JP5997609B2 - 親水性のα−ヒドロキシホスホン酸コンジュゲートによる水不溶性ナノ粒子の処理、こうして修飾されたナノ粒子、及び造影剤としてのそれの使用 - Google Patents
親水性のα−ヒドロキシホスホン酸コンジュゲートによる水不溶性ナノ粒子の処理、こうして修飾されたナノ粒子、及び造影剤としてのそれの使用 Download PDFInfo
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- MONHYTQDWIXTLE-UHFFFAOYSA-N dimethyl-propyl-(2h-tetrazol-5-ylmethyl)azanium Chemical compound CCC[N+](C)(C)CC=1N=NNN=1 MONHYTQDWIXTLE-UHFFFAOYSA-N 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- 150000003216 pyrazines Chemical class 0.000 description 1
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- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229910052596 spinel Inorganic materials 0.000 description 1
- 239000011029 spinel Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003455 sulfinic acids Chemical class 0.000 description 1
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- 239000011593 sulfur Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
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- 150000003568 thioethers Chemical class 0.000 description 1
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- 238000002054 transplantation Methods 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- UIRAATSKVRBRFX-UHFFFAOYSA-O trimethyl-[3-(propanoylsulfamoyl)propyl]azanium Chemical compound CCC(=O)NS(=O)(=O)CCC[N+](C)(C)C UIRAATSKVRBRFX-UHFFFAOYSA-O 0.000 description 1
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Classifications
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- 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
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- 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
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- 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
- A61K49/0428—Surface-modified nanoparticles, e.g. immuno-nanoparticles
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- 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
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- 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
- A61K49/1842—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 the small organic molecule being a phosphate or a phosphonate, not being a phospholipid
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- 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]
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
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Description
PEG−350コンジュゲートの合成
PEG−350モノ(メチルエーテル)アセトアルデヒドの合成。CH2Cl2(98mL)に溶解したPEG−350モノ(メチルエーテル)(3.438g、9.82mmol)を含む溶液にDess−Martin Periodinane(5.00g、11.79mmol)を添加し、得られた溶液を室温で20時間撹拌した。反応中に微細な白色沈殿が生じたが、反応終了時にこれをセライトパッドでの濾過によって除去した。真空中で濾液から溶媒を除去したところ、黄色の油状物中に懸濁された白色の固体が残った。固体をジエチルエーテルでトリチュレートし、固体をセライトパッドでの濾過によって除去した。真空中で濾液から溶媒を除去したところ、生成物PEG−350モノ(メチルエーテル)アセトアルデヒド(3.42g、100%)が黄色の油状物として残った。1H NMR(CDCl3)δ 9.73(t,J=4Hz,1H),4.16(d,J=4Hz,2H),7.65(m,24H),3.38(s,3H)ppm。IR(neat)2873,1732,1455,1350,1109,1040,948,851,749cm-1。
