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WO1998023293A1 - Compose de contraste, milieu de contraste pour irm et procede d'irm - Google Patents

Compose de contraste, milieu de contraste pour irm et procede d'irm Download PDF

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Publication number
WO1998023293A1
WO1998023293A1 PCT/JP1997/004343 JP9704343W WO9823293A1 WO 1998023293 A1 WO1998023293 A1 WO 1998023293A1 JP 9704343 W JP9704343 W JP 9704343W WO 9823293 A1 WO9823293 A1 WO 9823293A1
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Prior art keywords
compound
mri
sugar chain
chain polymer
imaging
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Ceased
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PCT/JP1997/004343
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English (en)
Japanese (ja)
Inventor
Toshihiro Akaike
Masato Mikawa
Atsushi Maruyama
Masaya Takahashi
Tomoaki Miyazawa
Naoto Miwa
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Nihon Schering KK
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Nihon Schering KK
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Priority to AU51356/98A priority Critical patent/AU5135698A/en
Publication of WO1998023293A1 publication Critical patent/WO1998023293A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K49/12—Macromolecular compounds
    • A61K49/126—Linear polymers, e.g. dextran, inulin, PEG
    • A61K49/128—Linear polymers, e.g. dextran, inulin, PEG comprising multiple complex or complex-forming groups, being either part of the linear polymeric backbone or being pending groups covalently linked to the linear polymeric backbone
    • 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
    • A61K49/1863—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 a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
    • 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

