Methods for functional kidney imaging using small dendrimer contrast agents

• US 6,852,842 B2
• Filed: 08/26/2002
• Issued: 02/08/2005
• Est. Priority Date: 08/26/2002
• Status: Expired due to Fees

• Current Assignee: The United States of America, as represented by the Secretary, Department of Health and Human Services
• Original Assignee: United States Department Of Health And Human Services (Government of the United States of America)
• Inventors: Kobayashi, Hisataka, Brechbiel, Martin W., Star, Robert A.
• Primary Examiner(s): Jones, Dameron Levest
• Application Number:
  US10/229,316
• Publication Number:
  US 20040037777A1
• Time in Patent Office: 897 Days
• Field of Search: 424/1.11, 424/1.65, 424/9.1, 424/9.3, 424/9.36, 424/9.361, 424/9.362, 534/7, 534 10- 16
• US Class Current: 534/15
• CPC Class Codes: A61K 49/124 dendrimers, dendrons, hyperbranched compounds
• CPC Class Codes: A61K 51/065 conjugates with carriers being macromolecules
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

Small dendrimer-based MRI contrast agents are disclosed to accumulate in renal tubules. The accumulation enables visualization of renal structure and function, permitting assessment of structural and functional damage to the kidneys. In a disclosed embodiment, six, small dendrimer-based MRI contrast agents were synthesized, and their pharmacokinetics, whole body retention, and renal MRI images were evaluated in mice. Surprisingly, despite having unequal renal clearance properties, all of the dendrimer agents clearly visualized the renal anatomy and proximal straight tubules of the mice better than Gd-[DTPA]-dimeglumine. Dendrimer conjugate contrast agents prepared from PAMAM-G2D, DAB-G3D, and DAB-G2D dendrimers were excreted rapidly and may be acceptable for use in clinical applications.

Claims

1. A dendrimer conjugate, comprising:

a dendrimer selected from the group consisting of DAB-G2D and DAB-G3D; and

a gadolinium (III) chelate of 1B4M.

2. A method for kidney imaging, comprising:

administering an image enhancing amount of a dendrimer conjugate to a subject, the dendrimer conjugate comprising a dendrimer selected from the group consisting of DAB-G2D, DAB-G3D, DAB-G4D, PAMAM-G2D, PAMAM-G3D and PAMAM-G4D and a metal chelate;

detecting a difference in a magnetic resonance signal intensity of at least a portion of the kidney after the dendrimer conjugate is administered; and

measuring a thickness of the cortex and the outer medulla of the kidney in an MRI image to determine if the kidney exhibits thinning associated with chronic renal failure.

3. The method of claim 2, wherein the dendrimer is selected from the group consisting of DAB-G2D, DAB-G3D and PAMAM-G2D.

4. The method of claim 3, wherein the dendrimer is selected from the group consisting of DAB-G2D and DAB-G3D.

5. The method of claim 2, wherein the metal chelate is selected from the group consisting of metal chelates of diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3 A), 1-oxa-4,7, 10-triazacyclododecane-triacetic acid (DOXA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 1,4,8,11-tetraazacyclotetradecanetetraacetic acid (TETA), DOTA-N(2-aminoethyl)amide and DOTA-N-(2-aminophenethyl)amide, BOPTA, HP-DO3A, DO3MA, and derivatives and combinations thereof.

6. The method of claim 2, wherein the metal chelate comprises an ion of a metal selected from the group consisting of the metals having atomic numbers of 22-29, 42, 44 and 58-70 and combinations thereof.

7. The method of claim 6, wherein the ion is selected from the group consisting of chromium (III), manganese (II), iron (II), iron (III), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III), gadolinium (III, terbium (III), dysprosium (III), holmium (III), erbium (III), ytterbium (III) and combinations thereof.

8. The method of claim 7, wherein the ion is gadolinium (III).

9. The method of claim 2, wherein the dendrimer conjugate is a 1B4M conjugate and is selected from the group consisting of DAB-G2, DAB-G3, DAB-G4, PAMAM-G2, PAMAM-G3, PAMAM-G4 and combinations thereof.

10. The method of claim 2, wherein detecting a difference in a magnetic resonance signal intensity of at least a portion of the kidney comprises detecting a difference in a T1-weigthed signal at a position corresponding to the proximal straight tubules of the kidney.

