Optical determination of glucose utilizing boronic acid adducts
First Claim
1. A device for optically determining an analyte concentration, which device comprises:
- an analyte permeable component;
a fluorophore associated with the analyte permeable component and configured to absorb light at a first wavelength and emit light at a second wavelength;
a quencher associated with the analyte permeable component and configured to modify the light emitted by the fluorophore by an amount related to the analyte concentration, wherein the quencher comprises a boronic acid substituted viologen;
a light source; and
a detector.
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Accused Products
Abstract
The present invention concerns an improved optical method and optical sensing device for determining the levels of polyhydroxyl-substituted organic molecules in vitro and/or in vivo in aqueous media. The range of detection is between about 400 and 800 nm. In particular, a sensory devise is implemented in a mammal to determine sugar levels. Specifically, a dye is combined with a conjugated nitrogen-containing heterocyclic aromatic boronic acid-substituted bis-onium compound in the presence of a sugar, such as fructose or glucose. The viologens are preferred as the aromatic conjugated nitrogen-containing boronic acid substituted compounds. The method is useful to determine sugar levels in a human being.
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Citations
56 Claims
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1. A device for optically determining an analyte concentration, which device comprises:
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an analyte permeable component;
a fluorophore associated with the analyte permeable component and configured to absorb light at a first wavelength and emit light at a second wavelength;
a quencher associated with the analyte permeable component and configured to modify the light emitted by the fluorophore by an amount related to the analyte concentration, wherein the quencher comprises a boronic acid substituted viologen;
a light source; and
a detector. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 50, 53, 54, 56)
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22. A device for optically determining an analyte concentration in a physiological fluid, comprising:
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an analyte permeable component;
a fluorophore associated with the analyte permeable component and configured to absorb light at a first wavelength and emit light at a second wavelength, wherein the fluorophore comprises a substituted pyrene, a quencher associated with the analyte permeable component and configured to modify the light emitted by the fluorophore by an amount related to the analyte concentration;
a light source; and
a detector.
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23. An analyte sensor, comprising:
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a fluorophore configured to absorb light at a first wavelength and emit light at a second wavelength; and
a quencher configured to modify the light emitted by the fluorophore by an amount related to the analyte concentration, wherein the quencher comprises a boronic acid substituted viologen. - View Dependent Claims (24, 25)
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26. An analyte sensor, comprising:
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a fluorophore dye comprising a pyrene derivative configured to absorb light at a first excitation wavelength and emit light at a second emission wavelength; and
a quencher configured to bind an analyte, wherein the quencher is operably coupled to the fluorophore dye, and wherein the quencher is configured to modulate the light emitted by the fluorophore dye in relation to the binding of the analyte. - View Dependent Claims (27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 48, 55)
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45. A method of making an analyte sensor, comprising:
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reacting a dipyridyl with an alkylating agent comprising an arylboronic acid to produce a N,N′
-bis-benzylboronic acid viologen; and
operably coupling the N,N′
-bis-benzylboronic acid viologen to a fluorophore capable of being quenched by a viologen. - View Dependent Claims (46)