Definitions

  • the MRI diagnostic method is a new diagnostic method that has recently received a great deal of attention not only from the field of radiation diagnosis but also from the whole medical community.
  • MR I contrast media are superior in concentration resolution in tissues, and have high safety without X-ray exposure, indicating the presence of lesions, normality and disease. It has been pointed out that it is clinically useful for understanding the anatomical and functional images of the target site.
  • a contrast agent that 1) can detect target cells such as tumors at a low concentration (low dose) with high sensitivity specifically, 3) has low toxicity, and 4) can be rapidly excreted from the body. Have been.
  • Contrast agents using monoclonal antibodies, peptides, polysaccharides, ribosomes, etc. have been developed as a means for delivering contrast agents for MRI to target sites and organs.
  • the agent needs to be localized at a relatively high concentration, and there is no practical target-directed contrast agent at present.
  • MR I contrast agents are recognized as foreign substances in vivo, undergo phagocytosis by the reticuloendothelial system (RES), and provide sufficient target fingers. No tropism was obtained.
  • RES reticuloendothelial system
  • MRI contrast-enhancing compounds have specific organs and sites as glycopolymers corresponding to glycoprotein receptors expressed specifically in tumors and organs.
  • target directivity such as tumor tissue directivity and / or specific organ directivity.
  • the present invention is as follows.
  • OMRI contrast-enhancing compound especially a compound obtained by modifying magnetite with a sugar chain high molecule that specifically recognizes a target site.
  • Target site-directed contrast agents for MRI including MRI contrasting compounds, especially compounds obtained by modifying magnetite with high sugar chain molecules that specifically recognize target sites.
  • MRI-enhancing compounds are modified with high-sugar-chain molecules that specifically recognize the target site.
  • target site-directed MRI contrast agents including MRI contrasting compounds, especially compounds obtained by modifying magnetite with high molecular weight sugar chains that specifically recognize target sites MR I imaging method characterized by the following.
  • Imaging of tumor cells or liver by imaging tumor cells or liver with an MRI imaging agent that contains a compound that modifies MRI imaging compounds, especially magnetite with hyaluronic acid Method.
  • MRI imaging compounds especially compounds obtained by modifying magnetite with a sugar chain polymer that specifically recognizes the target site, for the production of a target site-directed MRI contrast agent .
  • Figure 1 HA-SPIO (1a and 2a), P VLA-SPIO (lb and 2b) and CDx-SPIO (1c and 2c) and EL4 cells fluorescently labeled with FITC at 4 ° C. Histogram showing the relationship between cell fluorescence intensity and cell number when incubated for 2 hours (1a, 1b and 1c) or at 37 ° C for 6 hours (2a, 2b and 2c) .
  • the solid line (1) shows the results when incubating in the presence of the fluorescently labeled MRI contrast agent described above, and the dashed line (1) shows the results without using the fluorescently labeled MRI contrast agent as a control. Only went to
  • FIG. 9 is a view showing a change in relative signal intensity of MRI in the liver 24 hours later.
  • the contrast mechanism of the MR I contrast agent is very different from other contrast agents.
  • the high X-ray absorption of the contrast agent itself directly affects the brightness on the image, whereas the contrast agent for MRI is not directly depicted itself,
  • the contrast agent activates the relaxation phenomenon of surrounding protons and indirectly increases the brightness of the image. Contrast is achieved by lowering the volume.
  • Two types of contrast agents for MRI are known: T1-weighted contrast agents and T2-weighted contrast agents.
  • the T1-weighted contrast medium is a positive contrast medium, and the brightness of the area where the contrast medium is present increases and glows white on the image.
  • the T2-weighted contrast medium is the negative contrast medium and the brightness of the area where the contrast medium is present is low on the image. It drops and looks dark.
  • a commonly used MRI contrast-enhancing compound can be used, and preferably, magnetite, which is a T2-weighted contrast agent that shortens the transverse relaxation time (T2) of the proton, is used.
  • magnetite which is a T2-weighted contrast agent that shortens the transverse relaxation time (T2) of the proton.
  • a superparamagnetic iron oxide fine particle (Superparamagnetic Iron Oxide: SPI0) colloided with a dextran derivative is used.
  • the sugar chain polymer used in the present invention is not particularly limited as long as it can specifically recognize a target site, for example, an organ such as a tumor tissue or a liver.
  • Hyaluronan that specifically recognizes the hyaluronan receptor that is highly expressed in cells, spleen, lymph nodes, and tumor tissues. And the like.
  • glucose-binding polystyrene or the like that specifically recognizes a glucose transporter from Tengen is exemplified. More preferably, it has a low flexibility and has a high hydrophilicity, so that it tends to have an extended linear structure.
  • the adsorption of the protein is suppressed with the hydrodynamic properties of the hydrophilic chain, and the phagocytic action of RES can be avoided. That is, nonspecific uptake of RES by phagocytosis can be suppressed, vascular retention can be improved, and uptake into tumors and the like can be increased.
  • Hyaluronic acid is strongly negatively charged because it has a carboxyl group in its glucanoic acid residue.
