WO2007091350A1 - Membrane en phase solide contenant de l'albumine a surface modifiee ou un complexe porphyrine metallique-albumine serique a surface modifiee - Google Patents

Membrane en phase solide contenant de l'albumine a surface modifiee ou un complexe porphyrine metallique-albumine serique a surface modifiee Download PDF

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WO2007091350A1
WO2007091350A1 PCT/JP2006/320114 JP2006320114W WO2007091350A1 WO 2007091350 A1 WO2007091350 A1 WO 2007091350A1 JP 2006320114 W JP2006320114 W JP 2006320114W WO 2007091350 A1 WO2007091350 A1 WO 2007091350A1
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serum albumin
solid phase
oxygen
phase film
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PCT/JP2006/320114
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Japanese (ja)
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Eishun Tsuchida
Teruyuki Komatsu
Yubin Huang
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Eishun Tsuchida
Teruyuki Komatsu
Yubin Huang
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0026—Blood substitute; Oxygen transporting formulations; Plasma extender
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
    • C08J5/20—Manufacture of shaped structures of ion-exchange resins
    • C08J5/22—Films, membranes or diaphragms
    • C08J5/2287—After-treatment
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2389/00—Characterised by the use of proteins; Derivatives thereof

Definitions

  • the present invention relates to a solid phase membrane containing surface-modified albumin or surface-modified serum albumin metal porphyrin complex and application thereof.
  • FeTpivPP complexes 5, 10, 15, 20-tetrakis (a, a, a, ⁇ -o pivaloylaminophenol) porphyrin iron (II ) Complexes (hereinafter referred to as “FeTpivPP complexes”) (JP Collman, et al., J. Am. Chem. Soc, 97, 1427 (1975)) are clearly able to form stable oxygen complexes at room temperature. became.
  • the FeTpivPP complex reversible molecular oxygen in organic solvents such as benzene, toluene, dichloromethane, tetrahydrofuran, N, N dimethylformamide, etc.
  • the solvent for dissolving these heme derivatives must be an aqueous physiological salt solution.
  • Iron porphyrin can exhibit reversible oxygen coordination activity only when the central iron is in a divalent state. When the central iron is oxidized, it becomes an oxygen (III) complex. Is lost. Generally water Since the oxidation of central iron (II) is accelerated in solution, the stability of the resulting oxygen complex is significantly reduced.
  • Serum albumin-iron (II) porphyrin complex strength obtained by actually encapsulating intramolecular base-bound FeTpivPP in human serum albumin It has been demonstrated that it acts as an artificial red blood cell that can transport oxygen in vivo (E. Tsuchida et al., Bioconju gate Chem. 11, 46 (2000)). In addition, this serum albumin-iron (II) porphyrin complex also has the characteristics that no side effects such as hypertension observed in molecular hemoglobin preparations are observed (E. Tsuchida et al., J. Biomed. Mater. Res. 64A, 257 (2003)).
  • an object of the present invention is to clarify new characteristics and functional expression of serum albumin or serum albumin-metal porphyrin complex surface-modified with poly (ethylene glycol) chains.
  • the present invention provides a solid phase membrane by removing poly (ethylene glycol) -modified serum albumin prepared as an aqueous solution (aqueous dispersion) or a dispersion medium (water) of serum albumin-metal porphyrin complex by drying.
  • aqueous dispersion aqueous dispersion
  • water dispersion medium
  • serum albumin-metal porphyrin complex can be provided as a stable film-like thin film, and in the case of a poly (ethylene glycol) -modified serum albumin-metal borphyrin complex, it can be provided as an oxygen-adsorbing membrane that can reversibly bind and dissociate oxygen.
  • these solid phase membranes are also soluble in an organic solvent, and an equivalent solid phase membrane can be provided again by removing the solvent by drying.
