Ethylenedicysteine (EC)-drug conjugates, compositions and methods for tissue specific disease imaging

• US 20060188438A1
• Filed: 04/17/2006
• Published: 08/24/2006
• Est. Priority Date: 10/25/1999
• Status: Active Grant

• Current Assignee: Chun W. Liu, David J. Yang, Dong-Fang Yu, Kim E. Edmund
• Original Assignee: Chun W. Liu, David J. Yang, Dong-Fang Yu, Kim E. Edmund
• Inventors: Yu, Dong-Fang, Yang, David J., Liu, Chun W., Kim, E. Edmund
• Granted Patent: US 7,632,484 B2
• Time in Patent Office: Days
• US Class Current: 424/1.110
• CPC Class Codes: A61K 51/04 Organic compounds
• CPC Class Codes: A61K 51/0478 complexes from non-cyclic ligands, e.g. EDTA, MAG3
• CPC Class Codes: A61K 51/0491 Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
• CPC Class Codes: A61K 51/0497 conjugates with a carrier being an organic compounds
• CPC Class Codes: A61K 51/087 the peptide being an annexin, e.g. annexin V
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10

Abstract

The invention provides, in a general sense, a new labeling strategy employing ^99mTc chelated with ethylenedicysteine (EC). EC is conjugated with a variety of ligands and chelated to ^99mTc for use as an imaging agent for tissue-specific diseases. The drug conjugates of the invention may also be used as a prognostic tool or as a tool to deliver therapeutics to specific sites within a mammalian body. Kits for use in tissue-specific disease imaging are also provided.

Claims

1-41. -41. (canceled)

42. A kit for preparing a radiopharmaceutical preparation, said kit comprising one or more sealed containers, and a predetermined quantity of a bis-aminoethanethiol (BAT)-targeting ligand conjugate composition in one or more of the sealed containiners.

43. The kit of claim 42, wherein the kit further comprises a reducing agent.

44. The kit of claim 42, wherein the targeting ligand is an anticancer agent, DNA topoisomerase inhibitor, antimetabolite, tumor marker, folate receptor targeting ligand, tumor apoptotic cell targeting ligand, tumor hypoxia targeting ligand, DNA intercalator, receptor marker, peptide, organ ligand, antibiotic, antifungal, glutamate pentapeptide or an agent that mimics glucose.

45. The kit of claim 42, wherein the targeting ligand is estradiol, topotecan, paclitaxel, raloxifen, etoposide, doxorubricin, mitomycin C, endostatin, annexin V, LHRH, octreotide, VIP, methotrexate or folic acid.

46. The kit of claim 42, wherein the composition further comprises a linker between said bis-aminoethanethiol (BAT) and said targeting ligand.

50. The reagent of claim 42, further comprising a linker between said targeting ligand and said bis-aminoethanethiol (BAT).

52. The kit of claim 42, wherein the bis-aminoethanethiol (BAT)-targeting ligand is ethylenedicysteine (EC).

53. The kit of claim 42, further defined as comprising a sealed containing comprising a reducing agent.

54. The kit of claim 53, wherein the bis-aminoethanethiol (BAT)-targeting ligand conjugate composition and the reducing agent are comprised together in a sealed container.

55. The kit of claim 42, further defined as comprising a sealed containing comprising a linker.

56. The kit of claim 42, wherein the kit comprises a first sealed containing comprising the bis-aminoethanethiol (BAT)-targeting ligand conjugate composition and a second sealed containing comprising a reducing agent.

57. The kit of claim 42, wherein one or more of the sealed containers is further defined as a bag.

58. The kit of claim 43, wherein the reducing agent is a dithionite ion, a stannous ion or a ferrous ion.

59. The kit of claim 42, wherein the targeting ligand is an anticancer agent.

60. The kit of claim 59, wherein the anticancer agent is methotrexate, doxorubicin, tamoxifen, paclitaxel, topotecan, LHRH, mitomycin C, etoposide tomudex, podophyllotoxin, mitoxantrone, camptothecin, colchicine, endostatin, fludarabin, gemcitabine, or tomudex.