  • Examples of a method for modifying an MRI contrast-enhancing compound with these sugar chain polymers include a method in which the two are bonded by ionic bonding. Specifically, depending on the sugar chain polymer used For example, when SPI0 is modified with hyaluronic acid, ferric chloride and ferric chloride are added to an aqueous solution of hyaluronic acid to add 60 to 100 ° C, preferably about 80 ° C. The reaction is carried out by adding sodium hydroxide solution and neutralizing the pH. It is more preferable to perform ultrafiltration treatment to further purify and increase the purity.
  • the binding ratio between the c- glycan polymer and the MRI imaging compound varies depending on the type of the glycan polymer and the MRI imaging compound used.
  • the sugar chain polymer is 0.2 to 5 parts by weight for hyaluronic acid, preferably 1 part by weight, and 0.2 for lactose per 1 part by weight of magnetite. To 5 parts by weight, preferably 1 part by weight.
  • hydrophilic polymer In order to more specifically deliver the MRI contrast-enhancing compound to a target organ or tumor tissue, it is preferable to further bind a hydrophilic polymer to the MRI contrast agent of the present invention.
  • the hydrophilic polymer that can be used is not particularly limited as long as it has the above-mentioned characteristics, but specific examples include polyethylene glycol, polyvinyl alcohol, and polyvinylolidone. These hydrophilic polymers can be bound using the same method as the above-mentioned method for binding the sugar chain polymer to the MRI contrast-enhancing compound.
  • the contrast agent for MRI of the present invention is not particularly limited as long as it includes a compound obtained by modifying an MRI contrast-enhancing compound with a sugar chain polymer that specifically recognizes a target site.
  • Specific examples thereof include a compound of the present invention, and a compound of the present invention suspended or dissolved in a solvent such as distilled water for injection, physiological saline, or Ringer's solution.
  • Additives such as physically acceptable carriers and excipients can be included.
  • the contrast agent can be applied to cells, etc. and administered to the living body by intravascular (venous or arterial) administration, oral administration, rectal administration, vaginal administration, lymphatic administration, intraarticular administration, etc. It is preferably administered in the form of a solution, emulsion or suspension.
  • Additives included in the MRI contrast agent of the present invention vary depending on the administration form, administration route, etc. Specifically, in the case of an injection, a buffer, an antibacterial agent, a stabilizer, a dissolution aid Preparations and vehicles are used alone or in combination. For oral administration (specifically, solutions, syrups, emulsions or suspensions, etc.), coloring agents, preservatives, stabilizers, A turbidity agent, an emulsifier, a thickener, a sweetener, a fragrance and the like are used alone or in combination. As the various additives, those usually used in the art are used.
  • the contrast agent of the present invention is directed to a target site, it is necessary to specifically image liver and tumor cells when hyaluronic acid is selected as a desired cell, tissue, or organ, particularly as a sugar chain polymer used for modification. Becomes possible. Furthermore, by binding hyaluronic acid, the function as a buffer component of joints and the like which hyaluronic acid originally has can be imparted to the present contrast agent. That is, when the present contrast agent is directly administered to a joint or the like, it becomes suitable for diagnosis of a joint disease such as rheumatism.
  • the dose of the MRI contrast agent of the present invention is determined according to the conventional MRI contrast agent, and the age, body size and target of the subject to be administered are determined.
  • the amount of the MRI contrast-enhancing compound that can be increased or decreased as appropriate depending on the organ to be used, or the amount of iron (F e) in the case of magnetite is 10 to 100 ⁇ mo 1 F ekg, preferably It is selected in the range of 10 to 20 / zmo 1 Fe / kg.
  • the contrast agent of the present invention can be suitably used as a contrast agent for various animals in addition to humans.
  • the administration form, administration route, dose, etc. depend on the weight and condition of the target animal. Select as appropriate.
  • the compound of the present invention and the contrast medium for MRI can be used for specific detection of a hyaluronic acid receptor (such as CD44) specifically expressed in tumor cells and sinusoidal endothelial cells of the liver. Be expected.
  • a hyaluronic acid receptor such as CD44
  • Hyaluronic acid is highly expressed on liver sinusoidal endothelial cells, spleen, lymph nodes and tumor tissue. It is known that it is specifically recognized by a given hyaluronic acid receptor.
  • 9 g of hyaluronic acid (manufactured by Denki Kagaku Kogyo Co., Ltd., average molecular weight: 590,000) is dissolved in 900 ml of water, and 180 mg of hyaluronidase (manufactured by Sigma) is added, and 50 ° The enzyme was digested with C for 3 hours. Thereafter, the mixture was boiled at 100 ° C. for 10 minutes to deproteinize. The reaction solution was cooled with water and filtered to remove proteins. The filtrate was freeze-dried to obtain hyaluronic acid having an average molecular weight of about 8,000.
  • PVLA Polyvinylvinyl-lactonamide
  • VLA Vinyl benzyl-lactone amide
  • AIBN azobisisobutyronitrile
  • mM a polymerization initiator
  • the reaction solution was dropped into ethanol, and the precipitate was collected.
  • the recovered precipitate was dissolved in water, dialyzed (fraction molecular weight: 3,500), and lyophilized to obtain PVLA.
  • Carboxydextran is non-specifically taken up by Kupffer cells of the liver.
  • a product manufactured by Meito Sangyo Co., Ltd. was used.
