Uses of formulations of thyroid hormone analogs and nanoparticulate forms thereof to increase chemosensitivity and radiosensitivity in tumor or cancer cells

• US 8,802,240 B2
• Filed: 01/06/2012
• Issued: 08/12/2014
• Est. Priority Date: 01/06/2011
• Status: Active Grant

• Current Assignee: NanoPharmaceuticals LLC
• Original Assignee: NanoPharmaceuticals LLC
• Inventors: Davis, Paul J., Mousa, Shaker A.
• Primary Examiner(s): RAO, SAVITHA M
• Application Number:
  US13/345,194
• Publication Number:
  US 20120315320A1
• Time in Patent Office: 949 Days
• Field of Search: 424/489, 424/649, 424/450, 514/34, 514/27, 514/110, 514/274, 514/449, 514/49, 514/492, 514/283, 514/64, 514/567, 977/773, 977/915
• US Class Current: 428/489
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/282 Platinum compounds
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 39/39533 against materials from animals
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07K 16/2848 : against integrin beta3-subunit-containing molecules, e.g. CD41, CD51, CD61
• CPC Class Codes: Y10T 428/12729 : Group IIA metal-base component
• CPC Class Codes: Y10T 428/31815 : Of bituminous or tarry residue

Abstract

Disclosed are methods of increasing the chemosensitivity of normal and/or chemoresistant tumor or cancer cells using thyroid hormone analogs and/or nanoparticulate or polymeric forms thereof. Also disclosed are methods of increasing radiosensitivity of normal and/or radioresistant tumor or cancer cells using thyroid hormone analogs and/or nanoparticulate or polymeric forms thereof.

Claims

1. A method for inducing radiosensitivity in normal cancer cells or radioresistant cancer cells comprising the steps of:

providing cancer cells having at least one of normal cancer cells and radioresistant cancer cells;

conjugating an anti-angiogenic thyroid hormone analog to a polymer via a linker;

formulating the anti-angiogenic thyroid hormone analog into a nanoparticle;

administering an effective amount of an anti-angiogenic thyroid hormone analog to a patient, wherein the anti-angiogenic thyroid hormone analog is selected from the group consisting of tetraiodothyroacetic acid (Tetrac), triiodothyroacetic acid (Triac), monoclonial antibody LM609, XT199 and combinations thereof, wherein the anti-angiogenic thyroid hormone analog acts exclusively at the cell surface receptor α

Vβ

3; and

irradiating the cancer cells with an external radiation source.

2. The method of claim 1, wherein the step of administering the anti-angiogenic thyroid hormone analog decreases a recovery of sublethal damage repair of the irradiated cancer cells through a nongenomic mechanism.

3. The method of claim 1, wherein the step of administering the anti-angiogenic thyroid hormone analog decreases a recovery of potentially lethal damage repair of the irradiated cancer cells through a nongenomic mechanism.

4. The method of claim 1, wherein the step of administering the anti-angiogenic thyroid hormone analog produces increased numbers of DNA double-strand breaks in the irradiated cancer cells through a nongenomic mechanism.

5. The method of claim 1, wherein the step of administering the anti-angiogenic thyroid hormone analog decreases the repair rate of DNA double-strand breaks in the irradiated cancer cells through a nongenomic mechanism.

6. The method of claim 1, wherein the step of administering the anti-angiogenic thyroid hormone analog produces increased numbers of DNA double-strand breaks in the irradiated cancer cells and decreases the repair rate of DNA double-strand breaks in the irradiated cancer cells through a nongenomic mechanism.

7. The method of claim 1, wherein said cancer cells are selected from the group consisting of a primary or metastatic tumor, breast cancer, thyroid cancer, neuroblastoma, glioma and glioblastoma multiforme and other brain cancers, colon cancer, head-and-neck cancers, melanoma and basal cell and squamous cell carcinomas of the skin, sarcoma, ovarian cancer, prostate cancer, kidney cancer, hepatoma, lung cancer, pancreatic cancer, stomach cancer, myeloma, and lymphoma.

21. The method of claim 1, wherein the step of irradiating cancer cells with an external radiation source includes providing a dose of radiation between 0.25 to 5 Sv.

23. The method of claim 1, comprising the additional step of decreasing potentially lethal damage repair by a factor of 1.9 to 3.4.

