Ethylenedicysteine (EC)-Drug Conjugates Compositions and Methods for Tissue Specific Disease Imaging

• US 20070122342A1
• Filed: 01/25/2007
• Published: 05/31/2007
• Est. Priority Date: 10/25/1999
• Status: Active Grant

• Current Assignee: David Yang, Dong-Fang Yu, E Kim, Rudy A. Mazzocchi
• Original Assignee: David Yang, Dong-Fang Yu, E Kim, Rudy A. Mazzocchi
• Inventors: Yu, Dong-Fang, Liu, Chun, Yang, David, Kim, E.
• Granted Patent: US 7,582,281 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

1-51. -51. (canceled)

52. A method of imaging a site within a subject comprising the steps of:

a) administering to the subject an effective amount of a composition comprising a radionuclide-labeled bis-aminoethanethiol (BAT)-targeting ligand conjugate, wherein the BAT comprises two carboxylic acid moieties and wherein a targeting ligand is conjugated to at least one carboxylic acid moiety of the BAT; and

b) detecting signal from the site.

53. The method of claim 52, wherein the signal is a radioactive signal.

54. The method of claim 53, wherein detecting comprises performing emission tomography.

55. The method of claim 52, wherein a first targeting ligand is conjugated to a first carboxylic acid moiety of the BAT and wherein a second targeting ligand is conjugated to a second carboxylic acid moiety of the BAT.

56. The method of claim 52, wherein the emission tomography is positron emission tomography (PET).

57. The method of claim 52, wherein the emission tomography is single photon emission computed tomography (SPECT).

58. The method of claim 52, wherein the targeting ligand is a tissue-specific ligand.

59. The method of claim 52, wherein the subject is a mammal.

60. The method of claim 52, wherein the subject is a human.

61. The method of claim 52, wherein the site is in the heart, breast, ovary, prostate, endometrium, lung, brain, or liver.

62. The method of claim 61, wherein the site is in the heart.

63. The method of claim 52, wherein the site is an area of inflammation.

64. The method of claim 63, wherein the area of inflammation is an infection.

65. The method of claim 52, wherein the site is a tumor.

66. The method of claim 65, wherein the tumor is breast cancer, lung cancer, prostate cancer, ovarian cancer, brain cancer, liver cancer, cervical cancer, colon cancer, renal cancer, skin cancer, head &

neck cancer, bone cancer, esophageal cancer, bladder cancer, uterine cancer, lymphatic cancer, stomach cancer, pancreatic cancer, testicular cancer, lymphoma, multiple myeloma, folate-positive cancer, or estrogen-positive cancer.

67. The method of claim 52, wherein the radioactive signal from the administered composition localizes at the site.

68. The method of claim 52, wherein the radionuclide is ^99mTc, ¹⁸⁸Re, ¹⁸⁶Re, ¹⁸³Sm, ¹⁶⁶Ho, ⁹⁰Y, ⁸⁹Sr, ⁶⁷Ga, ⁶⁸Ga, ¹¹¹In, ¹⁸³Gd, ⁵⁹Fe, ²²⁵Ac, ²¹²Bi, ²¹¹At, ⁶⁴Cu or ⁶²Cu.

69. The method of claim 52, wherein the radionuclide-labeled bis-aminoethanethiol (BAT)-targeting ligand conjugate is a radionuclide-labeled ethylenedicysteine-targeting ligand conjugate.

70. The method of claim 52, 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, nucleotide, organ specific ligand, antibiotic, antifungal, antibody, glutamate pentapeptide, or an agent that mimics glucose.

71. The method of claim 70, wherein the targeting ligand is an anticancer agent.

72. The method of claim 71, wherein the anticancer agent is methotrexate, doxorubicin, tamoxifen, paclitaxel, topotecan, LHRH, mitomycin C, etoposide tomudex, podophyllotoxin, mitoxantrone, camptothecin, colchicine, endostatin, fludarabin, gemcitabine, or tomudex.

73. The method of claim 70, wherein the targeting ligand is a tumor marker.

74. The method of claim 73, wherein the tumor marker is PSA, ER, PR, CA-125, CA-199, CEA AFP, interferons, BRCA1, HER-2/neu, cytoxan, p53, endostatin, or a monoclonal antibody.

75. The method of claim 70, wherein the targeting ligand is a folate receptor targeting ligand.

76. The method of claim 75, wherein the folate receptor targeting ligand is folate, methotrexate, or tomudex.

77. The method of claim 70, wherein the targeting ligand is a tumor apoptotic cell targeting ligand.

78. The method of claim 77, wherein the tumor apoptotic cell targeting ligand is annexin V.

79. The method of claim 70, wherein the targeting ligand is a tumor hypoxia targeting ligand.

80. The method of claim 79, wherein the targeting ligand is nitroimidazole, mitomycin, or metronidazole.

81. The method of claim 70, wherein the targeting ligand is glutamate pentapeptide.

82. The method of claim 70, wherein the targeting ligand is an agent that mimics glucose.

83. The method of claim 82, 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.

84. The method of claim 83, wherein the agent that mimics glucose is glucosamine or deoxyglucose.

85. The method of claim 52, wherein the radionuclide-labeled bis-aminoethanethiol (BAT)-targeting ligand conjugate further comprises a linker conjugating a carboxylic acid moiety of the BAT to the targeting ligand.

86. The method of claim 85, wherein the linker comprises a water soluble peptide, glutamic acid, aspartic acid, bromo ethylacetate, ethylene diamine, or lysine.

87. The method of claim 86, wherein said linker is glutamate peptide or poly-glutamic acid.

88. The method of claim 87, wherein the targeting ligand is estradiol, topotecan, paclitaxel, raloxifen, etoposide, doxorubricin, mitomycin C, endostatin, annexin V, LHRH, octreotide, VIP, methotrexate, or folic acid.

89. The method of claim 52, wherein detecting is performed from about 10 minutes to about 4 hours after administering to the subject the effective amount of the composition.

90. The method of claim 52, wherein the site is a site of infection, a tumor, an organ, hypoxic tissue, a myocardial infarction, apoptotic cells, Alzheimer'"'"'s disease, or endometriosis.

91. The method of claim 90, wherein the site is a tumor.

92. The method of claim 90, wherein the site is an organ.

93. The method of claim 92, wherein the organ is heart, lung, brain, liver, spleen, pancreas, or intestine.

94. The method of claim 93, wherein the organ is heart.

95. The method of claim 94, wherein the site is an area of myocardial infarction.