  • the magnetite was coated with the various sugar chains obtained in (1) above.
  • a magnetite suspension (6.25 mg Fe / l Oml) was added dropwise to the aqueous solution (50 mg of 4 Oml) of PVL A obtained in ii) of (1) above, and after stirring, Ultrafiltration (fraction molecular weight: 20 kDa) gave PVL A magnetite.
  • CDx 8 g was dissolved in 15 ml of water, and CDx and magnetite were bound in the same manner as in a) above in the case of hyaluronic acid to obtain CDX magnetite.
  • the particle size of SPIO was calculated by observation with a transmission electron microscope.
  • the sugar chain polymer concentration is! ! ! In the case of (8) and (8), it was calculated from the fluorescence intensity of each sugar chain fluorescently labeled with ITC, and in the case of CDX, it was determined by colorimetry at a wavelength of 630 nm (VIS) using anthrone. The electric potential is 10 The pH of the 0-fold diluted solution was adjusted to about 7, and measured under the following conditions.
  • Measuring device Zeta master particle electrophoresis analyzer (Ma 1V ern) Measuring temperature: 25 ° C
  • the magnetic balance was measured using a simple magnetic balance MS B MK1 (Fohnson Matthey) and a standard sample (N105) as a control. Note c The results are shown in Table 1, p H in the table are shown the pH of the preparation of the Magunetai bets that combines sugar chain macromolecule.
  • PVLA-SP 10 25.0 54.3 155.2 7.1 29079 7.0
  • the DLS particle diameter of SPIO0 to which the sugar chain polymer was bound was observed to be about 50 to 50 nm.
  • the potential value showed a strong positive potential (approximately 35 mV) in the case of SPI 0 alone, but by binding to a glycan polymer, for example, in the case of PVL A, a weak positive potential (about 35 mV) was obtained. (7 mV), the hyaluronic acid and CDX changed to a strong negative potential (about 150 mV), suggesting that a neutral or negative potential sugar chain polymer was bound. .
  • the value of the magnetic field shows that each of them has a strong magnetic property of about 20,000 to 30,000 regardless of the binding of the sugar chain polymer, confirming that the MRI contrast property is maintained.
  • cell binding assays and endcytosis assays were performed in vitro on each sugar chain polymer-bound magnetite.
  • EL4 cells a mouse lymphoma-derived cell line
  • EL 4 cells that are known to express the hyaluronic acid receptor on the cell membrane surface were used.
  • EL 4 cells were subcultured at 37 ° C and 5% CO 2 in RPM 1-1640 medium supplemented with 10% fetal calf serum inactivated by heat. .
  • HA hyaluronic acid
  • Example 1 550 mg of hyaluronic acid (HA) prepared in i) of (1) of Example 1 was dissolved in 15 ml of honolemamide.
  • a solution prepared by dissolving 250 mg of FITC (Fluorescein isothiocyanate; manufactured by Dojin), 100 mg of dibutyltin dilaurate and 100 mg of sodium hydrogen carbonate in 15 ml of dimethyl sulfoxide (DMS 0) Add 9 5. Stir and mix with C for 20 minutes. The mixture is dropped into ethanol, and a few drops of a saturated aqueous sodium chloride solution are further dropped to cause precipitation. The obtained precipitate is dissolved in formamide, and the solution is again precipitated in ethanol. This operation is repeated a total of 5 times.
  • FITC Fluorescein isothiocyanate
  • DMS 0 dimethyl sulfoxide
  • the PVL A 3 0111 prepared in (1) ii) of Example 1 was dissolved in 0] ⁇ 50 of 3111]. 30 mg of F ITC and 9 mg of dibutyltin dilaurate were added to the solution.
  • CDX 30 Omg was dissolved in 5 ml of DMSO.
  • a solution prepared by dissolving 30 mg of FITC and 9 mg of dibutyltin dilaurate in 0.5 ml of DMSO is added to the solution, and the mixture is stirred and mixed at 90 ° C for 1 hour.
  • the mixture is dropped into ethanol to cause precipitation.
  • the resulting precipitate is dissolved in DMS0, the solution is again dropped into ethanol, and a few drops of a saturated aqueous sodium chloride solution are dropped to form a precipitate. Repeat this operation three times.
  • the finally obtained precipitate is dried under reduced pressure, redissolved in water, and filtered through a cellulose acetate membrane having a pore size of 0.2 ⁇ m.
  • the filtrate was freeze-dried over a period to obtain FITC-labeled CDX [yield: 21.4 mg (yield: 65%)].
  • the labeled compound obtained under labeling under these conditions contains 0.9 mol of FITC per 100 glucose repeating structural units. Will be. )
  • HA-SP10 specifically recognizes the HA receptor, that is, it is a contrast agent having target site directivity.
  • CBHZH e mice were anesthetized with 40 mg / kg of pentobarbital sodium administered intraperitoneally, a contrast agent for MRI was injected from the tail vein with a butterfly needle, and placed in the center of the magnetic field.
  • HA-SPI0, PVLA-SPI0 and CDX-SPI0 prepared in Example 1 were used as contrast agents for MR I, and the concentrations of Fe contained in each were adjusted to 30 umo 1 / k. .
  • the relative signal intensity (%) [RSI (%)] detected in the liver MRI image is calculated by the following formula.
  • SI (after muscle): Signal intensity in muscle after injection of contrast agent SI (immediately before liver): Signal intensity in liver before injection of contrast agent SI (muscle-front): Signal intensity in muscle before injection of contrast agent
  • Modification of the MR I imaging compound with a sugar chain macromolecule corresponding to a glycoprotein receptor that is specifically expressed in tumors and organs allows the target site-directed MR I imaging compound and MR I A contrast agent is obtained.
  • hyaluronic acid having high hydrophilicity as the sugar chain polymer to be modified, it is expected that phagocytosis of RES will be avoided. Since the target site can be specifically imaged, diagnosis can be performed with a low dose, that is, it is possible to provide a contrast agent for MRI with reduced toxicity.

