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

• US 7,582,281 B2
• Filed: 01/25/2007
• Issued: 09/01/2009
• Est. Priority Date: 10/25/1999
• Status: Expired due to Term

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Yu, Dong-Fang, Yang, David J., Liu, Chun W., Kim, E. Edmund
• Primary Examiner(s): Jones; D. L
• Application Number:
  US11/627,299
• Publication Number:
  US 20070122342A1
• Time in Patent Office: 950 Days
• Field of Search: 424/1.11, 424/1.49, 424/1.65, 424/1.69, 424/1.73, 424/1.81, 424/1.85, 424/1.89, 424/9.1, 424/9.3, 424/9.4, 424/9.5, 424/9.6, 424/9.7, 424/9.8, 530/300, 530/311, 530/312, 530/317, 534/7, 534 10- 16
• US Class Current: 424/9.1
• 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. 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.

2. The method of claim 1, wherein the signal is a radioactive signal.

3. The method of claim 2, wherein detecting comprises performing emission tomography.

4. The method of claim 1, 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.

5. The method of claim 1, wherein the emission tomography is positron emission tomography (PET).

6. The method of claim 1, wherein the emission tomography is single photon emission computed tomography (SPECT).

7. The method of claim 1, wherein the targeting ligand is a tissue-specific ligand.

8. The method of claim 1, wherein the subject is a mammal.

9. The method of claim 1, wherein the subject is a human.

10. The method of claim 1, wherein the site is in the heart, breast, ovary, prostate, endometrium, lung, brain, or liver.

11. The method of claim 10, wherein the site is in the heart.

12. The method of claim 1, wherein the site is an area of inflammation.

13. The method of claim 12, wherein the area of inflammation is an infection.

14. The method of claim 1, wherein the site is a tumor.

15. The method of claim 14, 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.

16. The method of claim 1, wherein the radioactive signal from the administered composition localizes at the site.

17. The method of claim 1, wherein the radionuclide is ^99mTc, ¹⁸⁸Re, ¹⁸⁶Re, ¹⁸³Sm, ¹⁶⁶Ho, ⁹⁰Y, ⁸⁹Sr, ⁶⁷Ga, ⁶⁸Ga, ¹¹¹In, ¹⁸³Gd, ⁵⁹Fe, ²²⁵Ac, ²¹²Bi, ²¹¹At, ⁶⁴Cu or ⁶²Cu.

18. The method of claim 1, wherein the radionuclide-labeled bis-aminoethanethiol (BAT)-targeting ligand conjugate is a radionuclide-labeled ethylenedicysteine-targeting ligand conjugate.

19. The method of claim 1, 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.

20. The method of claim 19, wherein the targeting ligand is an anticancer agent.

21. The method of claim 20, wherein the anticancer agent is methotrexate, doxorubicin, tamoxifen, paclitaxel, topotecan, LHRII, mitomycin C, etoposide tomudex, podophyllotoxin, mitoxantrone, camptothecin, colchicine, endostatin, fludarabin, gemcitabine, or tomudex.

22. The method of claim 19, wherein the targeting ligand is a tumor marker.

23. The method of claim 22, 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.

24. The method of claim 19, wherein the targeting ligand is a folate receptor targeting ligand.

25. The method of claim 24, wherein the folate receptor targeting ligand is folate, methotrexate, or tomudex.

26. The method of claim 19, wherein the targeting ligand is a tumor apoptotic cell targeting ligand.

27. The method of claim 26, wherein the tumor apoptotic cell targeting ligand is annexin V.

28. The method of claim 19, wherein the targeting ligand is a tumor hypoxia targeting ligand.

29. The method of claim 28, wherein the targeting ligand is nitroimidazole, mitomycin, or metronidazole.

30. The method of claim 19, wherein the targeting ligand is glutamate pentapeptide.

31. The method of claim 19, wherein the targeting ligand is an agent that mimics glucose.

32. The method of claim 31, 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.

33. The method of claim 32, wherein the agent that mimics glucose is glucosamine or deoxyglucose.

34. The method of claim 1, 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.

35. The method of claim 34, wherein the linker comprises a water soluble peptide, glutamic acid, aspartic acid, bromo ethylacetate, ethylene diamine, or lysine.

36. The method of claim 35, wherein said linker is glutamate peptide or poly-glutamic acid.

37. The method of claim 36, wherein the targeting ligand is estradiol, topotecan, paclitaxel, raloxifen, etoposide, doxorubricin, mitomycin C, endostatin, annexin V, LHRH, octreotide, VIP, methotrexate, or folic acid.

38. The method of claim 1, wherein detecting is performed from about 10 minutes to about 4 hours after administering to the subject the effective amount of the composition.

39. The method of claim 1, wherein the site is a site of infection, a tumor, an organ, hypoxic tissue, a myocardial infarction, apoptotic cells, Alzheimer'"'"'s disease, or endometriosis.

40. The method of claim 39, wherein the site is a tumor.

41. The method of claim 39, wherein the site is an organ.

42. The method of claim 41, wherein the organ is heart, lung, brain, liver, spleen, pancreas, or intestine.

43. The method of claim 42, wherein the organ is heart.

44. The method of claim 43, wherein the site is an area of myocardial infarction.