Method of magnetic resonance focused surgical and therapeutic ultrasound

• US 6,461,586 B1
• Filed: 07/10/2000
• Issued: 10/08/2002
• Est. Priority Date: 12/22/1989
• Status: Expired due to Fees

• Current Assignee: Cerevast Therapeutics, Inc.
• Original Assignee: Imarx Therapeutics, Inc. (Sycamore Entertainment Group, Inc.)
• Inventors: Unger, Evan C.
• Primary Examiner(s): Travers, Russell
• Assistant Examiner(s): Wells, Lauren Q.
• Application Number:
  US09/613,210
• Time in Patent Office: 820 Days
• Field of Search: 424/9, 424/9.3, 424/9.32, 424/9.321, 424/9.322, 424/9.33, 424/9.34, 424/9.341, 424/9.35, 424/9.36, 424/9.5, 424/9.51, 424/9.52, 424/93, 600/420, 600/437
• US Class Current: 424/9.32
• CPC Class Codes: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 41/0052 Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
• CPC Class Codes: A61K 47/6911 the form being a liposome
• CPC Class Codes: A61K 47/6913 the liposome being modified on its surface by an antibody
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• CPC Class Codes: A61K 49/103 the complex-forming compound being acyclic, e.g. DTPA
• CPC Class Codes: A61K 49/16 Antibodies; Immunoglobulins; Fragments thereof
• CPC Class Codes: A61K 49/1806 Suspensions, emulsions, colloids, dispersions
• CPC Class Codes: A61K 49/1839 the small organic molecule being a lipid, a fatty acid having 8 or more carbon atoms in the main chain, or a phospholipid
• 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 49/1866 the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
• CPC Class Codes: A61K 49/1878 the nanoparticle having a magnetically inert core and a (super)(para)magnetic coating
• CPC Class Codes: A61K 49/22 Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 49/227 Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61K 9/1278 Post-loading, e.g. by ion or pH gradient
• CPC Class Codes: A61M 5/3145 Filters incorporated in syringes
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• 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
• CPC Class Codes: G01R 33/56308 : Characterization of motion or flow; Dynamic imaging

Abstract

A novel method for the controlled delivery of therapeutic compounds to a region of a patient, using magnetic resonance focused therapeutic ultrasound, is disclosed.

Claims

1. A method for the controlled delivery of therapeutic compounds to a region of a patient using magnetic resonance focused therapeutic ultrasound comprising:

administering a contrast medium for magnetic resonance imaging comprising gas filled vesicles which comprise a therapeutic compound to a patient;

scanning said patient with magnetic resonance imaging using said contrast medium to determine the presence of the vesicles in the region; and

applying ultrasound to said region to rupture said vesicles to release the therapeutic compound in the region.

2. A method of claim 1 wherein said application of ultrasound is simultaneous with a second scanning step whereby said patient is scanned with magnetic resonance imaging.

3. A method of claim 1 wherein said application of ultrasound is followed by a second scanning step whereby said patient is scanned with magnetic resonance imaging.

4. A method of claim 1 wherein said region of a patient is selected from the group consisting of:

cardiovascular region;

gastrointestinal region;

intranasal tract;

auditory canal;

intraocular region;

intraperitoneal region;

kidneys;

urethra;

genitourinary tract, brain, spine, pulmonary region, and soft tissues.

5. A method of claim 1 wherein said gas-filled vesicles comprise a targeting agent.

6. A method of claim 1 wherein said therapeutic compound is selected from the group consisting of an oligonucleotide sequence, an antisense sequence, an antibody, and a chemotherapeutic agent.

7. A method of claim 1 wherein said gas filled vesicles are administered intravenously.

8. A method of claim 1 wherein said gas is selected from the group consisting of air, nitrogen, carbon dioxide, oxygen, fluorine, helium, argon, xenon, neon, and combinations thereof.

9. A method of claim 1 wherein said gas comprises a fluorinated gas.

10. A method of claim 9 wherein the fluorinated gas comprises a perfluorocarbon or sulfur hexafluoride.

11. A method of claim 10 wherein the perfluorocarbon gas is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethane, perfluoroethane, perfluorohexane, and perfluoropentane.