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Abstract

Cette invention concerne une composition contenant un composé de contraste pour imagerie par résonance magnétique (IRM) lié à un polymère à chaîne glucidique, et notamment de l'acide hyaluronique, correspondant à un récepteur de glycoprotéines se manifestant spécifiquement dans une tumeur ou un organe. L'invention concerne aussi un milieu de contraste pour IRM contenant ladite composition, ainsi qu'un procédé de formation d'image d'une tumeur et/ou d'un foie au moyen dudit milieu de contraste. Cette invention se rapporte également à un procédé d'obtention d'un composé de contraste pour IRM et d'un milieu de contraste pour IRM dotés chacun d'une aptitude à se diriger vers un site cible, qui consiste à modifier un composé de contraste pour IRM avec un polymère à chaîne glucidique correspondant à un récepteur de glycoprotéines se manifestant spécifiquement dans une tumeur ou un organe. Le choix de l'acide hyaluronique, qui est fortement hydrophile, en tant que polymère de modification à chaîne glucidique, devrait s'avérer particulièrement judicieux s'agissant d'éviter la phagocytose par le système mononucléé phagocytaire. Parce qu'il permet la formation spécifique d'images de sites cibles, ce milieu de contraste peut être utilisé à faible dose à des fins de diagnostic, ce qui assure une réduction de la toxicité.
PCT/JP1997/004343 1996-11-28 1997-11-27 Compose de contraste, milieu de contraste pour irm et procede d'irm Ceased WO1998023293A1 (fr)