  • surface-modified serum albumin in which a poly (ethylene glycol) group is covalently bound to serum albumin, and a metal borfilin compound encapsulated in the surface-modified serum albumin
  • a solid phase membrane comprising a surface-modified serum albumin-metal porphyrin complex comprising
  • the surface-modified serum albumin or the surface-modified serum albumin-metal porphyrin complex containing the surface-modified serum albumin of the present invention is dissolved in an organic solvent, A solid phase membrane prepared by volatilizing the solvent is provided.
  • an oxygen adsorption film including the solid phase film of the present invention.
  • artificial skin including the solid phase film of the present invention, various coating agents, surface modification (hydrophilization treatment) agent, artificial blood vessel surface treatment agent, artificial organ surface treatment
  • an artificial plasma extender or artificial oxygen carrier that can be carried as an agent, a surface treatment agent for a medical device, a cell sheet, or a thin film is provided.
  • an oxygen adsorption membrane an oxygen enriched membrane, an oxygen permeable membrane, an oxygen removal membrane, or a gas selective separation membrane comprising the oxygen adsorption membrane of the present invention.
  • Serum albumin or serum albumin encapsulated with a metalloporphyrin compound Surface-modified serum albumin obtained by covalently bonding a poly (ethylene glycol) group to the surface, or an aqueous solution of a surface-modified serum albumin metalloporphyrin complex
  • a solid phase film having surface-modified serum albumin or surface-modified serum albumin-metal porphyrin complex strength can be obtained.
  • Serum albumin is preferably human serum albumin, rabbit serum albumin, recombinant human serum albumin, or albumin multimer.
  • the average number of poly (ethylene glycol) bonds per molecule of albumin is preferably 1 to 20 (that is, surface-modified serum albumin has an average of 1 to 20 poly ( Ethylene glycol) is preferred to have molecules)).
  • the number average molecular weight of poly (ethylene glycol) is preferably 500 to 50,000! / ⁇ .
  • the metal Borfilin compound included in serum albumin is preferably represented by the following formula [I], [II], [III], or [IV].
  • the metalloporphyrin compound represented by the formula [I] is disclosed in Japanese Patent Application Laid-Open No. 06-271577 and Japanese Patent Application Laid-Open No. 2003-040893.
  • JP 2002-128781 discloses a metalloporphyrin compound represented by the formula [III]
  • JP 2004-190189 discloses a metal porphyrin compound represented by the formula [IV]
  • Japanese Patent Laid-Open No. 2003-069760 has been disclosed.
  • These metal porphyrin compounds can be used alone or as a mixture of two or more.
  • R may have a substituent! Is a linear or alicyclic hydrocarbon group.
  • R is preferably a linear or alicyclic hydrocarbon group having a substituent at the 1-position.
  • chain or alicyclic hydrocarbon groups are: 1, 1 monodisubstituted C
  • Substituted cyclopropyl group, 1-substituted cyclopentyl group, 1-substituted cyclohexyl group, 2-substituted norbornyl group substituted with methyl group, alkylamide group (R 'CONH-), alkyl ester group (R, OOC- ) Or an alkyl ether group (R, O—)), 1-methyl-2-cyclohexyl group, or 1-adamantyl group.
  • the alkyl group represented by R ′ is preferably a C to C alkyl group.
  • R is an alkylene group, preferably a ⁇ C alkylene group.
  • R represents a central transition metal ion M of the imidazolyl group (periods 4 to 5 of the periodic table)
  • R It is a group that allows coordination to the transition metal ion).
  • An example of such R is hydrogen
  • X— represents a halide ion such as a chloride ion or a bromide ion
  • the number n of X— is a value obtained by subtracting 2 from the valence of the transition metal ion M.
  • R may have a substituent! Is a linear or alicyclic hydrocarbon group.
  • R is preferably a linear or alicyclic hydrocarbon group having a substituent at the 1-position. Such straight
  • chain or alicyclic hydrocarbon groups examples include 1, 1 mono-substituted C to C alkyl groups, 1
  • Substituted cyclopropyl group, 1-substituted cyclopentyl group, 1-substituted cyclohexyl group, 2-substituted norbornyl group substituted with methyl group, alkylamide group (R 'CONH-), alkyl ester group (R, OOC- ) Or an alkyl ether group (R, O—)), 1-methyl-2-cyclohexyl group, or 1-adamantyl group.
