Quaternary nitrogen heterocyclic compounds for detecting aqueous monosaccharides in physiological fluids

• US 7,718,804 B2
• Filed: 12/27/2005
• Issued: 05/18/2010
• Est. Priority Date: 06/27/2003
• Status: Expired due to Fees

• Current Assignee: Chris Geddes
• Original Assignee: University of Maryland Biotechnology Institute
• Inventors: Geddes, Chris D., Badugu, Ramachandram, Lakowicz, Joseph R.
• Primary Examiner(s): SEAMAN, D MARGARET M
• Application Number:
  US11/318,663
• Publication Number:
  US 20070020182A1
• Time in Patent Office: 1,603 Days
• Field of Search: 546/13, 546/171
• US Class Current: 546/13
• CPC Class Codes: A61K 49/0021 the fluorescent group being a small organic molecule
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: Y10T 436/143333 Saccharide [e.g., DNA, etc.]
• CPC Class Codes: Y10T 436/144444 Glucose
• CPC Class Codes: Y10T 436/193333 In aqueous solution

Abstract

Quaternary nitrogen heterocyclic boronic acid-containing compounds are described, which are sensitive to glucose and fructose, as well as a variety of other physiologically important analytes, such as aqueous chloride and iodide, and a method of using the compounds. Also disclosed is a contact lens doped with the quaternary nitrogen heterocyclic boronic acid-containing compound, and a method of using the doped contact lens to measure the concentration of analyte in tears under physiological conditions.

Claims

1. A fluorescence compound having the formula:

2. The compound of claim 1, wherein X is bromide and R is —

CH₃, —

OCH₃ or —

NH₂.

3. The compound of claim 1, wherein R is —

CH₃.

4. The compound of claim 1, wherein R is —

OCH₃.

5. The compound of claim 1, wherein the fluorescence intensity of the compound changes in the presence of analytes.

6. The compound of claim 5, wherein the analyte comprise a species selected from the group consisting of glucose, fructose, chloride and iodide.

7. The compound of claim 1, wherein the fluorescence intensity of the compound decreases in the presence of glucose.

8. A method of measuring the concentration of an analyte in a physiological fluid, said method comprising:

(a) contacting a fluorescence compound having the formula;

9. The method of claim 8, wherein the physiological fluid is blood, tears, interstitial fluid or aqueous humor.

10. The method of claim 8, wherein the measuring of the analyte is continuous.

11. The method of claim 8, wherein the physiological fluid is tears.

12. The method of claim 8, wherein X is bromide and R is CH₃ or —

OCH₃.

13. The method of claim 12, wherein R is —

CH₃.

14. The method of claim 8, wherein the analyte comprises a species selected from the group consisting of glucose, fructose, chloride and iodide.

15. The method of claim 8, wherein the analyte comprises glucose.

16. The method of claim 8, wherein the optical signal is a fluorescence signal.

17. The method of claim 16, wherein the fluorescence is measured based on the intensity, lifetime, anisotropy or ratiometric fluorescence platforms.

18. The method of claim 16, wherein the concentration of the analyte is determined by comparing the fluorescence measurement in the presence of analyte with the fluorescence measurement in the absence of analyte.

19. The method of claim 16, wherein the concentration of the analyte is determined by comparing the fluorescence measurement in the presence of analyte with the fluorescence measurement in the presence of a known concentration of analyte.

20. The method of claim 8, wherein the fluorescence compound is in solution.

21. The method of claim 8, wherein the fluorescence compound is contained in an analyte-permeable matrix.

22. An assay kit for measuring the concentration of an analyte in a physiological fluid comprising a container containing a fluorescence compound having the formula of:

23. The kit of claim 22, wherein the physiological fluid is blood.

24. The kit of claim 22, wherein the analyte comprises glucose.

25. The kit of claim 22, wherein X is bromide and R is —

CH₃ or —

OCH₃.

26. An ophthalmic sensor comprising:

a polymer matrix comprising a fluorescence compound contacting at least the outer surfaces of the polymer matrix, wherein the fluorescence compound interacts or reacts with an analyte to provide an optical signal which is indicative of the analyte concentration in an ocular fluid and wherein the fluorescence compound has the formula;

27. The ophthalmic sensor of claim 26, wherein X is bromide and R is —

CH₃ or —

OCH₃.

