Coordination complexes having tethered therapeutic agents and/or targeting moieties, and methods of making and using the same

• US 20040235712A1
• Filed: 01/12/2004
• Published: 11/25/2004
• Est. Priority Date: 01/13/2003
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Lippard, Stephen J., Haskel, Ariel, Barnes, Katie R., Barnes, Carmen M.
• Granted Patent: US 7,138,520 B2
• Time in Patent Office: Days
• US Class Current: 514/6
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/282 Platinum compounds
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: C07J 1/00 Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane

Abstract

In part, the present invention is directed to coordination complexes comprising a therapeutic agent. In one aspect, the subject compositions comprise a platinum metal center and a covalently attached therapeutic agent.

Claims

1. A compound comprising:

(a) a platinum metal center (b) two cis labile ligands bonded to the platinum metal center, and (c) one or more therapeutic agents and/or targeting moieties covalently attached to the platinum metal center, wherein the therapeutic agent is not covalently attached to the platinum metal center through the cis labile ligands.

2. The compound of claim 1, wherein the compound further comprises two cis non-labile ligands bonded to the platinum metal center, and wherein the therapeutic agent is not covalently attached to the platinum metal center through the cis non-labile ligands.

3. The compound of claim 1, wherein the two cis labile ligands are halides.

4. The compound of claim 3, wherein the halides are chlorides.

5. The compound of claim 1, wherein the therapeutic agent is a steroid.

6. The compound of claim 5, wherein the steroid is estrogen.

7. The compound of claim 1, wherein the targeting moiety is a peptide.

8. The compound of claim 7, wherein the peptide comprises asparagine, glycine, and arginine.

9. The compound of claim 1, wherein the therapeutic agent is covalently attached to the metal center through a tether.

10. The compound of claim 9, wherein the therapeutic agent is a steroid.

11. The compound of claim 10, wherein the steroid is estrogen.

12. The compound of claim 1, wherein the targeting moiety is covalently attached to the metal center through a tether.

13. The compound of claim 12, wherein the targeting moiety is a peptide.

14. The compound of claim 13, wherein the peptide comprises asparagine, glycine, and arginine.

15. The compound of claim 1, wherein the compound has the following formula:

16. The compound of claim 15, wherein M is a labile covalently bonded ligand and not a therapeutic agent or targeting moiety.

17. The compound of claim 15, wherein the compound is charged.

18. The compound of claim 15, wherein M is a therapeutic agent and is the same as R.

19. The compound of claim 15, wherein M is a therapeutic agent and is different than R.

20. The compound of claim 15, wherein M is a targeting moiety and is the same as R.

21. The compound of claim 15, wherein M is a targeting moiety and is different than R.

22. The compound of claim 15, wherein X, independently for each occurrence, is selected from the group consisting of halide, —

O-alkyl, —

O-aryl, alkyl, and aryl.

23. The compound of claim 15, wherein both of X are Cl.

24. The compound of claim 15, wherein at least one L is NH₃.

25. The compound of claim 15, wherein both of X are Cl, both of L are NH₃, R is a tethered steroid wherein the steroid is estrogen, and the tether comprises an amide moiety.

26. The compound of claim 15, wherein both of X are Cl, both of L are NH₃, R is a tethered peptide comprising asparagine, glycine, and arginine, and the tether comprises an amide moiety.

27. The compound of claim 15, wherein both of X are Cl, both of L are NH₃, both R and M are tethered steroids wherein the steroids are estrogen, and the tethers comprise an amide moiety.

28. The compound of claim 15, wherein both of X are Cl, both of L are NH₃, both R and M are tethered peptides comprising asparagine, glycine, and arginine, and the tethers comprise an amide moiety.

29. The compound of claim 15, wherein both of X are Cl, both of L are NH₃, both R and M are a tethered steroids wherein one steroid is estrogen and the other steroid is not, and the tethers comprise an amide moiety.

30. The compound of claim 15, wherein both of X are Cl, both of L are NH₃, R is a tethered steroid wherein the steroid is estrogen, M is a tethered peptide comprising asparagine, glycine, and arginine, and the tethers comprise an amide moiety.

35. A composition comprising any of the compounds of claims 1-34 and a pharmaceutically effective excipient.

36. A method of treating cancer, comprising administering to a subject any of the compounds of claims 1-34 or a combination thereof.

37. The method of claim 36, wherein at least some of the cancer cells for the cancer to be treated comprise a receptor for the therapeutic agent.

38. The method of claim 36, wherein after release from the platinum metal center after administration, the therapeutic agent causes increased expression of HMG.

39. The method of claim 36, wherein the subject has cancer cells that express a receptor for the therapeutic agent.

40. The method of claim 36, wherein prior to administering the compound comprising the platinum metal center, at least some of the cancer cells of the cancer to be treated are first determined to express a type of receptor for the therapeutic agent.

41. The method of claim 39, wherein the cancer cells express estrogen ER(+) receptors.

42. A kit comprising any of the compounds of claims 1-34 or a combination thereof and instructions for administering the compound to a patient.

31. A compound comprising a platinum metal center, two cis labile ligands covalently bonded to the platinum metal center, two cis non-labile ligands covalently bonded to the platinum metal center, and at least one therapeutic agent covalently tethered to the platinum metal center, wherein upon reduction in the platinum metal center from a +4 oxidation state to a +2 oxidation state the therapeutic agent is released form the platinum metal center.

33. The compound of claim 31, wherein after release of the therapeutic agent from the platinum metal center, the compound comprising the platinum metal center is therapeutically effective.

32. A compound comprising a platinum metal center, two cis labile ligands covalently bonded to the platinum metal center, two cis non-labile ligands covalently bonded to the platinum metal center, and at least one targeting moiety covalently tethered to the platinum metal center, wherein upon reduction in the platinum metal center from a +4 oxidation state to a +2 oxidation state the targeting moiety is released form the platinum metal center.

34. The compound of claim 32, wherein after release of the targeting moiety from the platinum metal center, the compound comprising the platinum metal center is therapeutically effective.