PYRIDINIUM BORONIC ACID QUENCHERS FOR USE IN ANALYTE SENSORS

• US 20120208286A1
• Filed: 04/25/2012
• Published: 08/16/2012
• Est. Priority Date: 05/01/2007
• Status: Active Grant

• Current Assignee: Medtronic Minimed Incorporated (Medtronic Plc)
• Original Assignee: GluMetrics, Inc.
• Inventors: GAMSEY, SOYA, WESSLING, RITCHIE A.
• Granted Patent: US 8,658,795 B2
• Time in Patent Office: Days
• US Class Current: 436/163
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: G01N 2400/00 Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
• CPC Class Codes: G01N 33/523 the element being adapted for a specific analyte
• CPC Class Codes: Y10T 436/104998 Glucose, ketone, nitrate standard or control
• CPC Class Codes: Y10T 436/144444 Glucose
• CPC Class Codes: Y10T 436/145555 Hetero-N

Abstract

Novel pyridinium salts functionalized with boronic acid and methods of making them are disclosed. When combined with a fluorescent dye, the compounds are useful in the detection of polyhydroxyl-substituted organic molecules.

Claims

1. An analyte sensor comprising:

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 said quencher comprises one or more pyridinium group(s).

2. The analyte sensor of claim 1, wherein said fluorophore comprises a pyranine derivative.

3. The analyte sensor of claim 2, wherein said pyranine derivative is a hydroxypyrene trisulfonamide derivative.

4. The analyte sensor of claim 2, wherein said pyranine derivative is a polymeric derivative of hydroxypyrene trisulfonic acid.

5. The analyte sensor of claim 2, wherein said pyranine derivative is HTPS-TriCys-MA.

6. The analyte sensor of claim 1, wherein said one or more pyridinium group(s) are functionalized with boronic acid(s).

7. The analyte sensor of claim 1, wherein said one or more pyridinium group(s) are substituted with carbonyl groups and are structurally configured and functionally adapted to bind a polyhydroxyl-substituted organic molecule.

8. The analyte sensor of claim 7, wherein said polyhydroxyl-substituted organic molecule is a sugar molecule.

9. The analyte sensor of claim 7, wherein a moiety that provides recognition of a polyhydroxyl-substituted organic molecule is an aromatic boronic acid.

10. The analyte sensor of claim 9, wherein the boronic acid is attached via a linker group or covalently bonded to a conjugated nitrogen-containing heterocyclic aromatic structure.

11. The analyte sensor of claim 6, wherein the boronic acid(s) have a pKa of between about 4 and 9 and react reversibly with glucose in aqueous media at a pH from about 6.8 to 7.8 to form boronate esters.

12. The analyte sensor of claim 1, wherein the fluorophore has different acid and base forms that exhibit a detectable difference in spectral properties.

13. The analyte sensor of claim 1 comprising at least one boronic acid per pyridinium.

14. The analyte sensor of claim 1 comprising a plurality of pyridinium rings, one or more of which are not substituted with boronic acid groups.

15. An analyte sensor of claim 1 comprising a means for immobilizing the fluorophore and the quencher, such that they remain physically close enough to one another to react.

16. The analyte sensor of claim 15, wherein the immobilizing means are insoluble in an aqueous environment, permeable to the target analytes, and impermeable to the fluorophore and the quencher.

17. The analyte sensor of claim 15, wherein the immobilizing means comprises a water-insoluble organic polymer matrix.

18. A method of ratiometric pH sensing comprising:

contacting the analyte sensor of claim 12 with analyte; and

detecting differences in spectral properties of the analyte sensor.