Targeted compositions for diagnostic and therapeutic use

• US 7,452,551 B1
• Filed: 10/30/2000
• Issued: 11/18/2008
• Est. Priority Date: 10/30/2000
• Status: Expired due to Fees

• Current Assignee: Cerevast Medical, Inc.
• Original Assignee: Imarx Therapeutics, Inc. (Sycamore Entertainment Group, Inc.)
• Inventors: Unger, Evan C., Matsunaga, Terry O., Schumann, Patricia A.
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US09/699,679
• Time in Patent Office: 2,941 Days
• Field of Search: 424/9.5, 424/450, 424/9.52, 424/9.51, 424/9.34, 424/9.341, 424/1.11, 424/1.65, 424/1.73, 424/1.29, 424/1.69, 424/9.1, 424/9.3, 424/9.321, 424/9.322, 424/9.35, 424/9.351, 424/9.4, 424/9.6, 424/9.7, 424/9.8, 424/1.21
• US Class Current: 424/452
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61K 47/6911 the form being a liposome
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Novel targeted compositions which may be used for diagnostic and therapeutic use. The compositions may comprise lipid, protein or polymer gas-filled vesicles which further comprise novel compounds of the general formula L-P-T, wherein L comprises a hydrophobic compound, P comprises a hydrophilic polymer, and T comprises a targeting ligand which targets tissues, cells or receptors, including myocardial cells, endothelial cells, epithelial cells, tumor cells and the glycoprotein GPIIbIIIa receptor. The compositions can be used in conjunction with diagnostic imaging, such as ultrasound, as well as therapeutic applications, such as therapeutic ultrasound.

Claims

1. A targeted vesicle composition for therapeutic or diagnostic use in vivo comprising, in an aqueous carrier, gas filled liposomes comprising a phosphatidylcholine selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine, wherein said liposomes further comprise a compound having the formula

2. A targeted vesicle composition according to claim 1 wherein:

X¹ is C(═

O)—

NH;

R¹ is acyl having from 16 to 20 carbons;

n has the value between 1 and 3; and

R⁴ is acyl having from 16 to 20 carbons.

3. A targeted vesicle composition according to claim 2 wherein:

R¹ is acyl having from 17 to 19 carbons;

n=1; and

R⁴ is acyl having from 17 to 19 carbons.

4. A targeted vesicle composition according to claim 1 wherein said phosphatidylcholine comprises dipalmitoylphosphatidylcholine.

5. A targeted vesicle composition according to claim 1 further comprising a phosphatidylethanolamine selected from the group consisting of dipalmitoyl-phosphatidylethanolamine, dioleoylphosphatidylethanolamine, N-succinyldioleoyl-phosphatidylethanolamine and 1-hexadecyl-2-palmitoylglycerophosphoethanolamine.

6. A targeted vesicle composition according to claim 5 wherein said phosphatidylethanolamine comprises dipalmitoylphosphatidylethanolamine.

7. A targeted vesicle composition according to claim 1 further comprising dipalmitoylphosphatidic acid.

8. A targeted vesicle composition according to claim 1, wherein said vesicles comprise a gas selected from the group consisting of perfluorocarbons and sulfur hexafluoride.

9. A targeted vesicle composition according to claim 8 wherein said perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluorocyclobutane.

10. A targeted vesicle composition according to claim 9 wherein said perfluorocarbon gas is selected from the group consisting of perfluoropropane and perfluorobutane.

11. A targeted vesicle composition according to claim 10 wherein said perfluorocarbon gas comprises perfluorobutane.

12. A targeted vesicle composition according to claim 1 wherein said gas is derived, at least in part, from a gaseous precursor.

13. A targeted vesicle composition according to claim 12 wherein said gaseous precursor has a boiling point of greater than about 37°

C.

14. A targeted vesicle composition according to claim 13 wherein said gaseous precursor comprises a perfluorocarbon.

15. A targeted vesicle composition according to claim 14 wherein said perfluorocarbon is selected from the group consisting of perfluoropentane and perfluorohexane.

16. A targeted vesicle composition according to claim 1 wherein said vesicles further comprise a bioactive agent that is different from said gas and said compound.