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47. An optical method for the in vivo detection of polyhydroxyl-substituted organic molecules as the analyte between about 400 and 800 nm detection, which method comprises:
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A. Obtaining a fluorophore dye D, which is compatible with the analyte solution, wherein D is selected from;
(a) D1 which is a fluorophore dye having the properties of i. A fluorophore, ii. An excitation in the range greater than 400 nm and less than 800 nm, iii. Resistant to photobleaching under the conditions of analysis, iv. A Stokes shift of about or greater than 30 nm, v. Compatibility with said analyte solution, and wherein said vi. Dye D1 is quenched by methyl viologen to produce an experimentally determined apparent Stern-Volmer quenching constant (Ksv) greater than or equal to 50, wherein the fluorophore dye D1 which is neutral or negatively charged is;
(i) a discrete compound having a molecular weight of 1,000 daltons or greater, with the proviso that if the dye is substituted with negatively charged groups the molecular weight is 500 daltons or greater;
(ii) a pendant group or chain unit in a water-soluble or dispersible polymer having a molecular weight greater than about 10,000 daltons, and optionally said polymer is non-covalently associated with a water-insoluble polymer matrix M1 and is physically immobilized within said polymer matrix M1 wherein said polymer matrix M1 is permeable to or in contact with said analyte solution; and
optionally where dye D1 is negatively charged and the polymer is immobilized as a complex with a cationic water-soluble polymer, said complex formed is permeable to or in contact with said analyte solution;
(b) D2 is a fluorophore dye having the properties of i. A fluorophore, ii. An excitation in the range greater than 400 nm and less than 800, iii. A Stokes shift of about or greater than 30 nm, iv. Resistant to photobleaching under the conditions of analyses, v. Compatibility in the analyte solution, and wherein vi. Said Dye D2 is quenched by methyl viologen to produce an apparent Stern-Volmer quenching constant (Ksv) greater than or equal to 50, wherein D2 is covalently bonded to an insoluble polymer matrix M1 wherein said polymer matrix M1 is permeable to or in contact with said analyte;
wherein said fluorophore dye D2 is a part of the structure;
M1-L1-D2 with the proviso that D2 which is polyfunctional is bonded to matrix M1 at one, two or three sites;
L1 is a hydrolytically stable covalent linking group selected from the group consisting of a direct bond, lower alkylene having 1 to 8 carbon atoms optionally terminated with or including one or more divalent connecting groups selected from sulfonamide, amide, ester, ether, sulfide, sulfone, phenylene, urethane, urea, and amine, and B. Combining with a boronic acid-containing quencher moiety Q, wherein Q is comprised of a conjugated nitrogen-containing heterocyclic, aromatic bis-onium salt having the properties of compatibility in said analyte solution and produces a detectable change in the emission of the fluorophore dye (D1 or D2) in the presence of said analyte, selected from;
(i) quencher Q1 which is a discrete compound having a molecular weight of about 400 daltons or greater or is a pendant group or a chain unit in a water-soluble or water-dispersible polymer having a molecular weight greater than 10,000 daltons and said polymer optionally is non-covalently associated with the optional polymer matrix M1 when present, and is physically immobilized in said polymer matrix, or optionally said polymer is immobilized as a complex with a negatively charged water-soluble polymer, or(ii) quencher Q2 which is covalently bonded by linking group L2 to M1 or to a second water insoluble polymer matrix M2 producing M2-L2-Q2 wherein L2 is selected from the group consisting of a direct bond, a lower alkylene having 1 to 8 carbon atoms optionally terminated with or including one or more divalent connecting groups selected from sulfonamide, amide, quaternary ammonium, pyridinium, ester, ether, sulfide, sulfone, phenylene, urea, thiourea, and urethane, or amine, wherein said quencher Q1 or Q2 is mixed at a molecular level with said fluorophore dye D1 or D2, and with the proviso that Q2 when polyfunctional is linked to the matrix M2 at one or two sites, C. contacting a physiological fluid which contains analyte, with a dye and a quencher in vivo with an excitation light source coupled with a detector;
