WO2012153820A1 - Nanoparticule fluorescente absorbant les rayons x - Google Patents

Nanoparticule fluorescente absorbant les rayons x Download PDF

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WO2012153820A1
WO2012153820A1 PCT/JP2012/062062 JP2012062062W WO2012153820A1 WO 2012153820 A1 WO2012153820 A1 WO 2012153820A1 JP 2012062062 W JP2012062062 W JP 2012062062W WO 2012153820 A1 WO2012153820 A1 WO 2012153820A1
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nanoparticles
ray absorbing
fluorescent
ray
nanoparticle
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PCT/JP2012/062062
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English (en)
Japanese (ja)
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古澤　直子
拓司 相宮
中野　寧
幸祐 権田
憲明 大内
智彦 中川
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コニカミノルタエムジー株式会社
国立大学法人東北大学
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Publication of WO2012153820A1 publication Critical patent/WO2012153820A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0065—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle
    • A61K49/0067—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle quantum dots, fluorescent nanocrystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • 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
    • A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
    • A61K49/0414—Particles, beads, capsules or spheres
    • A61K49/0423—Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer
    • 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
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/08—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials

Definitions

  • a quantum dot is a nanoparticle made of a semiconductor material, and in many cases, is a particle made of a core made of a first semiconductor and a shell made of a second semiconductor surrounding the core. Therefore, quantum dots are sometimes called “semiconductor nanoparticles”.
  • This quantum dot has a wavelength different from that of the bulk semiconductor due to the quantum size effect (a phenomenon in which the state of electrons in the material changes as the particle gets smaller, and absorbs and emits light of shorter wavelengths).
  • the amount of light emission is large, the light emission stability is excellent, and the light emission wavelength can be changed depending on the physical size.
  • Non-Patent Document 2 obtains fluorescent image images in mice administered with a complex formed by binding polyethylene glycol to core-shell cadmium selenide-zinc sulfide quantum dots. An attempt to do so has been disclosed.
  • the present invention provides X-ray absorbing fluorescent composite nanoparticles and X-ray contrast agents shown in [1] to [9] below.
  • [1] X-ray absorbing fluorescent composite nanoparticles having a volume average particle diameter of 10 nm or more and 1000 nm or less, formed by combining X-ray absorbing nanoparticles and fluorescent nanoparticles.
  • the fluorescent nanoparticles are composed of semiconductor nanoparticles containing at least one semiconductor selected from II-VI semiconductors, III-V semiconductors, and semiconductors made of silicon or germanium.
  • the X-ray absorbing fluorescent composite nanoparticles according to any one of [1] to [6].
  • An X-ray contrast agent comprising the X-ray absorbing fluorescent composite nanoparticles according to any one of [1] to [8] above.
  • the size of the X-ray absorbing fluorescent composite nanoparticles of the present invention is 10 nm to 1000 nm, preferably 40 nm to 200 nm, more preferably 50 nm to 200 nm, and still more preferably 40 nm to 100 nm as a volume average particle diameter. If it is smaller than 10 nm, it is rapidly discharged from the kidney, so the residence time in the blood is short, and selective adsorption to cancer may not be performed. On the other hand, if it is larger than 1000 nm, clogging of capillaries may occur, and it may be biotoxic at the time of administration, which is not preferable.
  • the volume average particle diameter can be measured by a dynamic light scattering method.
  • the X-ray absorbing fluorescent composite nanoparticle of the present invention has an X-ray absorbing nanoparticle as a core so that the fluorescence emission from the fluorescent nanoparticle can be efficiently emitted outside the X-ray absorbing fluorescent composite nanoparticle. It is preferred that the particles have a core-shell structure that surrounds as a shell. Accordingly, the ratio of the number of the fluorescent nanoparticles to the X-ray absorbing nanoparticles is preferably 1: 1 to 10000: 1, and more preferably 10: 1 to 1000: 1.
  • the particle number ratio between the X-ray absorbing nanoparticles and the fluorescent nanoparticles can be obtained as a ratio represented by the following formula (1).
