Ligand ionophore conjugates
The invention described herein pertains to ligand-ionophore conjugates, that may also comprise a linked therapeutic agent or imaging agent, and pharmaceutical compositions containing the conjugates. Also described are methods of using the conjugates for increasing the endosomal accumulation and escape of a therapeutic agent, or an imaging agent.
1. A conjugate comprising:
a ligand (B) that is a folate receptor binding ligand or a PSMA binding ligand;
one or more linkers (L); and
one or more ionophores (A) selected from the group consisting of nigericin and salinomycin which couples efflux of protons (H + ions) to influx of potassium ions (K + ions);
wherein (L) comprises at least one releasable linker; (B) is covalently linked to (L); and each (A) is covalently linked to (L).
2. The conjugate of claim 1 further comprising a therapeutic agent, and/or an imaging agent wherein the therapeutic agent or the imaging agent is covalently linked to (L).
3. The conjugate of claim 1 further comprising a therapeutic agent covalently linked to (L), wherein the therapeutic agent comprises a low molecular weight drug, a polypeptide, a peptide, an oligonucleotide, a nucleotide, an siRNA, an iRNA, a microRNA, a ribozyme, an antisense oligonucleotide, a protein, a glycoprotein, an antibody, an antigen, a synthetic amino acid, an aptamer, an oligosaccharide, or a polysaccharide.
4. The conjugate of claim 3 wherein the therapeutic agent comprises a low molecular weight chemotherapeutic agent.
5. The conjugate of claim 3 wherein the therapeutic agent comprises a low molecular weight anti-inflammatory agent.
6. The conjugate of claim 1 further comprising a fluorescent dye covalently linked to (L).
7. The conjugate of claim 1 wherein (B) is a folate.
8. The conjugate of claim 1 wherein (B) is a PSMA binding ligand.
9. The conjugate of claim 1 wherein (A) is an inhibitor of the Na + /H + exchanger.
10. The conjugate of claim 1 wherein (L) comprises a chain of about 7 to about 45 atoms.
11. The conjugate of claim 1 having a formula selected from the group consisting of
12. A pharmaceutical composition comprising the conjugate of claim 1 and at least one pharmaceutically acceptable carrier or excipient.
13. A pharmaceutical composition comprising the conjugate of claim 1 and at least one additional therapeutic agent.
14. A method of increasing the endosomal accumulation and escape of a therapeutic agent or an imaging agent, the method comprising the step of administering with the therapeutic agent or the imaging agent an effective amount of the conjugate of claim 1 .
15. The method of claim 14 wherein the therapeutic agent or the imaging agent is targeted to a cancer.
16. The method of claim 15 wherein the cancer is selected from the group consisting of ovarian, lung, breast, endometrial, brain, kidney, prostate, and colon cancer.
17. The method of claim 14 wherein the therapeutic agent or the imaging agent is targeted to a site of inflammation.
18. The method of claim 17 wherein the inflammatory disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, atherosclerosis, diabetes, graft-versus-host disease, multiple sclerosis, osteomyelitis, psoriasis, Crohn's disease, Sjögren's syndrome, lupus erythematosus, and ulcerative colitis.