11. The method of claim 10, further comprising comparing the difference in magnetic resonance signal intensity detected for the subject to a difference in signal intensity detected in a second subject to determine whether the kidneys of the subject and the second subject are similar in structure or function.

12. The method of claim 2, wherein the dendrimer conjugate is administered in a dose between about 0.001 mmol Gd/kg and about 0.10 mmol Gd/kg.

13. The method of claim 2, wherein detecting a difference in a magnetic resonance signal intensity of at least a portion of the kidney comprises detecting a signal associated with the appearance of urine in the pelvis of the kidney as the dendrimer conjugate is excreted.

14. The method of claim 2, further comprising detecting an image associated with the presence of cysts indicative of chronic renal failure.

15. A method for kidney imaging, comprising:

administering to a subject an image enhancing amount of a dendrimer conjugate selected from the group consisting of DAB-G2 and DAB-G3, and combinations thereof; and

detecting a difference in a magnetic resonance signal intensity of at least a portion of the kidney after the dendrimer conjugate is administered.

16. The method of claim 15, wherein detecting a difference in a magnetic resonance signal intensity of at least a portion of the kidney after the dendrimer conjugate is administered comprises detecting a signal associated with an accumulation of the dendrimer conjugate in the proximal straight tubules.

17. The method of claim 16, wherein detecting a signal associated with an accumulation of the dendrimer conjugate in the proximal straight tubules comprises detecting accumulation of the dendrimer conjugate in the outer stripe of the outer medulla of the kidney.

18. The method of claim 15, wherein detecting a difference in a magnetic resonance signal intensity of at least a portion of the kidney after the dendrimer conjugate is administered comprises detecting a signal associated with an accumulation of the dendrimer conjugate in pelvis of the kidney.

19. The method of claim 15, wherein the dendrimer conjugate is administered in a dose between about 0.001 mmol Gd/kg and about 0.10 mmol Gd/kg.

20. The method of claim 19, wherein the dendrimer conjugate is administered in a dose between about 0.003 mmol Gd/kg and about 0.03 mmol Gd/kg.

21. The method of claim 15, further comprising measuring the thickness of the cortex and outer medulla of the kidney in an MRI image to determine if the kidney exhibits thinning associated with chronic renal failure.

22. The method of claim 15, further comprising detecting an image associated with the presence of cysts indicative of chronic renal failure.

23. A method for kidney imaging, comprising:

administering an image enhancing amount of a dendrimer conjugate to a subject, the dendrimer conjugate comprising a dendrimer selected from the group consisting of DAB-G2D, DAB-G3D, DAB-G4D, PAMAM-G2D, PAMAM-G3D and PAMAM-G4D and a metal chelate;

detecting a difference in a magnetic resonance signal intensity of at least a portion of the kidney after the dendrimer conjugate is administered; and

detecting an image associated with the presence of cysts indicative of chronic renal failure.

24. The method of claim 23, wherein the dendrimer is selected from the group consisting of DAB-G2D, DAB-G3D and PAMAM-G2D.

25. The method of claim 24, wherein the dendrimer is selected from the group consisting of DAB-G2D and DAB-G3D.

26. The method of claim 23, wherein the metal chelate is selected from the group consisting of metal chelates of diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1-oxa-4,7,10-triazacyclododecane-triacetic acid (DOXA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 1,4,8,11-tetraazacyclotetradecanetetraacetic acid (TETA), DOTA-N(2-aminoethyl)amide and DOTA-N-(2-aminophenethyl)amide, BOPTA, HP-DO3A, DO3MA, and derivatives and combinations thereof.

27. The method of claim 23, wherein the metal chelate comprises an ion of a metal selected from the group consisting of the metals having atomic numbers of 22-29,42,44 and 58-70 and combinations thereof.

28. The method of claim 27, wherein the ion is selected from the group consisting of chromium (III), manganese (II), iron (II), iron (III), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), ytterbium (III) and combinations thereof.

29. The method of claim 28, wherein the ion is gadolinium (III).

30. The method of claim 23, wherein the dendrimer conjugate is a 1B4M conjugate and is selected from the group consisting of DAB-G2, DAB-G3, DAB-G4, PAMAM-G2, PAMAM-G3, PAMAM-G4 and combinations thereof.