  • Ma and Mb are compounds constituting the X-ray absorbing nanoparticles in the X-ray absorbing fluorescent composite nanoparticles of the present invention (hereinafter also referred to as “X-ray absorbing nanoparticle constituent compounds”) and Represents the content of the compound constituting the fluorescent nanoparticle (hereinafter also referred to as “fluorescent nanoparticle constituent compound”), and ⁇ a and ⁇ b represent the densities of the X-ray absorbing nanoparticle constituent compound and the fluorescent nanoparticle constituent compound, respectively. Da and db represent the average particle diameters of the X-ray absorbing nanoparticles and the fluorescent nanoparticle constituent compounds measured by the dynamic scattering method, respectively.
  • the X-ray absorbing nanoparticles constituting the X-ray absorbing fluorescent composite nanoparticles of the present invention have a function as an X-ray CT contrast agent.
  • the X-ray absorbing nanoparticles are not particularly limited as long as they can absorb X-rays, but are preferably composed of elements having high X-ray absorption performance. In general, an element having a larger atomic number tends to have higher X-ray absorption performance, and therefore, it is preferably composed of an element having a larger atomic number.
  • Specific examples of the elements constituting the X-ray absorbing nanoparticles include elements belonging to the fourth period or more of the periodic table.
  • these elements may exist as a simple substance, or may exist as a salt with a corresponding counter ion, as long as they are stable in vivo and exhibit little or no toxicity. And may be present as a constituent element of the organic compound.
  • the simple substance of these elements, and the salt and organic compound comprised from these elements can be used individually by 1 type or in combination of 2 or more types.
  • the simple substance of these elements may be the alloy which consists of 2 or more types of elements.
  • the method for producing the X-ray absorbing nanoparticles used in the present invention is not particularly limited, but a method obtained from the corresponding precursor through a liquid phase reaction is preferable in that the particle size distribution can be controlled. Take as an example.
  • X-ray absorption nanoparticles made of gold can be obtained by using chloroauric acid or a salt thereof with an appropriate reducing agent such as citric acid, ascorbic acid, hydrogen, formaldehyde, ethanol, tannic acid, diborane, or borohydride. It can be obtained by reduction.
  • citric acid ascorbic acid
  • hydrogen formaldehyde
  • ethanol formaldehyde
  • tannic acid diborane
  • diborane diborane
  • borohydride borohydride
  • X-ray absorption nanoparticles composed of oxides can be obtained by converting the corresponding water-soluble salt directly into an oxide, or once converting the corresponding water-soluble salt into an intermediate such as hydroxide or carbonate. And then heated to lead to the oxide.
  • X-ray absorption nanoparticles composed of rare earth oxides such as gadolinium oxide are prepared by heating urea in an aqueous solution of a water-soluble rare earth salt such as gadolinium nitrate, and carbonate ions and hydroxide ions generated by hydrolysis of urea.
  • the fluorescent nanoparticle constituting the X-ray absorbing fluorescent composite nanoparticle of the present invention has a function as a fluorescent labeling agent.
  • the fluorescent nanoparticles determine the distribution of the X-ray contrast agent taken into the living body. It plays a role of specifying in the form of fluorescence, specifically, fluorescence emitted within the range from the near ultraviolet region to the near infrared region.
  • This fluorescent nanoparticle is in a state in which the X-ray absorbing fluorescent composite nanoparticle of the present invention is taken into the living body and can be distinguished from a region where the X-ray absorbing fluorescent composite nanoparticle is not taken in.
  • the fluorescent material used as a constituent material is not particularly limited as long as it can cause the occurrence of, for example, preventing the use of particles obtained by supporting an organic fluorescent dye on a suitable carrier such as silica nanoparticles as fluorescent nanoparticles. It is not a thing.
  • the fluorescent nanoparticles are preferably composed of semiconductor nanoparticles having high emission intensity and high durability.
  • Examples of semiconductors constituting semiconductor nanoparticles that can be suitably used as fluorescent nanoparticles include II-VI group semiconductors and III-V group semiconductors, and semiconductors made of silicon or germanium.
  • magnesium, zinc, cadmium, mercury as group II elements, aluminum, gallium, indium as group III elements, nitrogen, phosphorus, arsenic, antimony as group V elements, oxygen as group VI elements Examples include sulfur, selenium, and tellurium.
  • Examples of the “II-VI group semiconductor” include ZnS, ZnSe, ZnTe, CdS, CdSe, CdTe, and the like.
