Contrast agents for NMR imaging

• US 4,728,575 A
• Filed: 04/10/1985
• Issued: 03/01/1988
• Est. Priority Date: 04/27/1984
• Status: Expired due to Term

• Current Assignee: NeXstar Pharmaceuticals, Inc. (Gilead Sciences Inc.)
• Original Assignee: Vestar, Inc. (Advanced Micro Devices, Inc.)
• Inventors: Gamble, Ronald C., Schmidt, Paul G.
• Primary Examiner(s): NOT, DEFINED
• Assistant Examiner(s): Wallen, T. J.
• Application Number:
  US06/720,954
• Time in Patent Office: 1,056 Days
• Field of Search: 128/653, 128/654, 128/660, 324/308, 428/402.2, 260/403, 264/4.3, 264/4.6, 424/38, 424/182, 424/1.1, 424/19, 436/829
• US Class Current: 424/9.321
• CPC Class Codes: A61K 49/1812 liposomes, polymersomes, e.g. immunoliposomes
• CPC Class Codes: G01R 33/5601 involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent

Abstract

An agent for contrast enhancement in nuclear magnetic resonance imaging is disclosed. Micellular particles such as phospholipid vesicles are associated with or enclose a paramagnetic material. The particles may be formulated with an agent, such as cholestrol, to promote vesicle stability and water exchange across the vesicle bilayer. The vesicles may or may not have antibodies or other cell recognition targeting agents attached to the surface to provide specific targeting. The vesicles provide enhanced target specificity, reduced burden of toxic contrast material and amplified contrast enhancement.

Claims

1. Magnetic resonance imaging contrast agents for scanning tissue comprising bilayer vesicles with paramagnetic material encapsulated therein, said vesicles formulated with an agent to promote vesicle stability for a sufficient time to allow biodistribution of said vesicles for scanning of said tissue and formulated to permit adequate water proton exchange across the vesicle bilayer to provide contrast for scanning said tissue.

2. The contrast agents of claim 1 in which said micellular particles are vesicles.

3. The contrast agents of claim 2 in which said vesicles are formulated with an agent to promote vesicle stability and water exchange across the vesicle bilayer.

4. The contrast agents of claim 3 in which said vesicles are formulated with cholestrol.

5. The contrast agents of claims 1, 2, 3 or 4 in which antibodies, carbohydrates, or other cell recognition targeting agents are attached to said micellular particles, to provide specific targeting.

6. The contrast agents of claim 5 in which said targeting agent is the antibody antimyosin.

7. The contrast agents of claim 5 in which said targeting agent is the antibody antifibrin.

8. The contrast agents of claims 1, 2 or 3 in which said paramagnetic material is a salt of a transition metal or the lanthanide or actinide series of the Periodic Table.

9. The contrast agents of claim 7 in which said paramagnetic material is a salt of a paramagnetic ion selected from manganese, copper, gadolinum, erbium, chromium, iron, cobalt and nickel.

10. The contrast agents of claims 1, 2 or 3 in which said paramagnetic material is a paramagnetic compound including a stable free radical.

11. The contrast agents of claims 1, 2 or 3 which said paramagnetic material is a paramagnetic compound of a paramagnetic ion and a chelate.

12. The contrast agents of claims 1, 2, or 3 in which said paramagnetic material is present in a concentration of at least approximately 50 mM.

13. The contrast agents of claims 1, 2 or 3 in which said paramagnetic material is present in a concentration of from about 50 mM to approximately 1 M.

14. The contrast agents of claim 10 in which the efficiency of said paramagnetic material is enhanced by the addition of a charged polymer thereto.

15. The contrast agents of claim 11 in which said charged polymer is poly-L-lysine.

17. The contrast agents of claim 13 in which said vesicles are formulated with cholestrol.

18. The contrast agents of claim 14 in which said paramagnetic material is Gd-DTPA.

19. The contrast agents of claims 18 in which said paramagnetic material is present in a concentration of at least approximately 50 mM.

20. The contrast agents of claim 19 in which said paramagnetic material is present in a concentration of from about 50 mM to approximately 1 M.

23. The contrast agents of claim 1 wherein said tissue is tumor tissue.

16. Magnetic resonance imaging contrast agents for scanning tissue comprising phospholipid bilayer esicles with paramagnetic material encapsulated therein, said paramagnetic material being a paramagnetic ion associated with a chelate and said vehicles formulated with an agent to promote vesicle stability for a sufficient time to allow biodistribution of said vesicles for scanning of said tissue and formulated to permit adequate water proton exchange across the vesicle bilayer to provide contrast for scanning of said tissue.

24. The contrast agents of claim 16 wherein said tissue is tumor tissue.

21. Magnetic resonance imaging contrast agents for scanning tissue comprising bilayer vesicles having a paramagnetic material associated therewith, said vesicles formulated with an agent to promote vesicle stability for a sufficient time to allow biodistribution of said vesicles for scanning of said tissue and formulated to permit adequate water proton exchange across the vesicle bilayer to provide contrast for scanning of said tissue.

22. The contrast agents of claim 21 in which said paramagnetic material is associated with a chelating agent bound to the surface of said micellular particles.

25. The contrast agents of claim 21 wherein said tissue is tumor tissue.