31. The method of claim 23, wherein detecting a difference in a magnetic resonance signal intensity of at least a portion of the kidney comprises detecting a difference in a T1-weigthed signal at a position corresponding to the proximal straight tubules of the kidney.

32. The method of claim 31, further comprising comparing the difference in magnetic resonance signal intensity detected for the subject to a difference in signal intensity detected in a second subject to determine whether the kidneys of the subject and the second subject are similar in structure or function.

33. The method of claim 23 wherein the dendrimer conjugate is administered in a dose between about 0.001 mmol Gd/kg and about 0.10 mmol Gd/kg.

34. The method of claim 23, wherein detecting a difference in a magnetic resonance signal intensity of at least a portion of the kidney comprises detecting a signal associated with the appearance of urine in the pelvis of the kidney as the dendrimer conjugate is excreted.

35. The method of claim 23, further comprising measuring a thickness of the cortex and outer medulla of the kidney in an MRI image to determine if the kidney exhibits thinning associated with chronic renal failure.

36. A method for kidney imaging, comprising:

administering an image enhancing amount of a dendrimer conjugate to a subject, the dendrimer conjugate comprising a dendrimer selected from the group consisting of DAB-G2D and DAB-G3D and a metal chelate; and

detecting a difference in a magnetic resonance signal intensity of at least a portion of the kidney after the dendrimer conjugate is administered.

37. The method of claim 36, wherein the metal chelate is selected from the group consisting of metal chelates of diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1-oxa-4,7,10-triazacyclododecane-triacetic acid (DOXA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 1,4,8,11-tetraazacyclotetradecanetetraacetic acid (TETA), DOTA-N(2-aminoethyl)amide and DOTA-N-(2-aminophenethyl)amide, BOPTA, HP-DO3A, DO3MA, and derivatives and combinations thereof.

38. The method of claim 36, wherein the metal chelate comprises an ion of a metal selected from the group consisting of the metals having atomic numbers of 22-29, 42, 44 and 58-70 and combinations thereof.

39. The method of claim 38, wherein the ion is selected from the group consisting of chromium (III), manganese (II), iron (II), iron (III), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), ytterbium (III) and combinations thereof.

40. The method of claim 39, wherein the ion is gadolinium (III).

41. The method of claim 36, wherein the dendrimer conjugate is a 1B4M conjugate and is selected from the group consisting of DAB-G2 and DAB-G3 and combinations thereof.

42. The method of claim 36, wherein detecting a difference in a magnetic resonance signal intensity of at least a portion of the kidney comprises detecting a difference in a T1-weigthed signal at a position corresponding to the proximal straight tubules of the kidney.

43. The method of claim 42, further comprising comparing the difference in magnetic resonance signal intensity detected for the subject to a difference in signal intensity detected in a second subject to determine whether the kidneys of the subject and the second subject are similar in structure or function.

44. The method of claim 36, wherein the dendrimer conjugate is administered in a dose between about 0.001 mmol Gd/kg and about 0.10 mmol Gd/kg.

45. The method of claim 36, wherein detecting a difference in a magnetic resonance signal intensity of at least a portion of the kidney comprises detecting a signal associated with the appearance of urine in the pelvis of the kidney as the dendrimer conjugate is excreted.

46. The method of claim 36, further comprising measuring a thickness of the cortex and outer medulla of the kidney in an MRI image to determine if the kidney exhibits thinning associated with chronic renal failure.

47. The method of claim 36, further comprising detecting an image associated with the presence of cysts indicative of chronic renal failure.

48. A method for kidney imaging comprising:

administering to a subject an image enhancing amount of a dendrimer conjugate selected from the group consisting of DAB-G2, DAB-G3, PAMAM-G2 and combinations thereof;

detecting a difference in a magnetic resonance signal intensity of at least a portion of the kidney after the dendrimer conjugate is administered; and

measuring a thickness of the cortex and outer medulla of the kidney in an MRI image to determine if the kidney exhibits thinning associated with chronic renal failure.

49. A method for kidney imaging, comprising:

administering to a subject an image enhancing amount of a dendrimer conjugate selected from the group consisting of DAB-G2, DAB-G3, PAMAM-G2 and combinations thereof;

detecting a difference in a magnetic resonance signal intensity of at least a portion of the kidney after the dendrimer conjugate is administered; and

detecting an image associated with the presence of cysts indicative of chronic renal failure.