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WO1997033177A1 - Detecteurs de sucres et d'autres analytes se liant a des metaux - Google Patents

Detecteurs de sucres et d'autres analytes se liant a des metaux Download PDF

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Publication number
WO1997033177A1
WO1997033177A1 PCT/US1997/003654 US9703654W WO9733177A1 WO 1997033177 A1 WO1997033177 A1 WO 1997033177A1 US 9703654 W US9703654 W US 9703654W WO 9733177 A1 WO9733177 A1 WO 9733177A1
Authority
WO
WIPO (PCT)
Prior art keywords
solution
metal complex
ligand
target molecule
glucose
Prior art date
Application number
PCT/US1997/003654
Other languages
English (en)
Inventor
Frances H. Arnold
Zhibin Guan
Chao-Tsen Chen
Guohua Chen
Original Assignee
California Institute Of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by California Institute Of Technology filed Critical California Institute Of Technology
Priority to EP97908968A priority Critical patent/EP0983511A4/fr
Priority to AU20738/97A priority patent/AU2073897A/en
Priority to US08/875,047 priority patent/US6063637A/en
Publication of WO1997033177A1 publication Critical patent/WO1997033177A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/001—Enzyme electrodes
    • C12Q1/005—Enzyme electrodes involving specific analytes or enzymes
    • C12Q1/006—Enzyme electrodes involving specific analytes or enzymes for glucose
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2600/00—Assays involving molecular imprinted polymers/polymers created around a molecular template
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2650/00—Assays involving polymers whose constituent monomers bore biological functional groups before polymerization, i.e. vinyl, acryl derivatives of amino acids, sugars

