Flexible Carbohydrate-Bearing Polymer

• US 20090187084A1
• Filed: 12/06/2006
• Published: 07/23/2009
• Est. Priority Date: 12/07/2004
• Status: Active Grant

• Current Assignee: Medtronic Minimed Incorporated (Medtronic Plc)
• Original Assignee: Precisense A/S (Medtronic Plc)
• Inventors: Yu, Yihua, Kristensen, Jesper Svenning, Gregorius, Klaus, Struve, Casper
• Granted Patent: US 8,691,517 B2
• Time in Patent Office: Days
• US Class Current: 600/310
• CPC Class Codes: A61B 5/145 Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissuemeasuring of blood pressure or blood flow A61B5/02; non-radiation detecting or locating of foreign bodies in blood A61B5/06
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: C08B 37/0063 Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
• CPC Class Codes: G01N 33/54373 involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
• CPC Class Codes: G01N 33/66 involving blood sugars, e.g. galactose

Abstract

A sensor for the detection or measurement of a carbohydrate analyte in fluid comprises components of a competitive binding assay the readout of which is a detectable or measurable optical signal retained by a material that permits diffusion of the analyte but not the assay components, the assay components comprising: a carbohydrate binding molecule labelled with one of a proximity based signal generating/modulating moiety pair; and a carbohydrate analogue capable of competing with the analyte for binding to the carbohydrate binding molecule, the carbohydrate analogue being a flexible water-soluble polymer comprising: polymerized or co-polymerised residues of monomer units, the monomer unit residues bearing pendant carbohydrate or carbohydrate mimetic moieties and pendant moieties which are the other of the proximity based signal generating/modulating moiety pair.

Claims

1. A sensor for the detection or measurement of a carbohydrate analyte in fluid, the sensor comprising components of a competitive binding assay the readout of which is a detectable or measurable optical signal retained by a material that permits diffusion of the analyte but not the assay components, the assay components comprising:

a carbohydrate binding molecule labelled with one of a proximity based signal generating/modulating moiety pair; and

a carbohydrate analogue capable of competing with the analyte for binding to the carbohydrate binding molecule, the carbohydrate analogue being a flexible water-soluble polymer comprising;

polymerized residues of monomer units, the monomer unit residues bearing pendant carbohydrate or carbohydrate mimetic moieties and pendant moieties which are the other of the proximity based signal generating/modulating moiety pair; and

/or

co-polymerised residues of first monomer units and second monomer units, the first monomer unit residues bearing pendant carbohydrate or carbohydrate mimetic moieties and the second monomer unit residues bearing pendant moieties which are the other of the proximity based signal generating/modulating moiety pair.

2. A sensor as claimed in claim 1, comprising a copolymer of said first and second monomer units polymerized from a reaction mixture, wherein the second monomer units are present in the reaction mixture in an amount of 5 to 15 mol %.

3. A sensor as claimed in claim 1, wherein the carbohydrate moieties are selected from optionally derivatised mannose, maltose, isomaltose, glucose, sophorose and/or 2-acetylglucosamine.

4. A sensor as claimed in claim 1, wherein the proximity based signal generating/modulating moieties are linked to amine, acid, alcohol, alkyne, azide and/or sulphone functional groups of the or the second monomer units.

5. A sensor as claimed in claim 1, wherein the proximity based signal generating/modulating moieties are energy donors or energy acceptors.

6. A sensor as claimed in claim 1, further comprising polymerized residues of third monomer units not bearing carbohydrate or carbohydrate mimetic moieties or proximity based signal generating/modulating moieties.

7. A sensor as claimed in claim 6, wherein the third monomer units are present in the reaction mixture in an amount of 0 to 80 mol %.

8. A sensor as claimed in claim 6, wherein the third monomer units contain hydrophilic groups.

9. A sensor as claimed in claim 8, wherein the third monomer units comprise 2-hydroxyethylacetate, vinyl pyrrolidone, MMA, HEMA, vinyl alcohol and/or ethylene glycol.

