Method of magnetic resonance focused surgical and therapeutic ultrasound

• US 6,088,613 A
• Filed: 06/07/1995
• Issued: 07/11/2000
• Est. Priority Date: 12/22/1989
• Status: Expired due to Fees

• Current Assignee: Cerevast Therapeutics, Inc.
• Original Assignee: Imarx Pharmaceutical Corp. (Sycamore Entertainment Group, Inc.)
• Inventors: Unger, Evan C.
• Primary Examiner(s): Jastrzab, J.
• Assistant Examiner(s): Mercader, Eleni Mantis
• Application Number:
  US08/476,317
• Time in Patent Office: 1,861 Days
• Field of Search: 424/9, 424/9.3, 424/9.32, 424/9.321, 424/9.322, 424/9.323, 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, 128/653.1, 128/653.4, 128/662.02, 604/190, 600/407, 600/410, 600/411, 600/420, 600/439
• US Class Current: 600/420
• 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 of magnetic resonance focused surgical and therapeutic ultrasound is disclosed where a patient is administered a contrast medium comprising a gas or gaseous precursor filled vesicle, and optionally a therapeutic compound.

Claims

1. A method of magnetic resonance focused surgical ultrasound comprising:

administering a contrast medium for magnetic resonance imaging comprising gas filled vesicles to a patient requiring surgery,

scanning said patient with magnetic resonance imaging using said contrast medium to identify the region of the patient requiring surgery, and

applying ultrasound to said region to carry out said surgery wherein said contrast medium is used to fascilitate the application of ultrasound.

2. The 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. The 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. The method of claim 1 wherein said surgery is carried out in one of the following regions:

vascular;

cardiovascular;

gastrointestinal;

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 vesicles comprise a targeting agent.

6. The method of claim 1 wherein said gas filled vesicles further comprise a therapeutic which is released upon application of ultrasound.

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

8. The method of claim 1 wherein said ultrasound repairs an aperture in said region of said patient.

9. The method of claim 8 wherein said aperture is in the vasculature of said patient.

10. The method of claim 1 wherein said gas filled vesicles are administered intravenously.

11. The method of claim 1 wherein the gas is selected from the group consisting of air, nitrogen, carbon dioxide, oxygen, fluorine, helium, argon, xenon, and neon.

12. The method of claim 1 wherein the gas is a fluorinated gas.

13. The method of claim 12 wherein the fluorinated gas is selected from the group consisting of perfluorocarbons and sulfur hexafluoride.

14. The method of claim 13 wherein the perfluorocarbon gas is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethane, perfluoroethane, perfluorohexane, and perfluoropentane.

15. The method of claim 1 wherein said gas is ¹⁷ O.

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

17. The method of claim 16 wherein the contrast agent is a paramagnetic agent.

18. The method of claim 17 wherein the paramagnetic agent comprises a paramagnetic ion selected from the group consisting of transition, lanthanide and actinide elements.

19. The method of claim 18 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).

20. The method of claim 19 wherein the paramagnetic ion is Mn(II).

21. The method of claim 17 wherein the paramagnetic agent comprises a nitroxide.

22. The method of claim 16 wherein the contrast agent is a superparamagnetic agent.

23. The method of claim 22 wherein the superparamagnetic agent comprises a metal oxide or metal sulfide.

24. The method of claim 23 wherein the superparamagnetic agent comprises a metal oxide wherein the metal is iron.

25. The method of claim 22 wherein the superparamagnetic agent is ferritin, iron, magnetic iron oxide, γ

-Fe₂ O₃, manganese ferrite, cobalt ferrite and nickel ferrite.

26. The method of claim 1 wherein said gas filled vesicles are filled with ¹⁹ F and said magnetic resonance imaging is nuclear magnetic resonance.

27. The method of claim 1 wherein said gas filled vesicles are administered interstitially.

28. The method of claim 1 wherein said gas is selected from the group consisting of rubidium enhanced xenon, rubidium enhanced argon, rubidium enhanced helium, and rubidium enhanced neon.