  • the alkyl group represented by R ′ is preferably a C to C alkyl group.
  • R is an alkylene group, preferably a C to C alkylene group.
  • R is an alkyl group, preferably a ⁇ C alkyl group.
  • M is a central transition metal ion (a transition metal ion having 4 to 5 periods in the periodic table). It represents a halide ion such as a chloride ion or a bromide ion, and the number of X's n is the number obtained by subtracting 2 from the valence of the transition metal ion M.
  • R is a linear or alicyclic hydrocarbon group which may have a substituent.
  • R is preferably a linear or alicyclic hydrocarbon group having a substituent at the 1-position.
  • Such straight Examples of chain or alicyclic hydrocarbon groups include 1, 1 substituted C to C alkyl groups, 1
  • Substituted cyclopropyl group, 1-substituted cyclopentyl group, 1-substituted cyclohexyl group, 2-substituted norbornyl group substituted with substituents in these groups are methyl group, alkylamide group (R 'C ONH-), alkyl ester group (R, OOC ⁇ ) or alkyl ether group (R, O—)), 1-methyl-2-cyclohexyl group, or 1-adamantyl group.
  • the alkyl group represented by R ′ is preferably a C to C alkyl group.
  • R is an alkylene group, preferably a ⁇ C alkylene group.
  • R represents a central transition metal ion M of the imidazolyl group (periodic table 4-5)
  • a group that allows coordination to a periodic transition metal ion preferably a hydrogen atom or a methyl group
  • X— represents a halide ion such as a chloride ion or a bromide ion
  • the number n of X— is a value obtained by subtracting 2 from the valence of the transition metal ion M.
  • R 1 is hydrogen or a hydrocarbon group.
  • R is a hydrogen atom, a vinyl group,
  • Ethyl group, formyl group, and acetyl group are preferred.
  • R is an alkyl group, preferably a C to C alkyl group.
  • R is an alkylene group, preferably a C to C alkylene group.
  • R represents a central transition metal ion M of the imidazolyl group (4 to 5 in the periodic table).
  • the number n of X— is the number obtained by subtracting 2 from the valence of the transition metal ion M.
  • Serum albumin in which a metal-borfilin compound is encapsulated in a solid-phase film having the surface-modified serum albumin metal porphyrin complex strength of the present invention is obtained by gene recombination technology using an amino acid that brings about the binding of the metal-borfilin compound.
  • At least one recombinant human serum albumin introduced therein can be used, and a metal borfilin compound can be axially coordinated to the recombinant human serum albumin.
  • Serum albumin subdomain IB is preferred for the amino acid introduced by histidine.
  • Each phosphorus compound has an axial base ligand in the molecule, such as metal protoporphyrin, metal deuteroporphyrin, metal diacetyl deuteroporphyrin, metal mesoporous porphyrin, metal diformyl porphyrin, metal Tetrafluoro-porphyrin, preferably metal octaethylporphyrin! /.
  • the central transition metal ion M is preferably Fe or Co.
  • the valence of Fe can be +2 (Fe (II)) or +3 (Fe (III)), and the valence of Co can be +2 (Co (II)).
  • the surface-modified serum albumin or the surface-modified serum albumin metal porphyrin complex has a solid phase film that can be obtained as a highly flexible thin film, so that it can be easily processed and has a wide range of applications.
  • it since it is composed of serum albumin cartridges, it is also suitable for applications such as direct application and direct attachment to the body surface, where biocompatibility is extremely high.