Definitions

  • Metal complexes with exchangeable ligands can be tailored so that only certain compounds, with both the right metal binding groups and the right binding strength, can cause the release of protons, hydroxide ions or other ligands upon binding to the metals.
  • the analytes that can be targeted by this approach include sugars, aminosugars, polyols, amino acids, amino alcohols, ⁇ -hydroxyl carboxylic acids, ions such as carbonate, phosphate and sulfate, and gaseous species, such as CO and NO, that have the ability to undergo ligand substitution on the metal complexes.
  • these metal complexing materials can be used for chemical sensing and monitoring applications.
  • the metal complexes are preferably attached or embedded in a solid support to provide both anchoring of the complexes and positioning of the metal ions to increase selectivity of the target binding interactions. Attachment or incorporation of the metal complexes in a porous solid support can also reduce fouling of the sensor from other components in the biological sample (e.g. proteins) and provide selectivity in terms of molecular size.
  • the sensor is especially well-suited for use in measuring the concentration of glucose in blood or serum and other bodily fluids. However, the sensor, when appropriately configured, is suitable for measuring the concentration of a wide variety of other sugars and chemically-related compounds that also bind the metal complexes.
  • FIG. 2 is a diagrammatic representation of an exemplary synthesis of a preferred sugar binding sensor polymer wherein the polymer is a macroporous solid which is formed by co-polymerization of a polymerizable copper complex and crosslinking agent.
  • FIG. 15 is a graph showing a comparison of glucose and glucosamine binding to polymer IV at pH 10.25.
  • Preferred exemplary metal complexes are those which have the formula
  • M is copper or iron
  • X is H or a functional group selected from styrene, methacrylate, acrylate, vinyl ether, vinyl acetate, trialkoxysilane, dialkyl- chlorosilane, epoxy and alkylhydroxyl or alkylamine groups having from 1 to 3 carbon atoms.
  • Y is H or a functional group selected from styrene, methacrylate, acrylate, vinyl ether, vinyl, vinyl acetate, trialkoxysilane, dialkylchlorosilane, epoxy and alkyl, alkylhydroxyl or alkylamine groups having from 1 to 3 carbon atoms.
  • Tridentate ring ligands consisting of pyridine or pyrazole or imidazole rings are also suitable for forming metal complexes which may be used in detector systems in accordance with the present invention and are illustrated in FIG 1 h.
  • the coordination geometry is similar to the saturated nitrogen donors set forth above.
  • Other functional groups which can provide additional interactions with the target molecules can be introduced, as described previously.
  • FIG. 1 h In FIG. 1 h,
  • FIG. 2 An exemplary synthesis is shown in FIG. 2 for forming a sugar sensing polymer by co-polymerization of a polymerizable copper(ll) complex with a cross- linking agent to form a macroporous polymer solid.
  • the cross-linker and polymerizable metal complex are initially polymerized (step 1 ) to form the macroporous polymer sensor wherein the metal complexes are exposed for interaction with glucose molecules in solution.
  • step 2 the glucose binds to the metal complex which is in turn bound by polymerization to the polymer support structure which is represented by the shaded region in FIG. 2.
  • the procedures and conditions which are use to copolymerize the polymeriz ⁇ able metal complex and cross-linking agent are conventional.
  • the polymerizable copper metal complex is allowed to bind a sugar (methyl-/?-D- glucopyranoside) to form an imprinting polymerizable monomer/template complex which is composed of the metal complex and the glucose analog.
  • This imprinting monomer/template complex is then co-polymerized with a suitable crosslinking agent to form a porous polymer structure which is schematically shown at 10 in
  • the polymerizable copper metal complex is allowed to bind a sugar (glucose) to form an imprinting polymerizable monomer/template complex which is composed this time of two metal complexes attached to the glucose.
  • This imprinting complex is then co-polymerized with a suitable crosslinking agent to form the polymer structure which is schematically shown at 1 1 in FIG. 3b.
  • the polymer 1 1 includes the sugar and the polymerizable metal complexes which are fixed in a three-dimensional spatial distribution within the surrounding polymer support structure.
  • the polymer support structure is shown as the shaded region in FIG. 3b.
  • the glucose template is removed in the final step of sensor polymer formation. Removal of the template molecule leaves a macroporous polymer (13) with complementary molecular cavities which include metal complexes which are positioned for binding with the template sugar or its analogs.
  • the same polymerization conditions described above can be used, except a sugar template molecule such as methyl- ⁇ -D-glucop ⁇ ranoside, ⁇ -D-glucose, a disaccharide or oligosaccharide, is first equilibrated with the polymerizable metal complex in aqueous solution at pH > 9 to form the polymerizable template complex.
  • a sugar template molecule such as methyl- ⁇ -D-glucop ⁇ ranoside, ⁇ -D-glucose, a disaccharide or oligosaccharide
  • other non-sugar template molecules such as a diol or dopamine, can be used.
  • the protons released upon glucose binding to the sensor material could be measured using a light addressable potentiometric sensor (LAPS), as described by McConnell, H.M. et al., "The cytosensor microphysio- meter: biological applications of silicon technology,” Science, 257, 1906-1912 (1992).
  • LAPS light addressable potentiometric sensor
  • the sensor material would be applied such that it would be in diffusive contact with the pH-sensitive surface of the LAPS chip.
  • the vessel was sealed, purged thoroughly with N 2 , and equilibrated to 25 °C by a constant temperature water bath.
  • the pH of the Cu(TACN) solution was adjusted to a desired value (9.0, 10.0, 1 .0, or 1 2.0) with the addition of 0.10 N sodium hydroxide solution.
  • a target molecule solution of the same pH as the Cu(TACN) solution in the titration vessel was titrated into the Cu(TACN) solution.
  • the concentration of an unknown sample of c/s-diol or Me-/S-D-Glc can be determined by adding a known quantity to one of the metal complex solutions, measuring the resulting depression in pH and comparing that value to these calibration curves prepared with known quantities.
  • the flask was sealed and heated at 60° C.
  • the solution was polymerized at 55 °C for 21 hours and at 70 °C for additional 4 hours.
  • the polymer was ground into a fine powder using a mortar and washed three times with 50/50 water/methanol.
  • the resin was equilibrated with 100 mM EDTA solution at 60°C for several hours to strip off most of the Cu(ll) ion and the template sugar molecule.
  • the polymer resin was then washed with water to remove extra EDTA, reloaded Cu(ll) with 20 mM
  • Polymer I (0.5 g) was suspended in 5 mL of pH 1 1 .50, 10.50 or 10.25 NaOH solution in the pH titration vessel maintained at 25 °C by a constant temperature water bath. The pH of the suspension was adjusted as necessary by addition of 6N sodium hydroxide solution to maintain the starting pH. A solution 0 f D.( + )-giucose with concentration of 0.208 M and pH of 1 1 .50, 10.50 or 10.25 was titrated into the polymer suspension sequentially. After each addition, 0.10 N sodium hydroxide solution was added to maintain pH of the system constant. The system was kept stirring for a few minutes until equilibrium was reached. The volumes of the glucose solution injected and of the 0.10 N sodium hydroxide solution added were recorded for data analysis. The data in terms of the total concentration of released protons versus glucose concentration are plotted in FIG. 1 1 for examples performed at the three values of pH.
  • FIG. 1 2 compares the titration results for polymers II to IV at pH 10.25 in terms of protons released versus glucose concentration.
  • the largest total signal per unit weight of polymer is provided by polymer IV, made with the largest amount of polymerizable metal complex. This polymer also gives the most linear response, with respect to protons released versus glucose concentration.
  • glucosamine can release protons upon binding to the polymer, this method is useful for monitoring its concentration in solution, provided large concentrations of other, competing compounds such as glucose are not present.
  • metal ion complexes are preferred to have the following characteristics: 1 ) one of the ligands, or one or more chelating groups of a ligand, can hold the metal ion tightly; and 2) there is at least one additional ligand, or one or more chelating groups of a ligand that binds to the metal ion loosely enough that it can be substituted and released from the metal ion by the target analyte.
  • Preferred exemplary metal complexes are those of the following general composition
  • R is a polymerizable functional group, which is selected from styrene, methacrylate, acrylate, vinyl, vinyl ether, vinyl acetate, trialkoxysilane, dialkylchlorosilane, epoxy, and the like.
  • protons or hydroxides upon binding of a target analyte to the metal complexes, either protons or hydroxides are released into solution. The release of protons or hydroxides provides a direct indication of the concentration of free sugar or other target analyte in the contacting solution.
  • L-i is one or more ligand(s) that binds to the metal very strongly.
  • L 2 is one or more ligand(s) that binds to the metal weaker than L-, , and which can be exchanged by the target molecule. The displacement generates a measurable chemical species.
  • R is the polymer support to which L 1 and L 2 are anchored. L 1 and L 2 could also be different functional groups that belong to the same ligand.
  • L 1 is (are) the chelation group(s) that binds (bind) to the metal very strongly.
  • L 2 is (are) the chelation group(s) that binds (bind) to the metal weaker than L 1 does, and can be exchanged by target molecules.
  • the solution was then filtered into a vial containing crosslinking monomer N,N'-methylenebisacrylamide (MBA, 99%, purchased from Aldrich Co., Milwaukee, WI) (0.385 g, 2.50 mmol) and free radical initiator AIBN (2,2'-azo-bisisobutyronitrile, 9 mg).
  • MSA crosslinking monomer N,N'-methylenebisacrylamide
  • AIBN free radical initiator
  • the vial was sealed and heated at 65 °C.
  • the solution was polymerized at 65 °C overnight and at 70 °C for 36 hours.
  • the resulting solid was ground into a fine powder and washed with 50/50 water/methanol, pH 4, to remove Me- ?-Glucopyranoside.