D. producing a detectable and quantifiable signal in the range of about 400 to 800 nm; and
E. determining the concentration of said polyhydroxyl-substituted analyte in said physiological fluid.
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49. An optical device for the in vivo detection of polyhydroxyl-substituted organic molecules as the analyte between about 400 and 800 nm detection, which device comprises:
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A. a fluorophore dye D, which is compatible with the analyte solution, wherein D is selected from;
(a) D1 which is a fluorophore dye having the properties of i. A fluorophore, ii. An excitation in the range greater than 400 nm and less than 800 nm, iii. Resistant to photobleaching under the conditions of analysis, iv. A Stokes shift of about or greater than 30 nm, v. Compatibility with said analyte solution, and wherein said vi. Dye D1 is quenched by methyl viologen to produce an experimentally determined apparent Stern-Volmer quenching constant (Ksv) greater than or equal to 50, wherein the fluorophore dye D1 which is neutral or negatively charged is;
(i) a discrete compound having a molecular weight of 1,000 daltons or greater, with the proviso that if the dye is substituted with negatively charged groups the molecular weight is 500 daltons or greater;
(ii) a pendant group or chain unit in a water-soluble or dispersible polymer having a molecular weight greater than about 10,000 daltons, and optionally said polymer is non-covalently associated with a water-insoluble polymer matrix M1 and is physically immobilized within said polymer matrix M1 wherein said polymer matrix M1 is permeable to or in contact with said analyte solution; and
optionally where dye D1 is negatively charged and the polymer is immobilized as a complex with a cationic water-soluble polymer, said complex formed is permeable to or in contact with said analyte solution;
(b) D2 is a fluorophore dye having the properties of i. A fluorophore, ii. An excitation in the range greater than 400 nm and less than 800, iii. A Stokes shift of about or greater than 30 nm, iv. Resistant to photobleaching under the conditions of analyses, v. Compatibility in the analyte solution, and wherein vi. Said Dye D2 is quenched by methyl viologen to produce an apparent Stern-Volmer quenching constant (Ksv) greater than or equal to 50, wherein D2 is covalently bonded to an insoluble polymer matrix M1 wherein said polymer matrix M1 is permeable to or in contact with said analyte;
wherein said fluorophore dye D2 is a part of the structure;
M1-L1-D2 with the proviso that D2 which is polyfunctional is bonded to matrix M1 at one, two or three sites;
L1 is a hydrolytically stable covalent linking group selected from the group consisting of a direct bond, lower alkylene having 1 to 8 carbon atoms optionally terminated with or including one or more divalent connecting groups selected from sulfonamide, amide, ester, ether, sulfide, sulfone, phenylene, urethane, urea, and amine, and B. a boronic acid-containing quencher moiety Q, wherein Q is comprised of a conjugated nitrogen-containing heterocyclic, aromatic bis-onium salt having the properties of compatibility in said analyte solution and produces a detectable change in the emission of the dye in the presence of said analyte, selected from;
(i) quencher Q1 which is a discrete compound having a molecular weight of about 400 daltons or greater or is a pendant group or a chain unit in a water-soluble or water-dispersible polymer having a molecular weight greater than 10,000 daltons and said polymer optionally is non-covalently associated with the optional polymer matrix M1 when present, and is physically immobilized in said polymer matrix, or optionally said polymer is immobilized as a complex with a negatively charged water-soluble polymer, or (ii) quencher Q2 which is covalently bonded by linking group L2 to M1 or to a second water insoluble polymer matrix M2 producing M2-L2-Q2 wherein L2 is selected from the group consisting of a direct bond, a lower alkylene having 1 to 8 carbon atoms optionally terminated with or including one or more divalent connecting groups selected from sulfonamide, amide, quaternary ammonium, pyridinium, ester, ether, sulfide, sulfone, phenylene, urea, thiourea, and urethane, or amine, wherein said quencher Q1 or Q2 is mixed at a molecular level with said fluorophore dye D1 or D2, and with the proviso that Q2 when polyfunctional is linked to the matrix M2 at more than one site, wherein when a dye and a quencher in contact with physiological fluid which contains an analyte in vivo is contact with an excitation light source coupled with a detector;
C. produces a detectable and quantifiable signal in the range of about 400 to 800 nm; and
D. determines the concentration of said polyhydroxyl-substituted analyte, wherein the Dye D components and quencher Q components are immobilized in or attached to a polymer matrix M1, M2 or combinations thereof and said device measures the concentration of polyhydroxyl-containing molecules periodically or continuously.
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- 51. A composition of matter selected from:
Specification