28. The ophthalmic sensor of claim 26, wherein the ophthalmic device is a contact lens.

29. The ophthalmic sensor of claim 28, wherein the fluorescence compound is coated on the surface of a contact lens.

30. The ophthalmic sensor of claim 28, wherein the fluorescence compound is impregnated into the polymer matrix of which the contact lens is fabricated thereof.

31. The ophthalmic sensor of claim 30, wherein the contact lens is disposable.

32. The ophthalmic sensor of claim 26, wherein the fluorescence compound is covalently attached to the surface of the ophthalmic device.

33. The ophthalmic sensor of claim 26, wherein the fluorescence compound is physically bonded to the surface of the ophthalmic device.

34. The ophthalmic sensor of claim 26, wherein the ophthalmic device is implantable.

35. The ophthalmic sensor of claim 26, wherein the analyte comprises a species selected from the group consisting of glucose, fructose, chloride, and iodide.

36. The ophthalmic sensor of claim 26, wherein the analyte comprises glucose.

37. The ophthalmic sensor of claim 26, wherein the optical signal is a fluorescence signal.

38. The ophthalmic sensor of claim 37, wherein the fluorescence is measured based on the intensity, lifetime, anisotropy or ratiometric fluorescence platforms.

39. A method of measuring the concentration of glucose in ocular fluid, said method comprising:

(a) contacting a fluorescence compound having a formula of;

40. The method of claim 39, wherein the optical signal decreases with the increased concentration of glucose.

41. The method of claim 39, wherein X is bromide and R is CH₃ or —

OCH₃.

42. The method of claim 39, wherein the concentration of glucose is in a range from about 50 uM to about 5 mM.

43. The method of claim 39, wherein the optical signal is a fluorescence signal.

44. The method of claim 43, wherein the fluorescence is measured based on the intensity, lifetime, anisotropy or ratiometric fluorescence platforms.

45. The method of claim 43, wherein the concentration of the glucose is determined by comparing the fluorescence measurement in the presence of glucose with the fluorescence measurement in the absence of glucose.

46. The method of claim 43, wherein the concentration of the glucose is determined by comparing the fluorescence measurement in the presence of glucose with the fluorescence measurement in the presence of a known concentration of glucose.

47. The method of claim 39, wherein the fluorescence compound is coated on a contact lens.

48. The method of claim 47, wherein the contact lens is disposable.

49. The method of claim 47, further comprising a second fluorescence compound that is sensitive to chloride.

50. An analyte sensor comprising:

a substrate comprising a fluorescence compound contacting at least the outer surfaces of the substrate, wherein the fluorescence compound interacts or reacts with an analyte to provide an optical signal which is indicative of the analyte concentration in a physiological fluid and wherein the fluorescence compound has a formula of;

(A)

51. The analyte sensor of claim 50, wherein X is bromide and R is —

CH₃ or —

OCH₃.

52. The analyte sensor of claim 50, wherein the substrate is a contact lens.

53. The analyte sensor of claim 50, wherein the substrate is implantable.

54. The analyte sensor of claim 50, wherein the analyte comprises a member selected from the group consisting of glucose, fructose, chloride, and iodide.

55. The analyte sensor of claim 50, wherein the optical signal is fluorescence and is measured based on the intensity, lifetime, anisotropy or ratiometric fluorescence platforms.

56. A fluorescence compound having the formula:

57. The compound of claim 56, wherein the B(OH)₂ functional is in the meta or para position.

58. The compound of claim 56, wherein X is bromide and R is —

CH₃, or —

OCH₃.

59. The compound of claim 56, wherein R is —

CH₃.

60. The compound of claim 56, wherein R is —

OCH₃.

61. The compound of claim 56, wherein the fluorescence intensity of the compound changes in the presence of an analyte.

62. The compound of claim 61, wherein the analyte comprises a species selected from the group consisting of glucose and fructose.

63. A method of measuring the concentration of an analyte in a physiological fluid, said method comprising:

(a) contacting a fluorescence compound having the formula;

64. The method of claim 63, wherein the physiological fluid is blood, tears, interstitial fluid or aqueous humor.

65. The method of claim 63, wherein the measuring of the analyte is continuous.

66. The method of claim 63, wherein the physiological fluid is tears.

67. The method of claim 63, wherein X is bromide and R is —

CH₃, or —

OCH₃.

68. The method of claim 63, wherein the analyte comprises a species selected from the group consisting of glucose and fructose.

69. A method of measuring the concentration of glucose in ocular fluid, said method comprising:

(a) contacting a fluorescence compound having a formula of;