Method to assess nodal disease using iron oxide nanoparticles in magnetic resonance imaging

Abstract

This invention relates to a method to assess nodal disease by magnetic resonance imaging with a contrast agent. The contrast agent comprises biofunctional magnetic nanoparticles coated with polymers outside the iron core and conjugated with antibodies specific to the tumor type to be assessed. Images produced from this magnetic resonance imaging with a contrast agent show heterogenous hypo intensity or heterogenous architecture in regions where binding by the antibodies is present.

Description

Abstract This invention relates to a method for evaluating lymph node diseases using magnetic resonance imaging with a contrast agent. The contrast agent comprises biofunctional magnetic nanoparticles coated with a polymer around an iron core and conjugated with antibodies specific to the type of tumor being evaluated. Images generated from this magnetic resonance imaging using the contrast agent show heterogeneous low-intensity or heterogeneous structures in regions where antibody binding is present.

Claims

CLAIMSWe claim:

1. A method of evaluating a target tissue by magnetic resonance imaging, comprising: introducing a biofunctional magnetic nanoparticle solution into a subject, wherein the biofunctional magnetic nanoparticle solution is comprised of a plurality of biofunctional magnetic nanoparticle structures, each nanoparticle structure comprises an iron core coated with oleic acid, one or more lipid or polymer, one or more stealth generating compound, and one or more targeting ligand adapted to bind a target molecule; permitting the biofunctional magnetic nanoparticle solution to bind the target molecule, if present, wherein the target molecule is indicative of a health condition in the subject; performing magnetic resonance imaging of the subject to obtain a magnetic resonance image or image file representative of a target tissue of the subject; and assessing the magnetic resonance image or image file for an area of heterogenous hypointensity in the target tissue representative of the presence of biofunctional magnetic nanoparticles bound to the target molecule, whereby identifying the area of heterogenous hypointensity in the target tissue is indicative of the presence of the target molecule in the subject tissue.

2. The method of claim 1, wherein each of the biofunctional magnetic nanoparticle structures within the nanoparticle solution has a diameter of between 10 and 150 nanometers.

3. The method of claim 1, wherein within the biofunctional magnetic nanoparticle solution the diameter of each of the nanoparticle structures in the nanoparticle solution is uniform.

4. The method of any of claims 1 to 3, wherein the biofunctional magnetic nanoparticle solution is an aqueous nanoparticle solution in 0.9% NaCl containing 0.05% polysorbate 20.

5. The method of any of claims 1 to 3, wherein the biofunctional magnetic nanoparticle solution is an isotonic solution that supports product stability and safe human injection.

6. The method of any of claims 1 to 3, wherein the at least one stealth generating compound is polyethylene glycol polymer.

7. The method of any of claims 1 to 3, wherein the at least one stealth generating compound comprises PEG with a molecular weight of between 500 Da and 20,000 Da.

8. The method of any of claims 1 to 3, wherein the at least one stealth generating compound comprises methoxy polyethylene glycol 2000 and methoxy polyethylene glycol 10000.

9. The method of any of claims 1 to 3, wherein the organic coating comprises an organic acid comprising oleic acid.

10. The method of claim 9, wherein the organic acid is oleic acid.

11. The method of any of claims 1 to 3, wherein the polymer coating comprises dextran.

12. The method of any of claims 1 to 3, wherein the targeting ligand is an anti-HER-2 antibody or a functional binding fragment thereof.

13. The method of any of claims 1 to 3, wherein the targeting ligand is trastuzumab or a functional binding fragment thereof.

14. The method of any of claims 1 to 3, wherein the polymer coating outside the organic coating is poly(maleic anhydride-alt-octadecene).

15. The method of any of claims 1 to 3, wherein the performing magnetic resonance imaging uses T1 imaging sequence.

16. The method of any of claims 1 to 3, wherein the performing magnetic resonance imaging uses T2 imaging sequence.

17. The method of any of claims 1 to 3, wherein the biofunctional magnetic nanoparticle solution is injected into a peritumoral region of a tumor present on the human subject.

18. The method of any of claims 1 to 3, wherein the performing of magnetic resonance imaging is conducted using a 1.5T or 3T clinical scanner.

19. The method of any of claims 1 to 3, further comprising assessing the image of the target tissue for heterogenous architecture.

20. The method of any of claims 1 to 3, further comprising assessing the morphology of the target tissue for presence of suspicious tumors.

21. The method of any of claims 1 to 3, further comprising performing magnetic resonance imaging on the human subject 24 hours after the first imaging and reevaluating the target tissue.

22. The method of any of claims 1 to 3, wherein the one or more target ligand is capable of specifically binding a protein or cell associated with a cancer.

23. The method of any of claims 1 to 3, wherein the target molecule is an HER2 protein, or domain or region thereof.

24. The method of any of claims 1 to 3, further comprising assessing the image of the target tissue for heterogenous architecture.

25. The method of any of claims 1 to 3, wherein identification of heterogenous hypointensity in the target tissue is further indicative of malignancy of the target tissue.

26. The method of any of claims 1 to 3, wherein identification of heterogenous architecture in the target tissue is further indicative of malignancy of the target tissue.

27. The method of any of claims 1 to 3, further comprising subjecting the subject to treatment for the health condition, which treatment involves administration of medicaments, biopsy, surgery, or foregoing biopsy or surgery.