12. A method of claim 1 wherein said gas comprises ¹⁷O.

13. A method of claim 1 wherein said contrast medium further comprises a paramagnetic agent or a superparamagnetic agent.

14. A method of claim 13 wherein the contrast medium comprises a paramagnetic agent.

15. A method of claim 14 wherein the paramagnetic agent comprises a paramagnetic ion selected from the group consisting of transition, lanthanide and actinide elements.

16. A method of claim 15 wherein the paramagnetic ion is selected from the group consisting of Gd(III), Mn(II), Cu(II), Cr(III), Fe(II), Fe(III), Co(II), Er(II), Ni(II), Eu(III) and Dy(III).

17. A method of claim 16 wherein the paramagnetic ion is Mn(II).

18. A method of claim 14 wherein the paramagnetic agent comprises a nitroxide.

19. A method of claim 13 wherein the contrast medium comprises a superparamagnetic agent.

20. A method of claim 19 wherein the superparamagnetic agent comprises a metal oxide or metal sulfide.

21. A method of claim 20 wherein the superparamagnetic agent comprises a metal oxide wherein the metal is iron.

22. A method of claim 20 wherein the superparamagnetic agent is selected from the group consisting of ferritin, iron, magnetic iron oxide, γ

-Fe₂O₃, manganese ferrite, cobalt ferrite and nickel ferrite.

23. A method of claim 1 wherein said gas filled vesicles comprise ¹⁹F and said magnetic resonance imaging is nuclear magnetic resonance.

24. A method of claim 1 wherein said gas filled vesicles are administered interstitially.

25. A method of claim 1 wherein said gas is selected from the group consisting of hyperpolarized xenon, hyperpolarized argon, hyperpolarized helium, and hyperpolarized neon.

26. A method of claim 1 wherein said vesicles comprise liposomes.

27. A method of claim 26 wherein said liposomes comprise crosslinked or polymerized liposomes.

28. A method of claim 26 wherein said liposomes comprise polymerized lipids.

29. A method of claim 26 wherein said liposomes further comprise polyethylene glycol.

30. A method of claim 1 wherein said vesicles comprise a monolayer.

31. A method of claim 30, wherein said monolayer comprises a phospholipid.

32. A method of claim 31, wherein said gas comprises perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, or sulfur hexafluoride.

33. A method of claim 31, wherein said monolayer comprises a phospholipid and said gas comprises perfluoropentane.

34. A method of claim 31, wherein said monolayer comprises a phospholipid and said gas comprises sulfur hexafluoride.

35. A method of claim 31, wherein said monolayer comprises a phospholipid and said gas comprises perfluoropropane.

36. A method of claim 1, wherein said vesicles comprise a polymer.

37. A method of claim 36, wherein said polymer comprises an acrylate.

38. A method of claim 37, wherein said gas comprises air.

39. A method of claim 36, wherein said polymer comprises a methacrylate.

40. A method of claim 39, wherein said gas comprises air.

41. A method of claim 36, wherein said polymer comprises a cyanoacrylate.

42. A method of claim 41 wherein said gas comprises air.

43. A method of claim 1, wherein said vesicles comprise a polysaccharide.

44. A method of claim 43, wherein said polysaccharide comprises galactose.

45. A method of claim 44, wherein said gas is nitrogen.

46. A method of claim 1, wherein said vesicles comprise a surfactant.

47. A method of claim 46, wherein said gas comprises perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, sulfur hexafluoride, nitrogen, or mixtures thereof.

48. A method of claim 47, wherein said gas comprises a mixture of perfluoropropane and nitrogen.

49. A method of claim 48, wherein said gas comprises a mixture of perfluorohexane and nitrogen.

50. A method of claim 46, wherein said vesicles have been rehydrated from lyophilized vesicles.

51. A method of claim 1, wherein said therapeutic compound comprises a bioactive agent.