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Abstract

L'invention concerne des détecteurs (20, 50, 70) utiles pour détecter la présence de sucres et d'autres analytes se liant à des métaux (molécules cibles). Le détecteur est constitué d'un complexe métallique qui se fixe à la molécule cible et qui libère un proton ou qui comprend un ligand interchangeable qui est échangé avec la molécule cible, durant l'interaction de liaison entre le complexe métallique et la molécule cible. Le résultat de cette interaction de liaison est la libération d'un proton, d'un ion hydroxyde ou d'un ligand généré durant l'échange de ligands. La mesure de la libération d'un proton, d'un ion hydroxyde ou d'un autre ligand du détecteur fournit une indication indirecte de la concentration de la molécule cible. Les complexes métalliques peuvent être fixés à des structures de support assurant aussi bien l'ancrage qu'un positionnement des ions métalliques permettant d'augmenter la sélectivité des interactions sucre/complexe métallique. L'invention concerne, également, des systèmes de détection dans lesquels le pH est utilisé comme indicateur de la libération d'un proton ou d'un hydroxyde, ainsi que les systèmes de détection utilisant la libération de Cl-. L'invention concerne, également, des méthodes de détermination de la concentration de sucres et de molécules proches, faisant appel à des détecteurs basés sur les complexes métalliques décrits.
PCT/US1997/003654 1995-12-13 1997-03-03 Detecteurs de sucres et d'autres analytes se liant a des metaux WO1997033177A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97908968A EP0983511A4 (fr) 1996-03-04 1997-03-03 Detecteurs de sucres et d'autres analytes se liant a des metaux
AU20738/97A AU2073897A (en) 1996-03-04 1997-03-03 Sensors for sugars and other metal binding analytes
US08/875,047 US6063637A (en) 1995-12-13 1997-03-03 Sensors for sugars and other metal binding analytes