  • Examples of “III-V group semiconductors” include AlN, AlP, GaN, GaP, InN, and InP. Further, a group consisting of three or more elements may be used as the II-VI group semiconductor and the III-V group semiconductor. In the semiconductor nanoparticles used in the present invention, these semiconductors may be used alone or in combination of two or more.
  • X-Y group semiconductor refers to a semiconductor formed by combining a group X element and a group Y element.
  • group II-VI semiconductor includes a group II element and a group VI element. Means a semiconductor formed by combining
  • the semiconductor nanoparticles that can be used as fluorescent nanoparticles in the present invention are core-shell type having a structure in which nanoparticles composed of a single-component first semiconductor are used as a core, and a shell composed of a second semiconductor is coated on the surface.
  • Semiconductor nanoparticles are preferred.
  • the use of such semiconductor nanoparticles is advantageous because the luminous efficiency is improved and the chemical stability and light resistance are increased.
  • the first semiconductor constituting the core-shell type semiconductor nanoparticles is preferably the above “II-VI group semiconductor” or “III-V group semiconductor”.
  • the second semiconductor constituting the shell a semiconductor different from the semiconductor constituting the core can be used.
  • the core-shell type semiconductor nanoparticles used in the present invention may have a shell made of an insulator instead of the shell made of the second semiconductor or together with the shell made of the second semiconductor.
  • an insulator that can be used as the shell a substance having a wider band gap than a semiconductor, specifically, SiO 2 , ZnO, or the like can be given.
  • the core includes nanoparticles composed of a first semiconductor selected from the above “II-VI group semiconductor” and the above “III-V group semiconductor”, Examples include a shell formed of a second semiconductor selected from the above “II-VI group semiconductor” and “III-V semiconductor” and / or a shell formed of an insulator.
  • the fluorescent nanoparticles used in the present invention have a volume average particle diameter of 1 nm to 50 nm so that the X-ray absorbing fluorescent composite nanoparticles obtained by combining with the X-ray absorbing nanoparticles have the volume average particle diameter described above. Or less, more preferably 2 nm or more and 20 nm or less.
  • the volume average particle diameter measured for the fluorescent nanoparticles to which an appropriate linker having a reactive functional group used for binding to the above-mentioned X-ray absorbing nanoparticles is bound is the particle size of the fluorescent nanoparticles referred to here. You may employ
  • the excitation wavelength and emission wavelength are preferably 350 nm or more so as not to damage the living body. Furthermore, in view of intraoperative observation, 500 nm or more with less autofluorescence is preferable. From these points, fluorescent nanoparticles having an excitation wavelength of 350 nm to 1200 nm, preferably 500 nm to 950 nm, and an emission wavelength of 400 nm to 1250 nm, preferably 650 nm to 1150 nm are preferably used. It is done.
  • Examples of the semiconductor nanoparticle composition that satisfies these conditions include CdSe / ZnS, CdTe / ZnS, and InP / ZnS. Of these, InP / ZnS has a low element toxicity and is a preferred composition for use as a contrast agent.
  • the fluorescent nanoparticles used in the present invention can be produced by a conventionally known method, or commercially available ones can also be used.
  • CdSe / ZnS can be obtained by reacting Se powder with CdO to obtain CdS, and then adding and reacting a sulfurizing agent such as hexamethyldisilylthiane with zinc acetate or the like.
  • a sulfurizing agent such as hexamethyldisilylthiane with zinc acetate or the like.
  • trialkylphosphine, trialkylphosphine oxide, or the like can be used as a solvent for the purpose of improving the solubility of the reaction raw materials and / or preventing aggregation of the generated particles.
  • InP / ZnS for example, in the presence of a suitable higher fatty acid, a phosphating agent such as higher indium carboxylate, trimethylsilylphosphine, etc., a higher carboxylate zinc such as zinc undecylenate, and alkanethiol are heated in a suitable high boiling solvent. Can be obtained.
  • a phosphating agent such as higher indium carboxylate, trimethylsilylphosphine, etc.
  • a higher carboxylate zinc such as zinc undecylenate, and alkanethiol
  • the X-ray absorbing fluorescent composite nanoparticles of the present invention are used as an X-ray contrast agent and also as a fluorescent labeling agent for the purpose of specifying the position, size, and range of a lesion during surgery.
  • target lesion In a lesion targeted for imaging by the X-ray absorbing fluorescent composite nanoparticles of the present invention (hereinafter referred to as “target lesion”), a specific biological substance (for example, a tumor marker) is often expressed.