28. A method to assess axillary nodal diseases by magnetic resonance imaging, the method comprises: introducing a biofunctional magnetic nanoparticle solution into a human subject diagnosed with or suspected of having breast cancer; performing magnetic resonance imaging of the region of interest of the human subject, the region comprising at least one lymph node; assessing an image of the at least one lymph node for heterogenous hypo-intensity; and assessing axillary nodal disease of the at least one lymph node, wherein the biofunctional magnetic nanoparticle solution comprises nanoparticle structures, each structure comprising an iron core surrounded with a layer of organic coating and a layer of polymer coating in contact with the organic coating, a targeting ligand specific for a target molecule conjugated to the polymer coating layer, and at least one stealth generating compound bound to the polymer coating layer, the presence of the target molecule being indicative of the presence of a cancer cell or protein associated with the presence of cancer.

29. The method of claim 28, wherein each of the biofunctional magnetic nanoparticle structures within the nanoparticle solution has a diameter of between 10 and 150 nanometers.

30. The method of claim 28, wherein within the biofunctional magnetic nanoparticle solution the diameter of each of the nanoparticle structures in the nanoparticle solution is uniform.

31. The method of claim 28, wherein the polymer coating outside the organic coating is poly(maleic anhydride-alt-octadecene).

32. The method of any of claims 28 to 31, wherein the biofunctional magnetic nanoparticle solution is an aqueous nanoparticle solution in 0.9% NaCl containing 0.05% polysorbate 20.

33. The method of any of claims 28 to 31, wherein the biofunctional magnetic nanoparticle solution is an isotonic solution that supports product stability and safe human injection.

34. The method of any of claims 28 to 31, wherein the at least one stealth generating compound is polyethylene glycol polymer.

35. The method of any of claims 28 to 31, wherein the at least one stealth generating compound comprises polyethylene glycol (PEG) polymer, including PEG with a molecular weight of between 500 Da and 20,000 Da.

36. The method of any of claims 28 to 31, wherein the at least one stealth generating compound comprises methoxy polyethylene glycol 2000 and methoxy polyethylene glycol 10000.

37. The method of any of claims 28 to 31, wherein the organic coating comprises an organic acid.

38. The method of claim 37, wherein the organic acid is oleic acid.

39. The method of any of claims 28 to 31, wherein the polymer coating comprises dextran.

40. The method of any of claims 28 to 31, wherein the targeting ligand is an anti-HER- 2 antibody or a functional binding fragment thereof.

41. The method of any of claims 28 to 31, wherein the targeting ligand is trastuzumab or a functional binding fragment thereof.

42. The method of any of claims 28 to 31, wherein one lymph node is assessed.

43. The method of any of claims 28 to 31, wherein more than one lymph nodes are assessed.

44. The method of any of claims 28 to 31, wherein the performing magnetic resonance imaging uses T1 imaging sequence.

45. The method of any of claims 28 to 31, wherein the performing magnetic resonance imaging uses T2 imaging sequence.

46. The method of any of claims 28 to 31 , wherein the human subj ect holds their breath while magnetic resonance imaging of the axilla region is conducted.

47. The method of any of claims 28 to 31, wherein the biofunctional magnetic nanoparticle solution is injected into a peritumoral region of a tumor present on the human subject.

48. The method of any of claims 28 to 31, wherein the performing of magnetic resonance imaging is conducted using a 1.5T or 3T clinical scanner.

49. The method of any of claims 28 to 31, further comprising performing a biopsy on the lymph node if assessed to be diseased.

50. The method of claim 28, further comprising assessing the image of the at least one lymph node for heterogenous architecture.

51. The method of any of claims 28 to 31, further comprising assessing the morphology of the at least one lymph node for presence of suspicious tumors.

52. The method of any of claims 28 to 31, further comprising performing magnetic resonance imaging on the human subject 24 hours after the first imaging and reassessing the axillary nodal disease of the at least one lymph node.

53. The method of any of claims 28 to 31, wherein identification of heterogenous hypointensity in the at least one lymph node is further indicative of malignancy of the lymph node.

54. The method of claim 28, 29, 30, 31, or 52, wherein identification of heterogenous architecture in the at least one lymph node is further indicative of malignancy of the lymph node.

55. A medicament for use in magnetic resonance imaging formulated for use in a method for evaluating and / or treating a health condition characterized by the presence a protein or cell associated with a cancer, the method comprising: introducing a biofunctional magnetic nanoparticle solution into a human subject diagnosed with or suspected of having breast cancer; performing magnetic resonance imaging of the region of interest of the human subject, the region comprising at least one lymph node; assessing an image of the at least one lymph node for heterogenous hypo-intensity; and assessing axillary nodal disease of the at least one lymph node, wherein the biofunctional magnetic nanoparticle solution comprises nanoparticle structures, each structure comprising an iron core surrounded with a layer of organic coating and a layer of polymer coating in contact with the organic coating, a targeting ligand specific for a target molecule conjugated to the polymer coating layer, and at least one stealth generating compound bound to the polymer coating layer, the presence of the target molecule being indicative of the presence of a cancer cell or protein associated with the presence of cancer.

56. The medicament of claim 55, wherein identification of heterogenous hypointensity in the target tissue or lymph node is further indicative of malignancy of the subject tissue.

57. The medicament of claim 55 or 56, further comprising assessing an image of the at least one lymph node for heterogenous architecture.

58. The medicament of claim 57, wherein identification of heterogenous architecture in the target tissue or lymph node is further indicative of malignancy of the subject tissue.

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