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Application Number Priority Date Filing Date Title
US1275696P 1996-03-04 1996-03-04
US60/012,756 1996-03-04

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WO1997033177A1 true WO1997033177A1 (fr) 1997-09-12

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000010007A2 (fr) * 1998-08-17 2000-02-24 California Institute Of Technology Dispositifs et procedes d'analyse de solutes non ioniques
US7153532B1 (en) * 1998-08-28 2006-12-26 Johnson Matthey Public Limited Company Sensing gaseous substances using metal complexes
US10775372B2 (en) 2014-02-04 2020-09-15 The University Of Birmingham Molecular sensor preparations and uses thereof
CN117554401A (zh) * 2024-01-12 2024-02-13 沧州市天津工业大学研究院 基于膜富集与x-射线荧光联用检测水中重金属的方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111624187A (zh) * 2020-06-28 2020-09-04 吉林大学 一种基于葡萄糖氧化酶和类手枪脱氧核酶构成的荧光型葡萄糖传感器

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US5244562A (en) * 1991-07-31 1993-09-14 Hewlett-Packard Company Use of templated polymers for analyte-activated microelectronic switching devices
US5310648A (en) * 1991-02-01 1994-05-10 California Institute Of Technology Composition of matter comprising an imprinted matrix exhibiting selective binding interactions through chelated metals
WO1997005489A1 (fr) * 1995-07-31 1997-02-13 California Institute Of Technology Matieres complexantes metalliques solubles et polymeres destinees a la mesure de sucres et de molecules apparentees dans une solution

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US5310648A (en) * 1991-02-01 1994-05-10 California Institute Of Technology Composition of matter comprising an imprinted matrix exhibiting selective binding interactions through chelated metals
US5244562A (en) * 1991-07-31 1993-09-14 Hewlett-Packard Company Use of templated polymers for analyte-activated microelectronic switching devices
WO1997005489A1 (fr) * 1995-07-31 1997-02-13 California Institute Of Technology Matieres complexantes metalliques solubles et polymeres destinees a la mesure de sucres et de molecules apparentees dans une solution

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HEDBORG E, ET AL.: "SOME STUDIES OF MOLECULARLY-IMPRINTED PLYMER MEMBRANES IN COMBINATION WITH FIELD-EFFECT DEVICES", SENSORS AND ACTUATORS A., ELSEVIER SEQUOIA S.A., LAUSANNE., CH, vol. 37/38, 1 June 1993 (1993-06-01), CH, pages 796 - 799, XP000997097, ISSN: 0924-4247, DOI: 10.1016/0924-4247(93)80134-3 *
REEVES R E, BRAGG P: "CUPRAMMONIUM-GLYCOSIDE COMPLEXES. VIII. THE COPPER TO DIOL COMBINING RATIO", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 26, 1 September 1961 (1961-09-01), US, pages 3467 - 3489, XP002906225, ISSN: 0022-3263, DOI: 10.1021/jo01067a112 *
See also references of EP0983511A4 *
STARODUB N.F. ET AL: "TEMPLATE SENSORS FOW LOW WEIGHT ORGANIC MOLECULES BASED ON SIO2 SURFACES", SENSORS AND ACTUATORS B, vol. 13/14, 1993, pages 708 - 710, XP001062317 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000010007A2 (fr) * 1998-08-17 2000-02-24 California Institute Of Technology Dispositifs et procedes d'analyse de solutes non ioniques
WO2000010007A3 (fr) * 1998-08-17 2000-08-17 California Inst Of Techn Dispositifs et procedes d'analyse de solutes non ioniques
US7153532B1 (en) * 1998-08-28 2006-12-26 Johnson Matthey Public Limited Company Sensing gaseous substances using metal complexes
US10775372B2 (en) 2014-02-04 2020-09-15 The University Of Birmingham Molecular sensor preparations and uses thereof
US11686727B2 (en) 2014-02-04 2023-06-27 The University Of Birmingham Molecular sensor preparations and uses thereof
CN117554401A (zh) * 2024-01-12 2024-02-13 沧州市天津工业大学研究院 基于膜富集与x-射线荧光联用检测水中重金属的方法
CN117554401B (zh) * 2024-01-12 2024-04-02 沧州市天津工业大学研究院 基于膜富集与x-射线荧光联用检测水中重金属的方法

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AU2073897A (en) 1997-09-22
EP0983511A4 (fr) 2001-12-05
EP0983511A1 (fr) 2000-03-08

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