17. A targeted vesicle composition according to claim 16 wherein said bioactive agent comprises a therapeutic agent selected from the group consisting of genetic material, dihydroergotamine, heparin sulfate, tissue plasminogen activator, streptokinase, urokinase, hirudin, and mixtures thereof.

18. A targeted vesicle composition according to claim 3 wherein:

each of R¹ and R⁴ is acyl of 18 carbons.

19. A targeted vesicle composition according to claim 3 wherein:

R¹ is an acyl of 18 carbons.

20. A targeted vesicle composition according to claim 1, wherein said targeting ligand T is a peptide having from 3 to 20 amino acids.

21. A targeted vesicle composition according to claim 20, wherein said peptide is cyclized by a linkage selected from the group consisting of sidechain to-sidechain covalent linkages, end-to-sidechain covalent linkages, and end-to-end covalent linkages.

38. A targeted vesicle composition according to claim 1, wherein X¹ is C(═

X³).

39. A targeted vesicle composition according to claim 38, wherein said phosphatidylcholine comprises dipalmitoylphosphatidylcholine.

40. A targeted vesicle composition according to claim 38, further comprising a phosphatidylethanolamine selected from the group consisting of dipalmitoyl-phosphatidylethanolamine, dioleoylphosphatidylethanolamine, N-succinyldioleoyl-phosphatidylethanolamine and 1-hexadecyl-2-palmitoylglycerophosphoethanolamine.

41. A targeted vesicle composition according to claim 40, wherein said phosphatidylethanolamine comprises dipalmitoylphosphatidylethanolamine.

42. A targeted vesicle composition according to claim 38, further comprising dipalmitoylphosphatidic acid.

43. A targeted vesicle composition according to claim 38, wherein said vesicles comprise a gas selected from the group consisting of perfluorocarbons and sulfur hexafluoride.

44. A targeted vesicle composition according to claim 43, wherein said perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluorocyclobutane.

45. A targeted vesicle composition according to claim 44, wherein said perfluorocarbon gas is selected from the group consisting of perfluoropropane and perfluorobutane.

46. A targeted vesicle composition according to claim 45, wherein said perfluorocarbon gas comprises perfluorobutane.

47. A targeted vesicle composition according to claim 38, wherein said gas is derived, at least in part, from a gaseous precursor.

48. A targeted vesicle composition according to claim 47, wherein said gaseous precursor has a boiling point of greater than about 37°

C.

49. A targeted vesicle composition according to claim 48, wherein said gaseous precursor comprises a perfluorocarbon.

50. A targeted vesicle composition according to claim 49, wherein said perfluorocarbon is selected from the group consisting of perfluoropentane and perfluorohexane.

51. A targeted vesicle composition according to claim 38, wherein said vesicles further comprise a bioactive agent that is different from said gas and said compound.

52. A targeted vesicle composition according to claim 51, wherein said bioactive agent comprises a therapeutic agent selected from the group consisting of genetic material, dihydroergotamine, heparin sulfate, tissue plasminogen activator, streptokinase, urokinase, hirudin, and mixtures thereof.

53. A targeted vesicle composition according to claim 38, wherein said targeting ligand T is a peptide having from 3 to 20 amino acids.

54. A targeted vesicle composition according to claim 53, wherein said peptide is cyclized by a linkage selected from the group consisting of sidechain to-sidechain covalent linkages, end-to-sidechain covalent linkages, and end-to-end covalent linkages.

22. A targeted vesicle composition for therapeutic or diagnostic use in vivo comprising, in an aqueous carrier, gas filled liposomes comprising a phosphatidylcholine selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine, wherein said liposomes further comprise a compound having the formula

23. The targeted vesicle composition according to claim 22, wherein said vesicles further comprise a bioactive agent that is different from said gas and said compound.

24. The targeted vesicle composition according to claim 23, wherein said bioactive agent comprises a therapeutic agent selected from the group consisting of genetic material, dihydroergotamine, heparin sulfate, tissue plasminogen activator, streptokinase, urokinase, hirudin, and mixtures thereof.

