Silanized biodegradable super paramagnetic metal oxides as contrast agents for imaging the gastrointestinal tract

• US 5,069,216 A
• Filed: 09/19/1989
• Issued: 12/03/1991
• Est. Priority Date: 07/03/1986
• Status: Expired due to Term

• Current Assignee: AMAG Pharmaceuticals, Inc. (Apollo Global Management, Inc.)
• Original Assignee: Advanced Magnetics, Inc.
• Inventors: Josephson, Lee, Groman, Ernest V., Lewis, Jerome M.
• Primary Examiner(s): Rosenbaum, C. Fred
• Assistant Examiner(s): NOT, DEFINED
• Application Number:
  US07/409,384
• Time in Patent Office: 805 Days
• Field of Search: 128/653 CA, 128/654, 600/9, 600/12-14, 424/1.1, 424/4, 424/9, 436/73, 436/74, 436/806
• US Class Current: 424/9.322
• CPC Class Codes: A61K 49/18 characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
• CPC Class Codes: A61K 49/1863 the organic macromolecular compound being a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
• CPC Class Codes: A61K 49/1869 coated or functionalised with a protein being an albumin, e.g. HSA, BSA, ovalbumin
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08G 18/1808 having alkylene polyamine groups
• CPC Class Codes: C08G 18/1816 having carbocyclic groups
• CPC Class Codes: C08G 18/1825 having hydroxy or primary amino groups
• CPC Class Codes: C08G 18/2036 having at least three nitrogen atoms in the ring
• CPC Class Codes: C08G 18/246 containing also tin-carbon bonds
• CPC Class Codes: C08G 18/26 of lead
• CPC Class Codes: C08G 2101/00 Manufacture of cellular products
• CPC Class Codes: C08J 2375/04 Polyurethanes
• CPC Class Codes: C08J 9/144 containing carbon, halogen and hydrogen only
• 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

This invention relates to materials exhibiting certain magnetic and biological properties which make them uniquely suitable for use as magnetic resonance imaging (MRI) agents to enhance MR images of animal organs and tissues. More particularly, the invention relates to the in vivo use of biologically degradable and metabolizable superparamagnetic metal oxides as MR contrast agents. Depending on their preparation, these metal oxides are in the form of superparamagnetic particle dispersoids or superparamagnetic fluids where the suspending medium is a physiologically-acceptable carrier, and may be uncoated or surrounded by a polymeric coating to which biological molecules can be attached. These materials are administered to animals, including humans, by a variety of routes and the metal oxides therein collect in specific target organs to be imaged; in the case of coated particles, the biological molecules can be chosen to target specific organs or tissues. The biodistribution of the metal oxides in target organs or tissues results in a more detailed image of such organs or tissues because the metal oxides, due to their superparamagnetic properties, exert profound effects on the hydrogen nuclei responsible for the MR image. In addition, the dispersoids and fluids are quite stable and, in the case of the fluids, can even be subjected to autoclaving without impairing their utility. Furthermore, the materials are biodegradable and, in the case of iron oxide compounds, can eventually be incorporated into the subject'"'"'s hemoglobin, making them useful in treating anemia. Thus, the materials are well-suited for in vivo use.

Claims

1. A method for obtaining an in vivo MR image of at least a portion of the gastrointestinal tract of an animal or human subject which comprises (a) administering enterally to such a subject an effective amount of a contrast agent in a physiologically acceptable carrier, which contrast agent comprises silanized aggregates of biodegradable superparamagnetic metal oxide crystals, said aggregates having an overall mean diameter of about 4000 angstroms or less as measured by light scattering;

and (b) obtaining such MR image.

3. The method of claim 1 or 2 in which the overall mean diameter of said aggregates is about 3000 angstroms or less as measured by light scattering.

4. The method of claim 1 or 2 in which the overall mean diameter of said aggregates is about 2000 angstroms or less as measured by light scattering.

5. The method of claim 1 or 2 in which the overall mean diameter of said aggregates is about 1000 angstroms or less as measured by light scattering.

6. The method of claim 1 or 2 in which said metal oxide is derived from a trivalent metal salt and a divalent metal salt.

7. The method of claim 1 or 2 in which said metal oxide is derived from a trivalent iron salt and a divalent metal salt.

8. The method of claim 1 or 2 in which said metal oxide is an iron oxide.

9. The method of claim 1 or 2 in which said contrast agent is administered to the subject orally.

10. The method of claim 1 or 2 in which said contrast agent is administered to the subject by intubation.

11. The method of claim 1 or 2 in which said contrast agent is administered to the subject by enema.

12. The method of claim 1 in which said physiologically acceptable carrier includes water.

14. The method of claim 1 or 2 in which said portion of the gastrointestinal tract includes the esophagus.

15. The method of claim 1 or 2 in which said portion of the gastrointestinal tract includes the stomach.

16. The method of claim 1 or 2 in which said portion of the gastrointestinal tract includes the small intestine.

17. The method of claim 1 or 2 in which said portion of the gastrointestinal tract includes the large intestine.

18. The method of claim 1 or 2 in which said portion of the gastrointestinal tract includes the colon.

19. The method of claim 1 or 2 in which the silanizing agent used to silanize said aggregates is a polymerizable organosilane.

20. The method of claim 1 or 2 in which the silanizing agent used to silanize said aggregates is N-2-aminoethyl-3-aminopropyltrimethoxysilane.

21. The method of claim 1 or 2 in which said silanized aggregates further comprise covalently coupled biological molecules which are recognized by receptors in the gastrointestinal tract.

22. The method of claim 21 in which said biological molecule is an antibody.

23. The method of claim 21 in which said biological molecule is an antibody against neoplastic tissue.

2. A method for obtaining an in vivo MR image of at least a portion of the gastrointestinal tract of an animal or human subject which comprises (a) administering enterally to such a subject an effective amount of a superparamagnetic fluid comprising a biodegradable superparamagnetic contrast agent in a physiologically acceptable buffered aqueous carrier, which contrast agent comprises silanized aggregates of biodegradable superparamagnetic metal oxide crystals, said aggregates having a overall mean diameter of about 4000 angstroms or less as measured by light scattering;

and (b) obtaining such MR image.

13. The method of claim 2 in which said physiologically acceptable buffered aqueous carrier includes a polycarboxylic acid.