  • a molecular recognition substance capable of recognizing such a biological substance is bound to the X-ray absorbing fluorescent composite nanoparticles of the present invention, a binding reaction between this molecular recognition substance and the target biological substance.
  • the X-ray absorbing fluorescent composite nanoparticles can be specifically induced to the target lesion.
  • the X-ray absorbing fluorescent composite nanoparticles of the present invention preferably have a molecular recognition substance bound thereto.
  • a biological substance that can be an antigen for example, a nucleic acid (DNA, RNA, polynucleotide, oligonucleotide, which may be single-stranded or double-stranded) , PNA (peptide nucleic acid) etc., or nucleoside, nucleotide and their modified molecules), protein (polypeptide, oligopeptide etc.), amino acid (including modified amino acid), carbohydrate (oligosaccharide, polysaccharide, sugar chain etc.) ), Lipids, or modified molecules or complexes thereof.
  • a biological substance that can be an antigen for example, a nucleic acid (DNA, RNA, polynucleotide, oligonucleotide, which may be single-stranded or double-stranded) , PNA (peptide nucleic acid) etc., or nucleoside, nucleotide and their modified molecules), protein (polypeptide, oligopeptide etc.), amino
  • the molecular recognition substance bound to the X-ray absorbing fluorescent composite nanoparticles is preferably a molecular recognition substance capable of recognizing such an antigen, that is, an antibody.
  • an antibody is used to include any antibody fragment or derivative, and includes, for example, Fab, Fab ′ 2 , CDR, humanized antibody, multifunctional antibody, single chain antibody (ScFv) and the like. .
  • the method of producing the X-ray absorption fluorescent composite nanoparticles according to the present invention is not particularly limited, but as a typical example, (A) introducing a first reactive functional group into the X-ray absorbing nanoparticle to obtain an X-ray absorbing nanoparticle having the first reactive functional group; (B) A fluorescent nanoparticle having a second reactive functional group is introduced by introducing a second reactive functional group capable of reacting with the first reactive functional group to form a bond into the fluorescent nanoparticle.
  • a chemical functional group such as a carboxyl group, an amino group, an aldehyde group, a thiol group, a maleimide group, biotin, streptavidin, avidin, etc.
  • a molecule that easily forms a bond based on an affinity interaction is included.
  • the method for introducing the first reactive functional group into the X-ray absorbing nanoparticle is not particularly limited.
  • the functional group capable of binding to the X-ray absorbing nanoparticle and the first reactive functional group are used.
  • a suitable linker having a group for example, a silane coupling agent having an amino group, a thiol compound having an amino group, or the like is reacted with the X-ray absorbing nanoparticles.
  • a silane coupling agent, a thiol compound, and the like may have a reactive functional group other than an amino group as the first reactive functional group.
  • the method for introducing the second reactive functional group into the fluorescent nanoparticle is not particularly limited.
  • a functional group having a binding property with the fluorescent nanoparticle and a second reactive functional group are added.
  • examples thereof include a method in which a suitable linker having a carboxyl group, for example, a silane coupling agent having a carboxyl group or a thiol compound having a carboxyl group is reacted with fluorescent nanoparticles. It goes without saying that such a linker may have a reactive functional group other than a carboxyl group as the second reactive functional group.
  • reaction between the first reactive functional group and the second reactive functional group one or both of these reactive functional groups are once more functional groups having higher reactivity.
  • the reaction may be carried out after conversion to.
  • the carboxyl group when reacting an amino group and a carboxyl group, the carboxyl group may be once converted into a corresponding active ester and then reacted with the amino group.
  • the production method includes (D) further comprising the step of binding the molecular recognition substance to the X-ray absorption fluorescent composite nanoparticles obtained in the step (c) to obtain X-ray absorption fluorescent composite nanoparticles to which the molecular recognition substance is bonded. May be included.
  • the binding reaction can be performed using a conventional method such as a known active ester method.
  • This step (d) may be performed as a series of steps with the step (c), or may be performed as an independent step after performing post-treatment once after the step (c).
  • the X-ray absorbing fluorescent composite nanoparticles described above are suitably used as an X-ray contrast agent. Therefore, the present invention also provides an X-ray contrast agent comprising the above-described X-ray absorbing fluorescent composite nanoparticles.