  • a film-like solid phase film having serum albumin strength is artificial skin, various coating agents, surface modification (hydrophilization) agent, artificial blood vessel surface treatment agent, artificial organ surface treatment agent, medical treatment
  • various coating agents surface modification (hydrophilization) agent
  • artificial blood vessel surface treatment agent artificial organ surface treatment agent
  • medical treatment In addition to instrument surface treatment agents and cell culture sheets, it is expected to be applied as an artificial plasma expander or artificial oxygen carrier that can be carried as a thin film.
  • oxygen can be reversibly bound and dissociated, so an oxygen adsorption membrane, an oxygen-enriched membrane, an oxygen-permeable membrane, an oxygen-removing membrane, a gas selective separation membrane Offered as.
  • porphyrin is a complex of metal ions belonging to the 4th to 5th cycles, the added value as a catalyst for oxidation-reduction reaction, oxygen oxidation reaction or oxygen addition reaction is also high.
  • gas molecules coordinated to the central metal there are carbon monoxide, nitrogen monoxide, nitrogen dioxide, cyanide and the like in addition to oxygen.
  • serum albumin includes non-specifically various low-molecular compounds in addition to the metalloporphyrin compounds described above.
  • surface modified serum albumin containing low molecular weight compounds and functional molecules other than metal borphyrin compounds is prepared, and it is dried and concentrated in the same way, and the surface modified serum albumin has one functional molecular force.
  • the solid thin film is also extremely useful for medical use.
  • the method for producing the surface-modified serum albumin of the present invention is not limited! /
  • Surface-modified serum albumin can be obtained by converting the amino group of the lysine residue present in the amine molecule to a thiolate group by iminothiolane and reacting it with poly (ethylene glycol) having a terminal maleimide group.
  • a phosphate buffered saline solution PBS, pH 7.4 of human serum albumin (albumin concentration: 0.1 to: LO wt%, preferably 0.5 to 5.0 wt%).
  • human serum albumin albumin concentration: 0.1 to: LO wt%, preferably 0.5 to 5.0 wt%).
  • iminothiolan Pierce Chemical, iminothiolane / albumin: 3 to 40 (mol / mol), preferably 10 to 30
  • the obtained mixture is repeatedly concentrated and washed with a few liters of PBS solution using an ultrafiltration device (for example, UHP-76K, manufactured by Advantech, 5 kDa).
  • the obtained surface-modified serum albumin aqueous solution is passed through a 0.45 m sterilization filter (DISMIC 25CS045AS manufactured by Advantech), then diluted and concentrated with several liters of pure water using the ultrafiltration device described above. Repeat desalting to obtain the desired surface modified serum albumin.
  • DISMIC 25CS045AS manufactured by Advantech
  • surface-modified serum albumin can be obtained by reacting poly (ethylene glycol) having a terminal succinimide group with an amino group of a lysine residue present in a serum albumin molecule.
  • the concentration of the surface-modified serum albumin can be measured by the promocresol green method (manufactured by Wako Pure Chemical Industries, Ltd., Albumin Test Co., Ltd.). Furthermore, the molecular weight of the surface-modified serum albumin can be measured by Matritus-assisted laser desorption / ionization mass spectrometry (MALDI-TOFMS) (KRATOS AXIMA-CFR manufactured by Shimadzu Corporation). These measurement results indicate that the number of poly (ethylene glycol) chains bonded to the albumin surface is 1 to 20.
  • the method for producing the surface-modified serum albumin of the present invention is not limited to the method for producing a solid phase membrane having the power of a metal porphyrin complex, but the method for producing the above-mentioned surface-modified serum albumin with respect to serum albumin including a metal porphyrin compound. Can be used to obtain a surface-modified serum albumin-metal porphyrin complex.
  • phosphate buffer 1-8 (mole Z moles)
  • a physiological saline solution PBS, pH 7.4
  • iminothiolane manufactured by Pierce Chemical Co., Ltd., iminothiolane Z albumin: 3 to 40 (mol Z mol), preferably 10 to 30
  • PBS physiological saline solution
  • iminothiolane manufactured by Pierce Chemical Co., Ltd., iminothiolane Z albumin: 3 to 40 (mol Z mol), preferably 10 to 30
  • the mixture is preferably stirred for 2 to 6 hours.
