Small Molecule Ligands of the Integrin RGD Recognition Site and Methods of Use

• US 20100159021A1
• Filed: 12/22/2009
• Published: 06/24/2010
• Est. Priority Date: 12/23/2008
• Status: Abandoned Application

• Current Assignee: NanoPharmaceuticals LLC
• Original Assignee: NanoPharmaceuticals LLC
• Inventors: Davis, Paul, Mousa, Shaker A., Davis, Faith B., Lin, Hung-Yun
• Application Number:
  US12/644,493
• Publication Number:
  US 20100159021A1
• Time in Patent Office: Days
• US Class Current: 424/499
• 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 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

Provided herein are compositions and methods for treating cancer by increasing the pro-apototic actions of small molecule ligands of integrin RGD recognition sites such as polyphenols by administering such compounds in conjunction with anti-angiogenic thyroid hormone analogs such as tetrac or triac.

Claims

1. A pharmaceutical composition for treating cancer comprising a combination of small molecule ligand of the integrin RGD recognition site and an anti-angiogenic thyroid hormone analog, wherein the combination induces apoptosis in cancer cells.

2. The pharmaceutical composition of claim 1, wherein the cancer cells are selected from the group consisting of:

breast cancer, lung cancer, kidney cancer, thyroid cancer, brain cancer (glioma), ovarian cancer, pancreatic cancer, prostate cancer, plasma cell cancer (myeloma), squamous cell head-and-neck cancer, liver cancer, muscle cancer (sarcoma), and colon cancer.

3. The pharmaceutical composition of claim 1, wherein the small molecule ligand of the integrin RGD recognition site is obtained or derived from a polyphenol compound and the thyroid hormone analog is tetrac or triac (triiodothyroacetic acid).

4. The pharmaceutical composition of claim 3, wherein the small molecule ligand of the integrin RGD recognition site is resveratrol.

5. The pharmaceutical composition of claim 4, wherein the thyroid hormone analog is tetrac.

6. The pharmaceutical composition of claim 5, wherein resveratrol, or tetrac or both are conjugated via a covalent bond to a polymer selected from polyvinyl alcohol, acrylic acid ethylene co-polymer, polyethyleneglycol (PEG), polyacrylic acid, polylactic acid, agarose, polyglycolide, polylactide, PEO, m-PEG, PVA, PLLA, PGA, poly-L-lysine, Human Serum Albumin, cellulose derivatives, carbomethoxy/ethyl/hydroxypropyl, hyaluronic acid, folate linked cyclodextrin/dextran, sarcosine/amino acid spaced polymer, alginate, carrageenan, pectin/chitosan, chitosan, dextran, collagen, polyamine, poly aniline, poly alanine, polytrytophan, poly tyrosine, polylactide-co-glycolide (PLGA) polyglycolide, polylactic acid, or co-polymers thereof, wherein said polymer is formulated into a nanoparticle, wherein said nanoparticle is between 150 and 250 nanometers in size, and wherein said tetrac binds to the cell surface receptor for thyroid hormone on integrin α

vβ

3.

7. The pharmaceutical composition of claim 5, wherein resveratrol is formulated as any of the conjugates shown in FIGS. 4-7.

8. The pharmaceutical composition of claim 1, further comprising an anti-estrogen compound.

9. The pharmaceutical composition of claim 6, wherein the anti-estrogen compound is selected from the group consisting of tamoxifen and aromatase inhibitors.

10. The pharmaceutical composition of claim 6, wherein the nanoparticles further comprise one or more additional chemotherapeutic agents.

11. The pharmaceutical composition of claim 10, wherein the one or more additional chemotherapeutic agents are targeted to the cancer cells.

12. The pharmaceutical composition of claim 1, wherein the combination blocks anti-apoptotic action of endogenous thyroid hormone.

13. A method of treating cancer comprising administering a therapeutically effective amount of a combination of a small molecule ligand of the integrin RGD recognition site and an anti-angiogenic thyroid hormone analog to a patient suffering therefrom.

14. The method of claim 13, wherein the small molecule ligand of the integrin RGD recognition site is obtained or derived from a polyphenol compound and the thyroid hormone analog is tetrac or triac.

15. The method of claim 14, wherein the small molecule ligand of the integrin RGD recognition site is resveratrol.

16. The method of claim 15, wherein the thyroid hormone analog is tetrac.

17. The method of claim 16, wherein resveratrol or tetrac or both are conjugated via a covalent bond to a polymer selected from polyvinyl alcohol, acrylic acid ethylene co-polymer, polyethyleneglycol (PEG), polyacrylic acid, polylactic acid, agarose, polyglycolide, polylactide, PEO, m-PEG, PVA, PLLA, PGA, poly-L-lysine, Human Serum Albumin, cellulose derivatives, carbomethoxy/ethyl/hydroxypropyl, hyaluronic acid, folate linked cyclodextrin/dextran, sarcosine/amino acid spaced polymer, alginate, carrageenan, pectin/chitosan, chitosan, dextran, collagen, polyamine, poly aniline, poly alanine, polytrytophan, poly tyrosine, polylactide-co-glycolide (PLGA) polyglycolide, polylactic acid, or co-polymers thereof, wherein said polymer is formulated into a nanoparticle, wherein said nanoparticle is between 150 and 250 nanometers in size, and wherein said tetrac binds to the cell surface receptor for thyroid hormone on integrin α

vβ

3.

18. The method of claim 16, wherein resveratrol is formulated as any of the conjugates shown in FIGS. 4-7.

19. The method of claim 13, further comprising administering an anti-estrogen compound to the subject.

20. The method of claim 19, wherein the anti-estrogen compound is selected from the group consisting of tamoxifen and aromatase inhibitors.

21. The method of claim 17, wherein the nanoparticles further comprise one or more additional chemotherapeutic agents.

22. The method of claim 17, wherein the nanoparticles induce chemosensitization of chemoresistant cancer cells.

23. The method of claim 17, wherein the nanoparticles induce radiosensitivity or oppose radioresistence of cancer cells.