Priority Applications (1)

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AU51356/98A AU5135698A (en) 1996-11-28 1997-11-27 Contrast compound, contrast medium for mri, and method for mri

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JP8/318350 1996-11-28
JP31835096 1996-11-28

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000069473A3 (fr) * 1999-05-14 2001-08-16 Univ California Support macromoleculaire pour medicament et administration d'un agent diagnostique
WO2001074406A3 (fr) * 2000-03-31 2002-10-24 Us Gov Health & Human Serv Composition dendrimere sensible au magnetisme et son utilisation pour l'analyse a resonance magnetique
JP2010208979A (ja) * 2009-03-09 2010-09-24 Tokyo Institute Of Technology 組織撮像用ｍｒｉ造影剤
US8906345B2 (en) 2006-09-20 2014-12-09 Isis Innovation Limited Multimeric particles
US9439985B2 (en) 2009-01-30 2016-09-13 Navidea Biopharmaceuticals, Inc. Compositions for radiolabeling diethylenetriaminepentaacetic acid (DTPA)-dextran
JP2019522004A (ja) * 2016-06-29 2019-08-08 ソウル ナショナル ユニバーシティ アールアンドディービー ファウンデーション 癌病変選択的標識のための水和ゲル基盤ナノエマルジョン、及びその製造方法
JP2019537612A (ja) * 2016-11-18 2019-12-26 ソウル ナショナル ユニバーシティ アールアンドディービー ファウンデーション 癌細胞の選択的蛍光標識のためのナノ伝達体及びその製造方法

Citations (1)

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JPH0812596A (ja) * 1994-06-23 1996-01-16 Nihon Medi Physics Co Ltd 画像診断用造影剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0812596A (ja) * 1994-06-23 1996-01-16 Nihon Medi Physics Co Ltd 画像診断用造影剤

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000069473A3 (fr) * 1999-05-14 2001-08-16 Univ California Support macromoleculaire pour medicament et administration d'un agent diagnostique
US6409990B1 (en) 1999-05-14 2002-06-25 The Regents Of The University Of California Macromolecular carrier for drug and diagnostic agent delivery
WO2001074406A3 (fr) * 2000-03-31 2002-10-24 Us Gov Health & Human Serv Composition dendrimere sensible au magnetisme et son utilisation pour l'analyse a resonance magnetique
US8906345B2 (en) 2006-09-20 2014-12-09 Isis Innovation Limited Multimeric particles
US9439985B2 (en) 2009-01-30 2016-09-13 Navidea Biopharmaceuticals, Inc. Compositions for radiolabeling diethylenetriaminepentaacetic acid (DTPA)-dextran
JP2010208979A (ja) * 2009-03-09 2010-09-24 Tokyo Institute Of Technology 組織撮像用ｍｒｉ造影剤
JP2019522004A (ja) * 2016-06-29 2019-08-08 ソウル ナショナル ユニバーシティ アールアンドディービー ファウンデーション 癌病変選択的標識のための水和ゲル基盤ナノエマルジョン、及びその製造方法
US11103600B2 (en) 2016-06-29 2021-08-31 Seoul National University R & Db Foundation Hydrogel-based nanoenulsion for selectively labeling cancer lesion, and preparation method therefor
JP2019537612A (ja) * 2016-11-18 2019-12-26 ソウル ナショナル ユニバーシティ アールアンドディービー ファウンデーション 癌細胞の選択的蛍光標識のためのナノ伝達体及びその製造方法
JP6996774B2 (ja) 2016-11-18 2022-01-17 ソウル ナショナル ユニバーシティ アールアンドディービー ファウンデーション 癌細胞の選択的蛍光標識のためのナノ伝達体及びその製造方法
US11298428B2 (en) 2016-11-18 2022-04-12 Seoul National University R&Db Foundation Nanocarrier for selective fluorescence labeling of cancer cell and preparation method therefor

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