  • one-end maleimide one-end methyl-poly (ethylene glycol) for example, Sunbright M E-020MA (Mw: 2,333, manufactured by NOF Corporation, poly (ethylene glycol) / albumin: 3 to 40 (mol Z mol), preferably Is added for 10 to 30) and allowed to react for 0.5 to 6 hours, preferably 1 to 3 hours under the same conditions.
  • the obtained red surface-modified serum albumin monoiron ( ⁇ ) porphyrin complex aqueous solution was passed through a 0.45 ⁇ m sterilization filter (DISMIC 25CS045AS manufactured by Advantech), and then the Dilution / concentration with 1 liter of pure water is repeated and desalted to obtain the desired surface-modified serum albumin metal volfilin complex.
  • the iron ion concentration of the surface-modified serum albumin-iron ( ⁇ ) porphyrin complex can be measured using induction plasma luminescence analysis (ICP, SPS7000A manufactured by Seiko Instruments Inc.), and can be used as an index of heme concentration.
  • the albumin concentration can be measured by the promocresol green method.
  • the molecular weight can be measured by MALDI-T OFMS of the surface-modified serum albumin-iron (II) porphyrin complex. From the above measurement results, it is evident that the number of poly (ethylene glycol) chains bound to the albumin surface is 1 to 20.
  • the surface-modified serum albumin or surface-modified serum albumin-metal porphyrin complex force obtained as described above is dissolved in an organic solvent, and the solid solution prepared by volatilizing the organic solvent from the homogeneous solution.
  • the phase membrane also exhibits the same function.
  • the organic solvent include methanol, ethanol, chloroform, formaldehyde, dichloromethane, benzene, toluene, tetrahydrofuran, jetyl ether, N, N dimethylformamide and the like.
  • the solid phase film having the surface-modified serum albumin force of the present invention includes artificial skin, various coating agents, surface modifying (hydrophilizing) agent, artificial blood vessel surface treating agent, artificial organ surface treating agent, medical instrument surface treating agent. Can be used as a cell sheet.
  • the solid phase film having the surface modified serum albumin-metal porphyrin complex strength of the present invention includes artificial skin, various coating agents, surface modification (hydrophilization) agent, artificial blood vessel surface treatment agent, artificial organ surface treatment agent, Medical device It can be used as a surface treatment agent, a cell sheet, and a portable artificial plasma expander or artificial oxygen carrier.
  • the solid phase membrane having the surface-modified serum albumin monometal porphyrin complex force of the present invention is effective in the case of an iron (II) or cobalt (II) complex, particularly an effective oxygen adsorption membrane, oxygen enriched membrane, oxygen permeable membrane.
  • porphyrin is a complex of metal ions belonging to the 4th to 5th cycles, for example, as an oxygen removal membrane or gas selective separation membrane, it should be used as a catalyst for acid reduction reaction, oxygen oxidation reaction or oxygen addition reaction. Can do.
  • the obtained mixture was repeatedly concentrated and washed with 1 L of PBS solution using an ultrafiltration device (manufactured by Advantech, UHP-76K, ultramolecular weight membrane: 5 kDa), and finally concentrated to 48 mL.
  • the obtained surface-modified serum albumin aqueous solution was passed through a 0.45 ⁇ m sterilization filter (DISMI C 25CS045AS manufactured by Advantech), and then diluted and concentrated with several liters of pure water using the above ultrafiltration device. , Desalted.
  • the concentration of the obtained surface-modified serum albumin was measured by a bromocresol green method (manufactured by Wako Pure Chemical Industries, Ltd., albumin test kit). Furthermore, the molecular weight of the surface-modified serum albumin was measured by matrix-assisted laser desorption / ionization-mass spectrometry (MALDI-TOFMS) (Shimadzu KRATOS AXIMA-CFR). From the above experimental results, it was found that the albumin concentration was 5.0% by weight, the molecular weight was 95 kDa, and the average number of poly (ethylene glycol) chains bound to the albumin surface was 6.