25. The targeted vesicle composition according to claim 24, wherein said bioactive agent is urokinase.

26. The targeted vesicle composition according to claim 22, wherein said phosphatidylcholine comprises dipalmitoylphosphatidylcholine.

27. The targeted vesicle composition according to claim 22, further comprising a phosphatidylethanolamine selected from the group consisting of dipalmitoyl-phosphatidylethanolamine, dioleoylphosphatidylethanolamine, N-succinyldioleoyl-phosphatidylethanolamine and 1-hexadecyl-2-palmitoylglycerophosphoethanolamine.

28. The targeted vesicle composition according to claim 27, wherein said phosphatidylethanolamine comprises dipalmitoylphosphatidylethanolamine.

29. The targeted vesicle composition according to claim 22, further comprising dipalmitoylphosphatidic acid.

30. The targeted vesicle composition according to claim 22, wherein said vesicles comprise a gas selected from the group consisting of perfluorocarbons and sulfur hexafluoride.

31. The targeted vesicle composition according to claim 30, wherein said perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluorocyclobutane.

32. The targeted vesicle composition according to claim 31, wherein said perfluorocarbon gas is selected from the group consisting of perfluoropropane and perfluorobutane.

33. The targeted vesicle composition according to claim 32, wherein said perfluorocarbon gas comprises perfluorobutane.

34. The targeted vesicle composition according to claim 22, wherein said gas is derived, at least in part, from a gaseous precursor.

35. The targeted vesicle composition according to claim 34, wherein said gaseous precursor has a boiling point of greater than about 37°

C.

36. The targeted vesicle composition according to claim 34, wherein said gaseous precursor comprises a perfluorocarbon.

37. The targeted vesicle composition according to claim 36, wherein said perfluorocarbon is selected from the group consisting of perfluoropentane and perfluorohexane.

55. A targeted vesicle composition for therapeutic or diagnostic use in vivo comprising, in an aqueous carrier, gas filled liposomes comprising a phosphatidylcholine selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine, wherein said liposomes further comprise a compound having the formula

56. The targeted vesicle composition according to claim 55, wherein said phosphatidylcholine comprises dipalmitoylphosphatidylcholine.

57. The targeted vesicle composition according to claim 55, further comprising a phosphatidylethanolamine selected from the group consisting of dipalmitoyl-phosphatidylethanolamine, dioleoylphosphatidylethanolamine, N-succinyldioleoyl-phosphatidylethanolamine and 1-hexadecyl-2-palmitoylglycerophosphoethanolamine.

58. The targeted vesicle composition according to claim 57, wherein said phosphatidylethanolamine comprises dipalmitoylphosphatidylethanolamine.

59. The targeted vesicle composition according to claim 55, further comprising dipalmitoylphosphatidic acid.

60. The targeted vesicle composition according to claim 55, wherein said vesicles comprise a gas selected from the group consisting of perfluorocarbons and sulfur hexafluoride.

61. The targeted vesicle composition according to claim 60, wherein said perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluorocyclobutane.

62. The targeted vesicle composition according to claim 61, wherein said perfluorocarbon gas is selected from the group consisting of perfluoropropane and perfluorobutane.

63. The targeted vesicle composition according to claim 62, wherein said perfluorocarbon gas comprises perfluorobutane.

64. The targeted vesicle composition according to claim 55, wherein said gas is derived, at least in part, from a gaseous precursor.

65. The targeted vesicle composition according to claim 64, wherein said gaseous precursor has a boiling point of greater than about 37°

C.

66. The targeted vesicle composition according to claim 64, wherein said gaseous precursor comprises a perfluorocarbon.

67. The targeted vesicle composition according to claim 66, wherein said perfluorocarbon is selected from the group consisting of perfluoropentane and perfluorohexane.

68. The targeted vesicle composition according to claim 55, wherein said vesicles further comprise a bioactive agent that is different from said gas and said compound.

69. The targeted vesicle composition according to claim 68, wherein said bioactive agent comprises a therapeutic agent selected from the group consisting of genetic material, dihydroergotamine, heparin sulfate, tissue plasminogen activator, streptokinase, urokinase, hirudin, and mixtures thereof.

70. The targeted vesicle composition according to claim 69, wherein said bioactive agent is urokinase.