PEG−1900コンジュゲートの合成
PEG−1900モノ(メチルエーテル)アセトアルデヒドの合成。CH2Cl2(86mL)に溶解したPEG−1900モノ(メチルエーテル)(16.32g、8.60mmol)を含む溶液にDess−Martin Periodinane(4.00g、9.44mmol)を添加し、得られた溶液を室温で20時間撹拌した。反応中に微細な白色沈殿が生じたが、反応終了時にこれをセライトパッドでの濾過によって除去した。真空中で濾液から溶媒を除去したところ、白色の固体が残った。これをTHF/ヘキサンから再結晶することで、所望生成物(11.6g、71%)を白色の固体として得た。1H NMR(CDCl3)δ 9.74(t,J=1Hz,1H),4.17(d,J=1Hz,2H),3.83(m,2H),3.65(m,170H),3.39(s,3H)。
親水性ホスフェートの合成
ジフェニルPEG−350モノ(メチルエーテル)ホスフェートの合成。CH2Cl2(80mL)に溶解したPEG−350モノ(メチルエーテル)(8.54g、24.4mmol)を含む溶液に、トリエチルアミン(3.68g、36.6mmol)を添加し、次いで4−N,N−ジメチルアミノピリジン(0.298g、2.44mmol)を添加した。得られた溶液を0℃に冷却し、ジフェニルクロロホスフェート(7.87g、29.3mmol)を滴下し、反応物を0℃で10分間撹拌した。次いで、反応物を室温に加温し、さらに16時間撹拌した。反応物を10%HCl(80mL)の添加で奪活し、得られた層を分離した。有機層を水(80mL)及びブライン(80mL)で洗浄し、無水物MgSO4上で乾燥した。濾過し、真空中で溶媒を除去したところ、所望生成物(14.2g、100%)が金色の油状物として残った。1H NMR(CDCl3)δ 7.34(m,4H),7.22(m,6H),4.38(m,2H),3.73(m,2H),3.64(m,24H),3.54(m,2H),3.38(s,3H)。
超常磁性酸化鉄(SPIO)ナノ粒子の合成。100mL三つ口丸底フラスコにFe(acac)3(0.706g、2.0mmol)及び無水ベンジルアルコール(20mL)を仕込んだ。得られた溶液を窒素でスパージし、窒素雰囲気下において165℃で4時間加熱した。次いで、得られた(DLSで測定して)5nm酸化鉄粒子のコロイド懸濁液を室温に冷却し、その温度で貯蔵した。
α−ヒドロキシPEG−350モノ(メチルエーテル)ホスホネートでコートした超常磁性酸化鉄ナノ粒子の合成。実施例3の超常磁性酸化鉄ナノ粒子をTHF中に懸濁した1mg Fe/mLのコロイド懸濁液に、(Fe 1モル当たりコンジュゲート1モルの比率で)実施例1のα−ヒドロキシホスホン酸コンジュゲートを添加し、得られた懸濁液を50℃で16時間加熱した。次いで、反応物を室温に冷却し、水で希釈し、褐色の水溶液をヘキサで3回洗浄した。水性層中に残留する揮発分を真空中で除去し、得られたナノ粒子を、接線流濾過を使用しながら30kDa分子カットオフフィルターに対してH2Oで洗浄することで精製した。
α−ヒドロキシPEG−1900モノ(メチルエーテル)ホスホネートでコートした超常磁性酸化鉄ナノ粒子の合成。実施例1のコンジュゲートの代わりに実施例2のコンジュゲートを用いて実施例4を繰り返した。
α−ヒドロキシPEG−350モノ(メチルエーテル)ホスフェートでコートした超常磁性酸化鉄ナノ粒子の合成。比較例1のコンジュゲートを用いて実施例4を繰り返した。
5−ブロモ−1−ペンタナールの合成。250mL丸底フラスコ内で、塩化オキサリル(2.42mL、0.022mol)を無水ジクロロメタン(40mL)と混合した。フラスコを窒素でブランケットし、溶液をドライアイス/アセトン浴中で−78℃に冷却した。反応混合物を撹拌し、無水ジメチルスルホキシド(3.4mL、0.044mol)をフラスコにゆっくりと添加し、次いで5−ブロモ−1−ペンタノール(3.34g、0.020mol)を添加し、反応混合物を−78℃で15分間撹拌した。トリエチルアミン(14.0mL、0.1mol)を反応混合物にゆっくりと添加した。トリエチルアミンの添加が完了した後、反応物を−78℃で5分間撹拌した。反応物をドライアイス/アセトン浴から取り出し、室温に加温し、室温で18時間撹拌した。
ジエチル(5−ブロモ−1−ヒドロキシ−ペンチル)ホスホネートの合成。250mL丸底フラスコ内で、5−ブロモペンタナール(1.64g、0.010mol)をジエチルエーテル(15mL)に溶解した。反応物を窒素でブランケットした。過塩素酸リチウム(7.92g、0.075mol)を反応物に添加し、反応溶液を氷浴中で0℃に冷却した。クロロトリメチルシラン(0.631mL、0.010mol)をフラスコに添加し、次いでトリメチルホスフィット(2.1mL、0.012mol)を添加した。反応混合物を室温で18時間撹拌した。
ジエチル5−(4−(エトキシカルボニル)ピペリジン−1−イル)−1−ヒドロキシペンチルホスホネートの合成。300mL丸底フラスコ内で、ジエチル(5−ブロモ−1−ヒドロキシ−ペンチル)ホスホネート(3.02g、0.0099mol)を無水トルエン(100mL)に溶解した。トリエチルアミン(2.08mL、0.015mol)を反応混合物に添加し、次いでエチルイソニペコテート(1.84mL、0.012mol)を添加した。混合物を18時間加熱還流した。真空下で溶媒を除去したところ、橙色のガムが残った。ガムをジクロロメタン(100mL)に溶解し、飽和NaHCO3水溶液(100mL)及びブライン(100mL)で順次に洗浄した。塩化メチレン溶液を硫酸マグネシウムで乾燥し、濾過によって回収した。真空下で溶媒を除去したところ、橙色の液体(1.70g)が残った。