10. A sensor as claimed in claim 1, wherein the average polymer molecular weight is in the range of 20 to 250 kDa.

11. A sensor as claimed in claim 1, wherein the carbohydrate analyte is glucose and the polymer is capable of competing with glucose at physiological calcium concentrations.

12. A sensor as claimed in claim 11, wherein the assay is capable of measuring blood glucose at concentrations over at least part of the range of 0 to 35 mM glucose.

13. A sensor as claimed in claim 1, wherein the carbohydrate binding molecule is a lectin.

14. A sensor as claimed in claim 13, wherein the carbohydrate binding molecule is mannose binding lectin or Concanavalin A.

15. A sensor as claimed in claim 1, wherein the components of the assay are retained by a shell or matrix material.

16. A sensor as claimed in claim 15, wherein the retaining material is biodegradable.

17. A method of preparing a sensor as claimed in claim 1, the method comprising at least one of phase separation (coacervation), solvent evaporation, extraction, spray drying, spray coating, spray chilling, rotary disk atomisation, fluid bed coating, coextrusion and pan coating.

18. A method of detecting a carbohydrate analyte using a sensor as claimed in claim 1, comprising implantation of the sensor into the skin of a mammal and transdermal detection or measurement of carbohydrate analyte using external optical means.

19. A method of detecting a carbohydrate analyte using a sensor as claimed in claim 1, comprising transdermal detection or measurement of a carbohydrate analyte using external optical means by illumination of a said sensor present in or below the skin of a mammal.

20. A method of synthesizing a flexible water-soluble polymer comprising polymerized residues of first monomer units, the first monomer unit residues bearing pendant carbohydrate or carbohydrate mimetic moieties and pendant moieties which are the other of the proximity based signal generating/modulating moiety pair and/or co-polymerised residues of first monomer units and second monomer units, the first monomer unit residues bearing pendant carbohydrate or carbohydrate mimetic moieties and the second monomer unit residues bearing pendant moieties which are the other of the proximity based signal generating/modulating moiety pair, the method comprising one of the following procedures:

a) polymerising monomer units each bearing a pendant carbohydrate or carbohydrate mimetic moiety and a pendant proximity based signal generating/modulating moiety and optionally third monomer units;

b) co-polymerising first monomer units each bearing a pendant carbohydrate or carbohydrate mimetic moiety and second monomer units each bearing a pendant proximity based signal generating/modulating moiety and optionally third monomer units;

c) polymerising monomer units each bearing a pendant carbohydrate or carbohydrate mimetic moiety and a pendant functional group for linking to an proximity based signal generating/modulating moiety and optionally third monomer units, then reacting the monomer unit residues with the proximity based signal generating/modulating moieties;

d) co-polymerising first monomer units each bearing a pendant carbohydrate or carbohydrate mimetic moiety and second monomer units each bearing a pendant functional group for linking to an proximity based signal generating/modulating moiety and optionally third monomer units, then reacting the second monomer unit residues with the proximity based signal generating/modulating moieties;

e) polymerising monomer units each bearing a pendant functional group for linking to a carbohydrate or carbohydrate mimetic moiety and a pendant different functional group for linking to an proximity based signal generating/modulating moiety and optionally third monomer units, then reacting the monomer unit residues with the carbohydrate or carbohydrate mimetic moieties and proximity based signal generating/modulating moieties;

or f) co-polymerising first monomer units each bearing a pendant functional group for linking to a carbohydrate or carbohydrate mimetic moiety and second monomer units each bearing a pendant different functional group for linking to an proximity based signal generating/modulating moiety and optionally third monomer units, then reacting the first monomer unit residues with the carbohydrate or carbohydrate mimetic moieties and the second monomer unit residues with proximity based signal generating/modulating moieties.

21. A method as claimed in claim 20, wherein the monomer units are reacted by addition polymerization.

22. A method as claimed in claim 20, wherein the monomer units and/or first monomer units comprise allyl or vinyl containing derivatives of carbohydrate or carbohydrate mimetic moieties.

23. A method as claimed in claim 20, wherein the monomer units and/or second monomer units comprise double bond-containing molecules containing an amine functional group.