  • one-end maleimide one-end methylolene poly (ethylene glycolol) (Sunbright ME-020MA, Mw: 2,333, manufactured by NOF Corporation, 1.44 g) was added and reacted for 2 hours under the same conditions.
  • an ultrafiltration device Advanced Tech, UHP-76K, ultramolecular weight membrane: 5 kDa
  • 1 L of PB Concentration 'washing with S solution was repeated, and finally the solution was concentrated to 48 mL.
  • the obtained red surface-modified serum albumin monoiron ( ⁇ ) porphyrin complex aqueous solution was passed through a 0.45 ⁇ m sterilization filter (DISMIC 25CS045AS manufactured by Advantech), and then the above ultrafiltration device was used. Dilution / concentration was repeated with 1 liter of pure water for desalting.
  • the iron ion concentration of the obtained surface-modified serum albumin monoiron ( ⁇ ) porphyrin complex was measured using induction plasma emission analysis (ICP, SPS7000A manufactured by Seiko Instruments Inc.) and used as an index of heme concentration.
  • the albumin concentration was measured by the bromocresol green method (manufactured by Wako Pure Chemical Industries, Ltd., albumin test kit).
  • the molecular weight of the surface-modified serum albumin-iron (II) vorphiline complex was measured by matrix-assisted laser desorption / ionization mass spectrometry (MALDI-TOFMS) (KRATOS AXIMA-CFR manufactured by Shimadzu Corporation). From the above experimental results, the iron (II) porphyrin concentration is 3. OmM, the albumin concentration is 5.0 wt%, the molecular weight is 80 kDa, and the average number of poly (ethylene glycol) chains bound to the albumin surface is six. I understood it.
  • the obtained mixture was repeatedly concentrated and washed with 1 L of PBS solution using an ultrafiltration device (Advantech, UHP-76K, ultra molecular weight membrane: 5 kDa), and finally concentrated to 48 mL.
  • the resulting red surface-modified serum albumin monoiron ( ⁇ ) porphyrin complex aqueous solution was added to a 0.45 ⁇ m sterilization filter (DISMIC 25CS04 manufactured by Advantech). 5AS), and then diluted with several liters of pure water and concentrated repeatedly using the ultrafiltration device described above, and desalted.
  • the iron ion concentration of the obtained surface-modified serum albumin monoiron ( ⁇ ) porphyrin complex was measured using induction plasma emission analysis and used as an index of heme concentration.
  • the albumin concentration was measured by the bromocresol green method. Furthermore, the molecular weight was measured by MALDI-TOFMS (KR ATOS AXIMA-CFR manufactured by Shimadzu Corporation) of surface-modified serum albumin-iron ( ⁇ ) porphyrin complex. From the above experimental results, the iron (II) porphyrin concentration is 3. OmM, the albumin concentration is 5.0 wt%, the molecular weight is 80 kDa, and the average number of poly (ethylene glycol) chains bound to the albumin surface is six.
  • Example 5 2 (N— (8— (2-Methylimidazolyl) otatanyloxy)) methyl-5, 10, 15, 20—tetrakis (a, a, a, ⁇ —o— (1 —Methylcyclohexanamide) Phenol) Borufinato Iron ( ⁇ )
  • N— (8— (2-Methylimidazolyl) otatanyloxy) methyl-5, 10, 15, 20—tetrakis (a, a, a, ⁇ —o— (1 —Methylcyclohexanamide) Phenol) Borufinato Iron ( ⁇ )
  • ⁇ Borufinato Iron
  • a solid phase film having the surface-modified serum albumin-iron (II) porphyrin complex force exemplified in Example 2 was prepared in the quartz spectroscopic cell by the same method, and was exactly the same as shown in Example 8. Measurement was performed to confirm adsorption / desorption of oxygen molecules. When 3 mL of ethanol was added to the quartz cell, the solid phase film was dissolved and a red ethanol solution was obtained. When the circular dichroism spectrum of the ethanol solution was measured, ⁇ ⁇ appeared at 208 and 222 nm, and the peak intensity ratio was different from the value in the aqueous solution of albumin. It became clear that the next and higher order structures were retained.