61. The kit of claim 42, wherein the targeting ligand is an agent that mimics glucose.

62. The kit of claim 61, wherein the agent that mimics glucose is glucosamine, deoxyglucose, neomycin, kanamycin, gentamicin, paromycin, amikacin, tobramycin, netilmicin, ribostamycin, sisomicin, micromicin, lividomycin, dibekacin, isepamicin, astromicin, or an aminoglycoside.

63. The kit of claim 42, wherein the targeting ligand is a tumor marker.

65. The kit of claim 42, wherein the targeting ligand is a DNA topoisomerase inhibitor.

66. The kit of claim 42, wherein the targeting ligand is a folate receptor targeting ligand.

67. The kit of claim 66, wherein the folate receptor targeting ligand is folate, methotrexate, or tomudex.

68. The kit of claim 42, wherein the targeting ligand is a tumor apoptotic cell targeting ligand or a tumor hypoxia targeting ligand.

69. The kit of claim 68, wherein the targeting ligand is annexin V, colchicine, nitroimidazole, mitomycin, or metronidazole.

70. The kit of claim 42, wherein the targeting ligand is glutamate pentapeptide.

71. The kit of claim 42, wherein the components of the kit are in a liquid form, frozen form, or dry form.

72. The kit of claim 42, wherein the components of the kit are in a lyophilized form.

73. The kit of claim 46, wherein the linker is a water soluble peptide, glutamic acid, polyglutamic acid, aspartic acid, polyaspartic acid, bromoethylacetate, ethylenediamine or lysine.

74. The kit of claim 42, wherein the kit further comprises one or more pharmaceutical adjunct materials.

75. The kit of claim 74, wherein the one or more pharmaceutical adjunct materials are selected from the group consisting of a pharmaceutically acceptable salt, a buffer, a preservative, and antioxidant, and a scavenger

76. The kit of claim 75, wherein the kit comprises an antioxidant.

77. The kit of claim 76, wherein the antioxidant is vitamin C.

78. The kit of claim 75, wherein the kit comprises a scavenger.

79. The kit of claim 78, wherein the scavenger is glucoheptonate or EDTA.

80. The kit of claim 42, wherein the kit is a home-made kit.

81. The kit of claim 42, wherein the kit comprises EC, SnCl₂, Na₂IPO₄, ascorbic acid, and NaEDTA.

82. The kit of claim 81, wherein the kit comprises lyophilized EC (3 mg), SnCl₂ (100 μ

g), Na₂IPO₄ (13.5 mg), ascorbic acid (0.5 mg) and NaEDTA (0.5 mg) at pH 10.

83. The kit of claim 42, wherein the kit comprises EC-folate, SnCl₂, Na₂IPO₄, ascorbic acid, and NaEDTA.

84. The kit of claim 83, wherein the kit comprises lyophilized residue of EC-folate (3 mg), SnCl₂ (100 μ

g), Na₂IPO₄ (13.5 mg), ascorbic acid (0.5 mg), and NaEDTA (0.5 mg).

85. The kit of claim 42, wherein the kit comprises EC-MN or EC-NIM, SnCl₂, Na₂IPO₄, ascorbic acid, and NaEDTA.

86. The kit of claim 85, wherein the kit comprises lyophilized residue of EC-MN or EC-NIM (3 mg), SnCl₂ (100 μ

g), Na₂IPO₄ (13.5 mg), ascorbic acid (0.5 mg), and NaEDTA (0.5 mg).

47. A reagent for preparing a scintigraphic imaging agent comprising a targeting ligand covalently linked to a bis-aminoethanethiol (BAT).

48. The reagent of claim 47, wherein the bis-aminoethanethiol (BAT) is ethylenedicysteine.

49. The reagent of claim 47, wherein the targeting ligand is an anticancer agent, DNA topoisomerase inhibitor, antimetabolite, tumor marker, folate receptor targeting ligand, tumor apoptotic cell targeting ligand, tumor hypoxia targeting ligand, DNA intercalator, receptor marker, peptide, organ specific ligand, antibiotic, antifungal, glutamate pentapeptide or an agent that mimics glucose.

51. (canceled)

64. The kit of claim 64, wherein the tumor marker is PSA, ER, PR, CA-125, CA-199, CEA AFP, interferons, BRCA1, HER-2/neu, cytoxan, p53, or endostatin.