24. The method of claim 1, wherein the step of irradiating the cancer cells with an external radiation source comprises the step of exposing the cancer cells to X-rays.

26. The method of claim 24, wherein the X-ray radiation is dosed at 1 Gy per minute.

27. The method of claim 26, wherein the step of irradiating the cancer cells with external radiation lasts between 1 minute to 60 minutes.

8. A method for inducing radiosensitivity in normal cancer cells or radioresistant cancer cells in a patient comprising the steps of:

conjugating an anti-angiogenic thyroid hormone analog to a polymer via a linker;

formulating the anti-angiogenic thyroid hormone analog into a nanoparticle;

administering an effective amount of the anti-angiogenic thyroid hormone analog to the patient wherein said anti-angiogenic thyroid hormone analog is selected from the group consisting of tetraiodothyroacetic acid (Tetrac), triiodothyroacetic acid (Triac), monoclonial antibody LM609, XT199 and combinations thereof, wherein said thyroid hormone analog binds exclusively to the cell surface receptor for thyroid hormone on integrin α

vβ

3 at the cell membrane level; and

exposing the patient to an external radiation source.

9. The method of claim 8, wherein said nanoparticle is less than 250 nanometers in size.

10. The method of claim 8 wherein the polymer is selected from the group consisting of:

polyvinyl alcohol (PVA), acrylic acid ethylene co-polymer, polyethyleneglycol (PEG), methoxypolyethylene glycol-poly(lactide-co-glycolide), polyacrylic acid, polylactic acid, agarose, polyethylene oxide (PEO), m-PEG, poly-L-lactide (PLLA), polyglycolic acid (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, polylactic acid pectin/chitosan, chitosan, dextran, collagen, polyamine, poly aniline, poly alanine, polytrytophan, poly tyrosine, polylactide-co-glycolide (PLGA), poly(lactic-co-glycolic acid), polylysyl glycolide, polyglycolide, polylactide, and co-polymers thereof.

11. The method of claim 8, wherein the linker is between 4 and 15 atoms long.

12. The method of claim 8, wherein the polymer is selected from the group consisting of polyglycolide, polylactide, and co-polymers thereof.

13. The method of claim 8, wherein the amount of thyroid hormone or thyroid hormone analog in the nanoparticle is between 0.1 and 25%.

14. The method of claim 8, wherein the step of administering the anti-angiogenic thyroid hormone analog occurs before the patient is subjected to the step of exposing the patient to radiation.

15. The method of claim 8, wherein the step of administering the anti-angiogenic thyroid hormone analog decreases a recovery of sublethal damage repair of the cancer cells exposed to the external radiation source, through a nongenomic mechanism.

16. The method of claim 8, wherein the step of administering the anti-angiogenic thyroid hormone analog decreases a recovery of potentially lethal damage repair of the cancer cells exposed to the external radiation source, through a nongenomic mechanism.

17. The method of claim 8, wherein the step of administering the anti-angiogenic thyroid hormone analog produces increased numbers of DNA double-strand breaks in the cancer cells exposed to the external radiation source, through a nongenomic mechanism.

18. The method of claim 8, wherein the step of administering the anti-angiogenic thyroid hormone analog decreases the repair rate of DNA double-strand breaks in the cancer cells exposed to the external radiation source, through a nongenomic mechanism.

19. The method of claim 8, wherein the step of administering the anti-angiogenic thyroid hormone analog produces increased numbers of DNA double-strand breaks in the cancer cells exposed to the external radiation source, and decreases the repair rate of DNA double-strand breaks in the cancer cells exposed to the external radiation source, through a nongenomic mechanism.

20. The method of claim 8, wherein said cancer cells are selected from the group consisting of a primary or metastatic tumor, breast cancer, thyroid cancer, neuroblastoma, glioma and glioblastoma multiforme and other brain cancers, colon cancer, head-and-neck cancers, melanoma and basal cell and squamous cell carcinomas of the skin, sarcoma, ovarian cancer, prostate cancer, kidney cancer, hepatoma, lung cancer, pancreatic cancer, stomach cancer, myeloma, and lymphoma.

22. The method of claim 8, wherein the dose of radiation administered is between 0.25 to 5 Sv.

25. The method of claim 8, wherein the external radiation source is X-rays.