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

• US 7,229,604 B2
• Filed: 09/26/2003
• Issued: 06/12/2007
• 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, DAMERON LEVEST
• Application Number:
  US10/672,142
• Publication Number:
  US 20050079133A1
• Time in Patent Office: 1,355 Days
• Field of Search: 424/1.11, 424/1.49, 424/1.65, 424/1.69, 424/1.73, 424/9.1, 424/9.2, 424/9.4, 424/9.5, 424/9.6, 424/9.7, 424/9.8, 534/7, 534 10- 16, 530/300, 530/311, 530/312, 530/317, 206/223, 206/569, 206/570
• 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 delivering a radionuclide into target cells of a human subject, comprising:

a) obtaining a composition comprising a radionuclide-labeled bis-aminoethanethiol (BAT) dicarboxylic acid-targeting ligand conjugate; and

b) administering the conjugate to the subject, wherein the conjugate is take up into the target cells.

2. The method of claim 1, wherein the target cells are in the breast, ovary, prostate, endometrium, lung, brain, or liver.

3. The method of claim 1, wherein the target cells comprise a tumor.

4. The method of claim 3, 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, or multiple myeloma.

5. The method of claim 1, wherein the target cells comprise an inflammatory lesion in the subject.

6. The method of claim 5, wherein the inflammatory lesion is a lesion that is secondary to infection.

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

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

9. The method of claim 8, wherein the targeting ligand conjugate comprises the targeting ligand conjugated to one or both arms of ethylenedicysteine.

10. The method of claim 1, wherein the targeting ligand conjugate comprises more than one targeting ligand.

11. The method of claim 1, wherein radioactive signal from the administered targeting ligand conjugate localizes in the target cells.

12. The method of claim 1, wherein the radionuclide is ^99mTc, ¹⁸⁸Re, ¹⁸⁶Re, ¹⁸³Sm, ¹⁶⁶Ho, ⁹⁰Y, ⁸⁹Sr, ⁶⁷Ga, ⁶⁸Ga, ¹¹¹In, ¹⁵³Gd, ⁵⁹Fe, ²²⁵Ac, ²¹²Bi, ²¹¹At, ⁶²Cu, or ⁶⁴Cu.

13. The method of claim 12, wherein the radionuclide is ^99mTc.

14. 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, glutamate pentapeptide, or an agent that mimics glucose.

15. The method of claim 14, wherein the targeting ligand is an anticancer agent.

16. The method of claim 15, wherein the anticancer agent is methotrexate, doxorubicin, tamoxifen, paclitaxel, topotecan, LHRH, mitomycin C, etoposide tomudex, podophyllotoxin, mitoxantrone, camptothecin, colchicine, endostatin, fludarabin, gemcitabine, or tomudex.

17. The method of claim 14, wherein the targeting ligand is a tumor marker.

18. The method of claim 17, wherein the tumor marker is PSA, ER, PR, CA-125, CA-199, CEA AFP, interferons, BRCA1, HER-2/neu, cytoxan, p53, or endostatin.

19. The method of claim 14, wherein the targeting ligand is a folate receptor targeting ligand.

20. The method of claim 19, wherein the folate receptor targeting ligand is folate, methotrexate, or tomudex.

21. The method of claim 14, wherein the targeting ligand is a tumor apoptotic cell targeting ligand or a tumor hypoxia targeting ligand.

22. The method of claim 21, wherein the targeting ligand is annexin V, colchicine, nitroimidazole, mitomycin, or metronidazole.

23. The method of claim 14, wherein the targeting ligand is glutamate pentapeptide.

24. The method of claim 14, wherein the targeting ligand is an agent that mimics glucose.

25. The method of claim 24, 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.

26. The method of claim 25, wherein the agent that mimics glucose is glucosamine or deoxyglucose.

27. The method of claim 1, wherein said radionuclide-labeled bis-aminoethanethiol (BAT) dicarboxylic acid-targeting ligand conjugate comprises a linker conjugating the BAT dicarboxylic acid to the targeting ligand.

28. The method of claim 27, wherein the linker comprises a water soluble peptide, glutamic acid, aspartic acid, bromo ethylacetate, ethylene diamine, or lysine.

29. The method of claim 28, wherein said linker is glutamate peptide or poly-glutamic acid.

30. The method of claim 28, wherein the targeting ligand is estradiol, topotecan, paclitaxel, raloxifen, etoposide, doxorubricin, mitomycin C, endostatin, annexin V, LHRH, octreotide, VIP, methotrexate, or folic acid.