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

• US 7,138,520 B2
• Filed: 01/12/2004
• Issued: 11/21/2006
• Est. Priority Date: 01/13/2003
• Status: Expired due to Fees

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Barnes, Katie R., Barnes, Carmen M., Lippard, Stephen J., Haskel, Ariel
• Primary Examiner(s): Tsang, Cecilia J.
• Assistant Examiner(s): Kosar, Andrew D.
• Application Number:
  US10/755,855
• Publication Number:
  US 20040235712A1
• Time in Patent Office: 1,044 Days
• Field of Search: None
• US Class Current: 540/3
• 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(IV) metal center (b) two cis labile ligands bonded to the platinum metal center, and (c) one or more therapeutic agents covalently attached to the platinum metal center directly or through a tether, wherein the therapeutic agent is a steroid and 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 steroid is estrogen.

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

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

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

9. The compound of claim 8, wherein M is a labile covalently bonded ligand and not a therapeutic agent or targeting moiety.

10. The compound of claim 8, wherein the compound is charged.

11. The compound of claim 8, wherein M is a therapeutic agent and is the same as R.

12. The compound of claim 8, wherein M is a therapeutic agent and is different than R.

13. The compound of claim 8, wherein X, independently for each occurrence, is selected from the group consisting of halide, —

O-alkyl, —

O-aryl, alkyl, and aryl.

14. The compound of claim 8, wherein both of X are Cl.

15. The compound of claim 8, wherein at least one L is NH₃.

16. The compound of claim 8, 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.

17. The compound of claim 8, 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.

18. The compound of claim 8, wherein both of X are Cl, both of L are NH₃, both R and M are tethered steroids wherein one steroid is estrogen and the other steroid is not, and the tethers comprise an amide moiety.

19. The compound of claim 8, 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.

22. A composition comprising a compound of any one of claims 1–

4, 5, 6, 7, 8–

12, 13–

16, 17, 18–

20, or 21 and a pharmaceutically effective excipient.

23. A kit comprising a compound of any one of claims 1–

4, 5, 6, 7, 8–

12, 13–

16, 17, 18–

20, or 21 and instructions for administering the compound to a patient.

20. 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 attached to the platinum metal center, wherein the therapeutic agent is a steroid attached directly to the platinum metal center or through a tether, and wherein upon reduction in the platinum metal center from a +4 oxidation state to a +2 oxidation state the therapeutic agent is released from the platinum metal center.

21. The compound of claim 20, wherein after release of the therapeutic agent from the platinum metal center, the compound comprising the platinum metal center is therapeutically effective.