Macromolecular imaging agents for liver imaging

• US 20050019267A1
• Filed: 06/24/2002
• Published: 01/27/2005
• Est. Priority Date: 06/25/2001
• Status: Abandoned Application

• Current Assignee: Fraunhofer Gesellschaft Zur Foerderung Der Angewandten Forsching E.V., United States Department Of Health And Human Services (Government of the United States of America)
• Original Assignee: United States Department Of Health And Human Services (Government of the United States of America)
• Inventors: Kobayashi, Hisataka, Brechbiel, Martin W
• Application Number:
  US10/481,706
• Publication Number:
  US 20050019267A1
• Time in Patent Office: Days
• US Class Current: 424/9.322
• CPC Class Codes: A61K 49/124 dendrimers, dendrons, hyperbranched compounds

Abstract

Macromolecular imaging agents comprising a polyalkylenimine dendrimer conjugated to a metal chelate are disclosed. In particular embodiment, the imaging agent is a diaminobutane-core polypropylenimine dendrimer having surface amino groups conjugated to gadolinium metal chelates. Administration of this gadolinium conjugate to a subject permits visualization of liver micrometastases as small as about 0.3 mm in a magnetic resonance image of the subject'"'"'s liver.

Claims

1. A macromolecular imaging agent, comprising:

a polyalkylenimine dendrimer; and

a metal chelate conjugated to the dendrimer.

2. The imaging agent of claim 1 where the polyalkylenimine dendrimer comprises a polypropylenimine dendrimer.

3. The imaging agent of claim 1 where the polyalkylenimine dendrimer comprises a DAB dendrimer.

4. The imaging agent of claim 3 where the DAB dendrimer comprises a DAB-Am dendrimer.

5. The imaging agent of claim 4 where the DAB-Am dendrimer comprises a polypropylenimine tetrahexacontaamine dendrimer.

6. The imaging agent of claim 5 where the metal chelate comprises a 1B4M metal chelate.

7. The imaging agent of claim 6 where the 1B4M metal chelate comprises a gadolinium chelate.

8. The imaging agent of claim 1 where the polyalkylenimine dendrimer comprises a polybutylenimine dendrimer.

9. The imaging agent of claim 1 where the metal chelate comprises a gadolinium metal chelate.

10. The imaging agent of claim 9 where the gadolinium chelate comprises a GdDPTA chelate.

11. The imaging agent of claim 1 where the dendrimer comprises a DAB-Am dendrimer and the metal chelate comprises a gadolinium chelate.

12. A method for making a macromolecular imaging agent, comprising:

reacting a reactive group of a bifunctional chelating agent with a surface group of a polyalkylenimine dendrimer; and

reacting a metal ion with a metal chelating group of the bifunctional chelating agent.

13. The method of claim 12 where the surface group of the dendrimer comprises an amino group and the reactive group is capable of reacting with the amino group.

14. The method of claim 13 where the reactive group comprises an isothiocyanate group.

15. The method of claim 12 where the metal chelating group is selected from consisting of DOTA, DTPA, DOTA derivatives, DTPA derivatives, and combinations thereof.

16. The method of claim 12 where the metal comprises a paramagnetic ion.

17. The method of claim 16 where the paramagnetic ion comprises Gd(III).

18. The method of claim 12 where the polyalkylenimine dendrimer comprises a polypropylenimine dendrimer.

19. The method of claim 18 where the polypropylenimine dendrimer comprises a DAB dendrimer.

20. The method of claim 19 where the DAB dendrimer comprises a DAB-Am dendrimer.

21. The method of claim 12 where the bifunctional chelating agent comprises 1B4M, the reactive group comprises an isothiocyanate group and the metal ion comprises Gd(III).

22. A method for imaging the liver of a subject, comprising:

administering to the subject an image-enhancing amount of a polyalkylenimine dendrimer conjugated to a metal chelate; and

measuring the MRI signal intensity of two or more regions of the subject'"'"'s liver to detect differences in a signal intensity between the regions.

23. The method of claim 22 where the image enhancing amount of the dendrimer conjugate comprises between about 0.001 mg/kg and about 0.10 mg/kg of the subject'"'"'s weight.

24. The method according to claim 22 where the polyalkylenimine dendrimer comprises a polypropylenimine dendrimer.

25. The method according to claim 22 where the metal chelate comprises a gadolinium chelate.

26. The method according to claim 22 where the dendrimer conjugated to a metal chelate comprises a DAB dendrimer conjugated to a gadolinium metal chelate.

27. The method according to claim 26 where the DAB dendrimer comprises DAB-Am64 and the gadolinium metal chelate comprises Gd-1B4M.

28. The method according to claim 22 where the polyalkylenimine dendrimer conjugated to a metal chelate comprises DAB-Am64-(1B4M-Gd)₆₄.

29. The method according to claim 22 where the polyalkylenimine dendrimer conjugated to a metal chelate comprises DAB-Am32-(1B4M-Gd)₃₂.

30. A method for imaging the liver of a subject, comprising;

administering to a subject an image-enhancing amount of a DAB dendrimer conjugated to a gadolinium chelate; and

examining the subject'"'"'s liver by magnetic resonance imaging to obtain a T₁-weighted image.

31. The method of claim 30 further comprising detecting a liver micrometastesis by detecting a dark image of the liver micrometastasis against a bright image of normal liver parenchyma in the T₁-weighted image.

32. The method of claim 30 where the DAB dendrimer conjugated to a gadolinium chelate comprises DAB-Am64-(1B4M-Gd)₆₄.

33. The method of claim 30 where the DAB dendrimer conjugated to a gadolinium chelate comprises DAB-Am32-(1B4M-Gd)₃₂.

34. A method for detecting changes in the size of a liver tumor during a period of time, comprising:

administering to a subject an image-enhancing amount of a polyalkylenimine dendrimer conjugated to a gadolinium chelate;

obtaining a T₁-weighted magnetic resonance image of the subject'"'"'s liver;

detecting a liver tumor in the magnetic resonance image by a contrast between the tumor and surrounding normal liver parenchyma; and

repeating the steps of administering, obtaining, and detecting two or more times during a period of time to detect changes in the size of the liver tumor.

35. The method of claim 34 where the polyalkylenimine dendrimer conjugated to a gadolinium chelate comprises a polypropylenimine dendrimer conjugated to a gadolinium chelate.

36. The method of claim 35 where the polypropylenimine dendrimer conjugated to a gadolinium chelate comprises a DAB dendrimer conjugated to a gadolinium chelate.

37. The method of claim 36 where the DAB dendrimer conjugated to a gadolinium chelate comprises a DAB-Am64 dendrimer conjugated to a gadolinium chelate.

38. The method of claim 37 where the gadolinium chelate comprises a 1B4M chelate.

39. The method of claim 36 where the DAB dendrimer conjugated to a gadolinium chelate comprises a DAB-Am32 dendrimer conjugated to a gadolinium chelate.

40. The method of claim 39 where the gadolinium chelate comprises a 1B4M chelate.