5−(4−(エトキシカルボニル)ピペリジン−1−イル)−1−ヒドロキシペンチルホスホン酸の合成。100mLフラスコ内で、ジエチル5−(4−(エトキシカルボニル)ピペリジン−1−イル)−1−ヒドロキシペンチルホスホネート(0.66g、0.0017mol)をジクロロメタン(25mL)に溶解した。ブロモトリメチルシラン(0.69mL、0.0052mol)を反応混合物に添加した。反応物を室温で一晩撹拌した。一晩の撹拌後、真空下で溶媒を除去したところ、橙色のガムが残った。ガムをアセトン(20mL)に溶解した。水(0.4mL)を添加した。ガムが沈殿した。真空下で溶媒を除去したところ、赤色のガム(0.6g)が残った。ガムを1H NMRによって特性決定し、生成物は5−(4−(エトキシカルボニル)ピペリジン−1−イル)−1−ヒドロキシペンチルホスホン酸であることが確認された。1H NMR(400MHz,CD3OD)δ 4.3−4.1(m,2H),3.9−3.4(m,3H),3.4−2.5(m,7H),2.5−1.35(m,11H),1.35−1.2(m,3H)。
5−(4−(エトキシカルボニル)ピペリジン−1−イル)−1−ヒドロキシペンチルホスホネートでコートした酸化タンタルナノ粒子の合成。イソ酪酸(0.242g、2.75mmol)及び水(0.08g、4.44mmol)を含む無水メタノール(17mL)の溶液を、N2でスパージすることで40分間ガス抜きした。これにTa2(OEt)2(1g、2.46mmol)を滴下し、反応混合物をN2雰囲気下で5時間撹拌することで、3〜4nmナノ粒子の懸濁液を得た。5−(4−(エトキシカルボニル)ピペリジン−1−イル)−1−ヒドロキシペンチルホスホン酸(0.088g、0.205mmol)をメタノール(0.5mL)に溶解した溶液を酸化タンタルナノ粒子懸濁液(1mL)に滴下し、N2下において70℃で一晩加熱した。室温に冷却した後、水(約3mL)を反応混合物に滴下した。ロータリーエバポレーター上においてメタノールを減圧下で蒸発させて除去した後、1M NH4OH(0.33mL)を添加し、反応物を50℃で一晩撹拌した。3500Da分子量カットオフ再生セルロース膜を用いて、反応混合物を水(3×2L)に対して24時間透析した。DLSによれば、粒度は水中で7nmであると確認された。
SPIOナノ粒子のコロイド懸濁液の特性決定。実施例4及び実施例5並びに比較例2において接線流濾過の結果として得られたコロイド懸濁液を、安定性及びゼータ電位に関して評価した。
MRIによるインビボ腫瘍のイメージング。動物に関係するすべての手続きは、GE Global Research Institutional Animal Care and Use Committeeによって承認されたプロトコルの下で完了した。雌のFischer 344ラット(約150g)において、0.1mLのハンクス平衡塩類溶液中の2×106 Mat B III細胞(ATCC# CRL1666、ATCC(マナサス、米国ヴァージニア州))を皮下注射することで腫瘍を誘導した。注射部位は肩胛骨の間の背中に位置していた。移植から9日後、腫瘍が直径約1cmになった時に腫瘍のイメージングを行った。
Claims (7)
- ヒト被験体への注射に適したMRI造影剤として使用される組成物であって、次式の1以上のα−ヒドロキシホスホネート部分が付着した水不溶性ナノ粒子を含む組成物。
- Rがエチレンオキシド単位に基づくポリマー親水性部分である、請求項1記載の組成物。
- 前記ポリマー親水性部分がエチレンオキシドに基づくものであって、ポリ(エチレンオキシド)が5000ダルトン以下の分子量を有する、請求項1又は請求項2記載の組成物。
- 前記ナノ粒子が酸化鉄に基づく超常磁性ナノ粒子である、請求項1乃至請求項3のいずれか1項記載の組成物。
- 薬学的に許容されるキャリヤー又は賦形剤をさらに含む、請求項1乃至請求項4のいずれか1項記載の組成物。
- 診断イメージングの方法に用いられる請求項1乃至請求項5のいずれか1項記載の組成物であって、前記方法が、
a.前記組成物を被験体に投与する段階、及び
b.前記ナノ粒子が造影剤として作用する診断イメージングに前記被験体を付す段階
を含んでいる、組成物。 - 請求項1乃至請求項6のいずれか1項記載の組成物の製造方法であって、
a.懸濁剤中でナノ粒子の懸濁液を用意する段階、及び
b.前記懸濁液を前記α−ヒドロキシホスホネート部分に接触させる段階
によって前記水不溶性ナノ粒子を製造することを含む方法。
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AU2010311437A1 (en) | 2012-04-12 |
BR112012010113A2 (pt) | 2019-09-24 |
JP2013509381A (ja) | 2013-03-14 |
ES2720152T3 (es) | 2019-07-18 |
EP2493512B1 (en) | 2019-01-23 |
CN102639153B (zh) | 2017-02-22 |
WO2011051422A2 (en) | 2011-05-05 |
CA2777871A1 (en) | 2011-05-05 |
US20110104072A1 (en) | 2011-05-05 |
IN2012DN02804A (ja) | 2015-07-24 |
WO2011051422A3 (en) | 2011-07-21 |
US20160038617A1 (en) | 2016-02-11 |
EP2493512A2 (en) | 2012-09-05 |
KR20120101362A (ko) | 2012-09-13 |
US9827335B2 (en) | 2017-11-28 |
MX2012005022A (es) | 2012-06-08 |
RU2012116880A (ru) | 2013-12-10 |
CN102639153A (zh) | 2012-08-15 |
US9205155B2 (en) | 2015-12-08 |
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