affected cells not expressing HER2/neu antigen, but killed HER2/neu antigen-expressing cells when present at 25 /zg/ml or higher.
  • the nanohybrid particles according to the present invention are able to stably disperse and diffuse in an aqueous solution, and thus may enhance tumor diagnosis and efficiency and accuracy in cancer treatment. Also, the nanohybrid particles according to the present invention may enable both the diagnosis and treatment of tumors.

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Abstract

Cette invention concerne des particules nanohybrides utilisées pour diagnostiquer ou traiter des tumeurs et dans lesquelles des nanoparticules sont entourées d'un ligand multifonctionnel comprenant une zone de fixation, une zone de réticulation et une zone de liaison à un ingrédient actif, laquelle zone de réticulation du ligand multifonctionnel est réticulée avec une zone de réticulation d'un autre ligand multifonctionnel, tandis que la zone de liaison à un ingrédient actif est liée à une substance capable de se lier spécifiquement à un marqueur tumoral. Cette invention concerne également une composition de diagnostic ou de traitement de tumeurs comprenant les particules nanohybrides et un excipient pharmaceutiquement acceptable, ainsi qu'une méthode de diagnostic ou de traitement de tumeurs consistant à injecter la composition dans un corps ou un spécimen, à diagnostiquer la présence de tumeurs en détectant un signal émis par les particules nanohybrides depuis le corps ou le spécimen et, éventuellement, à tuer sélectivement les cellules tumorales identifiées.
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EP2148675A1 (fr) * 2007-05-29 2010-02-03 Youl Chon Chemical Co. Ltd. Médicament anticancérigène pour le diagnostic et le traitement du cancer
EP2148675A4 (fr) * 2007-05-29 2012-05-30 Youl Chon Chemical Co Ltd Médicament anticancérigène pour le diagnostic et le traitement du cancer
US8389002B2 (en) 2007-05-29 2013-03-05 Youl Chon Chemical Co., Ltd. Anti-cancer medicine both for diagnosing and treating cancer
WO2009031859A2 (fr) * 2007-09-06 2009-03-12 Anygen Co., Ltd. Complexe multifonctionnel pour l'imagerie et l'administration de médicaments
WO2009031859A3 (fr) * 2007-09-06 2009-05-14 Anygen Co Ltd Complexe multifonctionnel pour l'imagerie et l'administration de médicaments
KR101169029B1 (ko) * 2007-09-06 2012-07-27 애니젠 주식회사 조영 및 약물운반용 다기능 복합체
US9168225B2 (en) 2010-04-23 2015-10-27 The Board Of Trustees Of The University Of Illinois Nano-hybrid delivery system for sequential utilization of passive and active targeting

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