  • the X-ray contrast agent of the present invention is generally blended with an X-ray contrast agent such as an adjuvant such as a stabilizer or a pharmaceutically acceptable filler, if necessary.
  • an X-ray contrast agent such as an adjuvant such as a stabilizer or a pharmaceutically acceptable filler, if necessary.
  • Subcomponents that can be contained, and the concentration and blending thereof can be appropriately changed depending on the application.
  • Nanoparticle Synthesis Formulation [Preparation Example 1-1] Synthesis of Au nanoparticles As the X-ray absorbing nanoparticles, aminopropyl-modified Au nanoparticles were synthesized by the following method. First, ⁇ solution and ⁇ solution were prepared as follows: Preparation of ⁇ solution: Mix 3 ml of 1% chloroauric acid with pure water to make 80 ml. Preparation of ⁇ solution: Dissolve citric acid in pure water to make 4 ml of 1% citric acid solution.
  • ⁇ solution and ⁇ solution were prepared as follows: Preparation of ⁇ solution: urea was dissolved in pure water to 0.8 mol / l 500 cc Adjustment of ⁇ solution: gadolinium nitrate was dissolved in pure water to make 0.05 mol / l 100 cc.
  • this ⁇ liquid and ⁇ liquid were mixed and reacted at 100 ° C. for 30 min with vigorous stirring. After completion of the reaction, the mixture was centrifuged, washed with pure water, and then fired at 600 ° C. for 1 hour to obtain Gd 2 O 3 nanoparticles. Thereafter, 350 mg of Gd 2 O 3 was dispersed in 5 cc of pure water, 300 ⁇ L of aminopropyltriethoxysilane was added, reacted at 70 ° C. for 24 hours, centrifuged to remove by-products, and then redispersed in pure water. Thus, a solution (solution Xb) of aminopropyl-modified Gd 2 O 3 nanoparticles was obtained. The particles in the obtained solution Xb were observed with a transmission electron microscope, and it was confirmed that Gd 2 O 3 particles having an average particle diameter of 60 nm were formed.
  • CdSe / ZnS particles were synthesized by the following method. Se powder (0.7896 g) was added to trioctylphosphine (TOP, 7.4 g) and the mixture was heated to 150 ° C. (under a nitrogen stream) to make a TOP-Se stock solution.
  • TOP trioctylphosphine
  • CdO (0.450 g) and stearic acid (8 g) were heated to 150 ° C. in a three-necked flask under an argon atmosphere. After CdO dissolved, the solution was cooled to room temperature. To the solution is added trioctylphosphine oxide (TOPO, 8 g) and 1-heptadecyl-octadecylamine (HDA, 12 g), and the mixture is heated again to 150 ° C., where the TOP-stock solution is quickly added. . Thereafter, the temperature of the chamber was heated to 220 ° C., and further increased to 250 ° C. over 120 minutes at a constant rate.
  • TOPO trioctylphosphine oxide
  • HDA 1-heptadecyl-octadecylamine
  • InP / ZnS particles were synthesized by the following method. Indium myristate 0.1 mmol, stearic acid 0.1 mmol, trimethylsilylphosphine 0.1 mmol, dodecanethiol 0.1 mmol, and undecylenic acid zinc 0.1 mmol are placed in a three-necked flask together with octadecene 8 ml and heated at 300 ° C. for 1 hour while refluxing in a nitrogen atmosphere. did.
  • solution D InP / ZnS solution having an emission peak wavelength of 620 nm and a concentration of 3.0 M based on InP.
  • the average particle diameter of InP / ZnS particles by dynamic light scattering was 16 nm.
  • Example 2 Sample [About the number ratio of X-ray absorbing nanoparticles and fluorescent nanoparticles]
  • the particle number ratio of X-ray absorbing nanoparticles and fluorescent nanoparticles in the composite nanoparticles was calculated based on the following procedure. First, the solution of the X-ray absorbing nanoparticles used in each Example (that is, the above solution Xa or Xb) is once dried to obtain a solid content, and the mass of the solid content is measured. The sample obtained by dissolving in water was subjected to elemental analysis using ICP, and the content of the X-ray absorbing nanoparticle constituting compound in the solid content was measured.