  • the quartz cell was sealed with a septum rubber, when the ultraviolet-visible absorption spectrum measurement of the surface-modified serum albumin iron (II) Borufuirin double combined ethanol solutions, the maximum absorption wavelength e max is
  • the surface-modified serum albumin of the present invention or the surface-modified serum albumin metal borphyrin complex has a solid phase film in which the surface of the albumin molecule is sufficiently covered with a poly (ethylene glycol) group, so Even when the material is removed by drying, the higher-order structure of albumin itself is stably maintained. Further, when a metal borfilin compound is included in the inside, the inclusion molecule can also exist stably in the inside of albumin, so that it has a feature that it can reversibly bind and dissociate oxygen molecules.
  • the surface-modified serum albumin of the present invention or the solid-phase membrane having the surface-modified serum albumin-metal porphyrin complex strength can be used practically as a film-like thin film while maintaining the oxygen binding ability that can be expressed in the aqueous phase system. It can be provided as an oxygen adsorption film.
  • the surface-modified serum albumin or the surface-modified serum albumin metal porphyrin complex strength solid-phase film of the present invention is not only an oxygen adsorption film, but also artificial skin, various coating agents, and a surface modification (hydrophilization treatment) agent.
  • Artificial blood vessel surface treatment agent artificial organ surface treatment agent, medical device surface treatment agent, cell sheet, artificial plasma bulking agent or artificial oxygen carrier that can be carried as a thin film, or oxygen-enriched membrane, oxygen-permeable membrane, oxygen It is a useful material provided as a removal membrane and a gas selective separation membrane.

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Abstract

L'invention concerne une membrane en phase solide contenant de l'albumine sérique à surface modifiée, un groupement poly(éthylène glycol) étant lié de manière covalente à l'albumine sérique ou un complexe porphyrine métallique-albumine sérique à surface modifiée, un groupement poly(éthylène glycol) étant lié de manière covalente à l'albumine sérique et un composé de porphyrine métallique étant compris dans l'albumine sérique à surface modifiée.
PCT/JP2006/320114 2006-02-09 2006-10-06 Membrane en phase solide contenant de l'albumine a surface modifiee ou un complexe porphyrine metallique-albumine serique a surface modifiee WO2007091350A1 (fr)

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JP2006032809A JP2007209543A (ja) 2006-02-09 2006-02-09 表面修飾アルブミンからなる固相膜および酸素吸着膜

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112828279A (zh) * 2020-12-31 2021-05-25 昆明理工大学 一种金属粉末气相脱氧方法
CN114712332A (zh) * 2022-03-15 2022-07-08 陕西师范大学 一种改性水性材料及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004063250A1 (fr) * 2003-01-06 2004-07-29 Nektar Therapeutics Al, Corporation Derives polymeriques solubles dans l'eau et a selectivite de thiol
WO2004074345A2 (fr) * 2003-02-19 2004-09-02 Pharmacia Corporation Esters de polyethyleneglycol actives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004063250A1 (fr) * 2003-01-06 2004-07-29 Nektar Therapeutics Al, Corporation Derives polymeriques solubles dans l'eau et a selectivite de thiol
WO2004074345A2 (fr) * 2003-02-19 2004-09-02 Pharmacia Corporation Esters de polyethyleneglycol actives

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112828279A (zh) * 2020-12-31 2021-05-25 昆明理工大学 一种金属粉末气相脱氧方法
CN114712332A (zh) * 2022-03-15 2022-07-08 陕西师范大学 一种改性水性材料及其制备方法和应用
CN114712332B (zh) * 2022-03-15 2024-01-30 陕西师范大学 一种改性水性材料及其制备方法和应用

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