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

• US 7,632,484 B2
• Filed: 04/17/2006
• Issued: 12/15/2009
• 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, DAMERON LEVEST
• Application Number:
  US11/405,334
• Publication Number:
  US 20060188438A1
• Time in Patent Office: 1,338 Days
• Field of Search: 424/1.11, 424/1.37, 424/1.49, 424/1.65, 424/1.73, 424/1.81, 424/1.85, 424/1.89, 424/9.1, 424/9.2, 424/9.3, 424/9.4, 424/9.5, 424/9.6, 424/9.7, 424/9.8, 206/223, 206/569, 206/570, 534/7, 534 10- 16, 530/300, 530/311, 530/312, 530/317
• US Class Current: 424/1.65
• 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 reagent for preparing a scintigraphic imaging agent comprising a targeting ligand covalently linked to ethylenedicysteine (EC), wherein the targeting ligand is an anticancer agent that is methotrexate, doxorubicin, tamoxifen, paclitaxel, topotecan, LHRH, mitomycin C, etoposide tomudex, podophyllotoxin, mitoxantrone, camptothecin, colchicine, endostatin, fludarabin, gemcitabine, or tomudex;

an agent that mimics glucose;

a folate receptor targeting ligand;

or a tumor apoptotic cell targeting ligand or a tumor hypoxia targeting ligand that is annexin V, colchicine, nitroimidazole, mitomycin, or metronidazole.

2. The reagent of claim 1, wherein the targeting ligand is an agent that mimics glucose.

3. The reagent of claim 1, further comprising a linker between said targeting ligand and said ethylenedicysteine (EC).

16. The kit of claim 2, wherein the agent that mimics glucose is deoxyglucose.

17. The kit of claim 2, wherein the agent that mimics glucose is glucosamine.

4. A kit comprising one or more sealed containers, and a predetermined quantity of an ethylenedicysteine (EC)-targeting ligand conjugate composition in one or more of the sealed containers, wherein the targeting ligand is an anticancer agent that is methotrexate, doxorubicin, tamoxifen, paclitaxel, topotecan, LHRH, mitomycin C, etoposide tomudex, podophyllotoxin, mitoxantrone, camptothecin, colchicine, endostatin, fludarabin, gemcitabine, or tomudex;

an agent that mimics glucose;

a folate receptor targeting ligand;

a DNA topoisomerase inhibitor;

a tumor apoptotic cell targeting ligand or a tumor hypoxia targeting ligand that is annexin V, colchicine, nitroimidazole, mitomycin, or metronidazole;

or glutamate pentapeptide.

5. The kit of claim 4, wherein the kit further comprises a reducing agent.

6. The kit of claim 4, wherein the targeting ligand is paclitaxel.

7. The kit of claim 4, wherein the composition further comprises a linker between said ethylenedicysteine (EC) and said targeting ligand.

8. The kit of claim 5, further defined as comprising a sealed containing comprising a reducing agent.

9. The kit of claim 8, wherein the ethylenedicysteine (EC)-targeting ligand conjugate composition and the reducing agent are comprised together in a sealed container.

10. The kit of claim 7, further defined as comprising a sealed containing comprising a linker.

11. The kit of claim 8, wherein the kit comprises a first sealed containing comprising the ethylenedicysteine (EC)-targeting ligand conjugate composition and a second sealed containing comprising a reducing agent.

12. The kit of claim 4, wherein one or more of the sealed containers is further defined as a bag.

13. The kit of claim 5, wherein the reducing agent is a dithionite ion, a stannous ion or a ferrous ion.

14. The kit of claim 4, wherein the targeting ligand is an anticancer agent that is methotrexate, doxorubicin, tamoxifen, paclitaxel, topotecan, LHRH, mitomycin C, etoposide tomudex, podophyllotoxin, mitoxantrone, camptothecin, colchicine, endostatin, fludarabin, gemcitabine, or tomudex.

15. The kit of claim 14, wherein the anticancer agent is methotrexate.

18. The kit of claim 4, wherein the targeting ligand is a DNA topoisomerase inhibitor.

19. The kit of claim 4, wherein the folate receptor targeting ligand is folate.

20. The kit of claim 4, wherein the folate receptor targeting ligand is tomudex.

21. The kit of claim 4, wherein the targeting ligand is a tumor apoptotic cell targeting ligand or a tumor hypoxia targeting ligand that is annexin V, colchicine, nitroimidazole, mitomycin, or metronidazole.

22. The kit of claim 21, wherein the targeting ligand is nitroimidazole.

23. The kit of claim 4, wherein the components of the kit are in a liquid form, frozen form, or dry form.

24. The kit of claim 4, wherein the components of the kit are in a lyophilized form.

25. The kit of claim 7, wherein the linker is a water soluble peptide, glutamic acid, polyglutamic acid, aspartic acid, polyaspartic acid, bromoethylacetate, ethylenediamine or lysine.

26. The kit of claim 4, wherein the kit further comprises one or more pharmaceutical adjunct materials.

27. The kit of claim 26, 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.

28. The kit of claim 27, wherein the kit comprises an antioxidant.

30. The kit of claim 27, wherein the kit comprises a scavenger.

31. The kit of claim 30, wherein the scavenger is glucoheptonate or EDTA.

32. The kit of claim 4, wherein the kit is a home-made kit.

29. A kit comprising one or more sealed containers, a predetermined quantity of an ethylenedicysteine (EC)-targeting ligand conjugate composition in one or more sealed containers, and vitamin C.

33. A kit comprising one or more sealed containers, a predetermined quantity of ethylenedicysteine (EC)-targeting ligand conjugate composition in one or more sealed containers, SnCl₂, Na₂IPO₄, ascorbic acid, and NaEDTA.

34. The kit of claim 33, 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.

35. A kit comprising one or more sealed containers, a predetermined quantity of ethylenedicysteine (EC)-folate in one or more sealed containers, SnCl₂, Na₂IPO₄, ascorbic acid, and NaEDTA.

36. The kit of claim 35, 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).

37. A kit comprising one or more sealed containers, a predetermined quantity of ethylenedicysteine (EC)-MN or EC-NIM, SnCI₂, Na₂IPO₄, ascorbic acid, and NaEDTA.

38. The kit of claim 37, 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).