  • content Ma of the X-ray absorption nanoparticle constituent compound in a composite nanoparticle was computed. Further, the fluorescent nanoparticle solution used in each example (that is, the above solution C or D) is measured by the same procedure to measure the mass of the solid content and the content of the fluorescent nanoparticle constituting compound in the solid content, Using these measured values, the content Mb of the fluorescent nanoparticle-constituting compound in the composite nanoparticles was calculated. Further, the average particle diameter da of the X-ray absorbing nanoparticles and the average particle diameter db of the fluorescent nanoparticles were measured using a dynamic scattering method.
  • solution C was mixed with aminopropyl-modified Au nanoparticles and CdSe / ZnS particles at a ratio of 1: 100 particles to obtain EDC (1-ethyl-3- (3-dimethylaminopropyl).
  • Carbodiimide was added, stirred and reacted for 1 hour, and then unreacted substances were removed by centrifugation. After this, 200 ⁇ g of anti-HER2 antibody was added, EDC was added again, stirred, reacted for 1 hour, then unreacted material was removed by centrifugation, redispersed in 1 ml of PBS solution, 0.2 Au atom M and did.
  • Solution A This solution is designated as Solution A.
  • the average particle diameter of the Au—CdSe / ZnS composite nanoparticles by dynamic light scattering was 72 nm.
  • Example 2 Synthesis of Gd 2 O 3 —InP / ZnS Composite Nanoparticles Aminopropyl-modified Gd 2 O 3 nanoparticle solution obtained in Preparation Example 1-2 (solution Xb) and obtained in Preparation Example 2-2 The resulting solution of InP / ZnS particles (Solution D) was mixed with aminopropyl-modified Gd 2 O 3 nanoparticles and InP / ZnS particles at a ratio of 1: 100 particle number ratio, and 1-ethyl-3 -(3-Dimethylaminopropyl) carbodiimide was added, stirred and reacted for 1 hour, and then unreacted substances were removed by centrifugation.
  • Solution B This solution is designated as Solution B.
  • the average particle diameter of the Gd 2 O 3 —InP / ZnS composite nanoparticles by dynamic light scattering was 93 nm.
  • iopamidol is a compound containing iodine as a constituent atom.
  • X-ray contrast performance is performed by filling each sample in a 5 mm x 5 mm x 4 cm cell and using a Varian FPD Paxscan1313R with an X-ray acceleration voltage of 70 kV and an X-ray irradiation dose of 1 mR. This was done by taking an image and measuring the taken image count value at the time of shooting.
  • ⁇ Contrast performance is good
  • ⁇ Contrast performance is poor
  • the fluorescence performance was evaluated by measuring the fluorescence intensity of each sample with a Hitachi Fluorometer F7000. ⁇ : Fluorescence performance good ⁇ : Fluorescence performance failure ⁇ : No fluorescence emission The results are shown in Table 1 below.
  • the particles of the present invention have both contrast performance and fluorescence performance, and have been shown to function as bimodal contrast particles.

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Abstract

La présente invention a pour but de proposer une nanoparticule fluorescente absorbant les rayons X qui est un agent de contraste bimodal grâce auquel un cancer ou similaire peut être contrasté de manière spécifique avec des rayons X et qui peut servir comme marquage fluorescent hautement sensible et, ainsi, permet une détection en temps réel sans un besoin d'utiliser un agent de contraste coûteux de tomographie par émission de positrons (PET). L'invention concerne également une nanoparticule composite fluorescente absorbant les rayons X, ladite nanoparticule composite fluorescente absorbant les rayons X étant composée d'une nanoparticule absorbant les rayons X et de nanoparticules fluorescentes liées à celle-ci et ayant un diamètre de particule moyen en volume de 10-1 000 nm, bornes comprises, et un agent de contraste pour rayons X comprenant la nanoparticule composite fluorescente absorbant les rayons X précédemment mentionnée.
PCT/JP2012/062062 2011-05-12 2012-05-10 Nanoparticule fluorescente absorbant les rayons x WO2012153820A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017525832A (ja) * 2014-06-05 2017-09-07 ジョインスター バイオメディカル テクノロジー カンパニー リミテッド 担体粒子およびその製造方法
WO2022158377A1 (fr) 2021-01-22 2022-07-28 国立大学法人東北大学 Complexe, agent de contraste vasculaire, agent de contraste radiographique, procédé de fabrication de complexe et procédé d'imagerie permettant de capturer un changement structural dans un vaisseau

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