Coordination complexes having tethered therapeutic agents and/or targeting moieties, and methods of making and using the same
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.
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:
wherein:
X, independently for each occurrence, represents a labile covalently bonded ligand, or both of X taken together represent a bidentate ligand;
L, independently for each occurrence, represents a ligand bonded to the platinum metal center through a covalent bond, or both of L taken together represent a bidentate ligand;
M represents a therapeutic agent, a targeting moiety, or a labile covalently bonded ligand; and
R represents a steroid, wherein R and/or M is attached directly to the platinum metal center or through a tether.
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 NH 3 .
16. The compound of claim 8 , wherein both of X are Cl, both of L are NH 3 , 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 NH 3 , 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 NH 3 , 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 NH 3 , 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.
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.
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.