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

30. A method of claim 29 wherein said liposomes comprise crosslinked or polymerized liposomes.

31. A method of claim 29 wherein said liposomes comprise polymerized lipids.

32. A method of claim 29 wherein said vesicles further comprise polyethylene glycol.

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

34. A method of claim 33 wherein said monolayer comprises a phospholipid.

35. A method of claim 34 wherein said gas is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, and sulfur hexafluoride.

36. A method of claim 34 wherein said monolayer comprises a phospholipid and said gas is perfluoropentane.

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

38. A method of claim 34 wherein said monolayer comprises a phospholipid and said gas is perfluoropropane.

39. The method according to claim 1 wherein said vesicles comprise a polysaccharide.

40. The method according to claim 39 wherein said polysaccharide comprises galactose.

41. The method according to claim 40 wherein said gaseous phase is nitrogen.

42. The method according to claim 1 wherein said vesicles comprise a polymer.

43. The method according to claim 42 wherein said polymer comprises a methacrylate.

44. The method according to claim 43 wherein said gas is air.

45. The method according to claim 42 wherein said polymer comprises an acrylate.

46. The method according to claim 45 wherein said gas is air.

47. The method according to claim 42 wherein said polymer comprises a cyanoacrylate.

48. The method according to claim 47 wherein said gas is air.

49. The method according to claim 1 wherein said vesicles comprise a surfactant.

50. The method according to claim 49 wherein said vesicles have been rehydrated from lyophilized vesicles.

51. The method according to claim 49 wherein said gas is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, sulfur hexafluoride, and nitrogen.

52. The method according to claim 51 wherein said gas is a combination of perfluoropropane and nitrogen.

53. The method according to claim 51 wherein said gas is a combination of perfluorohexane and nitrogen.

54. A method of magnetic resonance focused surgical ultrasound comprising:

administering a contrast medium for magnetic resonance imaging comprising gaseous precursor filled vesicles to a patient requiring surgery,

allowing the gaseous precursor to undergo a phase transition from a liquid to a gas,

scanning said patient with magnetic resonance imaging using said contrast medium to identify the region of the patient requiring surgery, and

applying ultrasound to said region to carry out said surgery wherein said contrast medium is used to fascilitate the application of ultrasound.

55. The method of claims 54 wherein said gaseous precursor phase transition from a liquid to a gas and said imaging with magnetic resonance take place simultaneously.

56. A method of claim 54 wherein said vesicles comprise a monolayer.

57. A method of claim 56 wherein said monolayer comprises a phospholipid.

58. A method of claim 57 wherein said gaseous precursor is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, and sulfur hexafluoride.

59. A method of claim 57 wherein said monolayer comprises a phospholipid and said gaseous precursor is perfluoropentane.

60. A method of claim 57 wherein said monolayer comprises a phospholipid and said gaseous precursor is sulfur hexafluoride.

61. A method of claim 57 wherein said monolayer comprises a phospholipid and said gaseous precursor is perfluoropropane.

62. The method according to claim 54 wherein said vesicles comprise a polymer.

63. The method according to claim 62 wherein said polymer comprises an acrylate.

64. The method according to claim 63 wherein said gas is air.

65. The method according to claim 62 wherein said polymer comprises a methacrylate.

66. The method according to claim 65 wherein said gas is air.

67. The method according to claim 62 wherein said polymer comprises a cyanoacrylate.

68. The method according to claim 67 wherein said gas is air.

69. The method according to claim 54 wherein said vesicles comprise a polysaccharide.

70. The method according to claim 69 wherein said polysaccharide comprises galactose.

71. The method according to claim 70 wherein said gaseous phase is nitrogen.

72. The method according to claim 54 wherein said vesicles comprise a surfactant.

73. The method according to claim 72 wherein said gaseous precursor is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, sulfur hexafluoride, and nitrogen.

74. The method according to claim 73 wherein said gaseous precursor is a combination of perfluoropropane and nitrogen.

75. The method according to claim 73 wherein said gaseous precursor is a combination of perfluorohexane and nitrogen.

76. The method according to claim 72 wherein said vesicles have been rehydrated from lyophilized vesicles.