Nanoparticle and polymer formulations for thyroid hormone analogs, antagonists, and formulations and uses thereof

• US 9,289,395 B2
• Filed: 11/16/2010
• Issued: 03/22/2016
• Est. Priority Date: 12/22/2006
• Status: Active Grant

• Current Assignee: NanoPharmaceuticals LLC
• Original Assignee: NanoPharmaceuticals LLC
• Inventors: Davis, Paul J., Mousa, Shaker A.
• Primary Examiner(s): ZISKA, SUZANNE E
• Application Number:
  US12/947,389
• Publication Number:
  US 20110142941A1
• Time in Patent Office: 1,953 Days
• US Class Current: 1/1
• 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 47/593 Polyesters, e.g. PLGA or polylactide-co-glycolide
• CPC Class Codes: A61K 47/595 Polyamides, e.g. nylon polyamino acids A61K47/62
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/6935 the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
• CPC Class Codes: A61K 47/6937 the polymer being PLGA, PLA or polyglycolic acid
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/14 for lactation disorders, e.g. galactorrhoea
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

Disclosed are methods of treating subjects having conditions related to angiogenesis including administering an effective amount of a polymeric Nanoparticle form of thyroid hormone agonist, partial agonist or an antagonist thereof, to promote or inhibit angiogenesis in the subject. Compositions of the polymeric forms of thyroid hormone, or thyroid hormone analogs, are also disclosed.

Claims

1. A method of suppressing growth of cancer cells comprising the steps of:

conjugating to a polymer, an anti-angiogenic agent selected from at least one of tetrac, triac and analogs thereof, forming a conjugated anti-angiogenic agent;

encapsulating within the polymer of the conjugated anti-angiogenic agent, at least one chemotherapeutic agent;

administering to a subject in need thereof an amount of the conjugated anti-angiogenic agent, effective for performing at least one function selected from increasing the uptake of chemotherapeutic agents into the cancer cells and inhibiting export mechanisms for chemotherapeutic agents from the cancer cells.

2. 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, 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 and stomach cancer.

3. The method of claim 1, wherein the at least one chemotherapeutic agent is selected from the group consisting of:

doxorubicin, etoposide, cyclophosphamide, 5-fluorouracil, cisplatin, trichostatin A, paclitaxel, gemcitabine, taxotere, carboplatinum, irinotecan, topotecan, bortezomib and temozolomide, and derivatives of the foregoing agents.

4. The method of claim 1, further comprising the step of co-administering an additional chemotherapeutic agent.

5. The method of claim 4, wherein the chemotherapeutic drugs are selected from the group consisting of doxorubicin, etoposide, cisplatin, cyclophosphamide, 5-fluorouracil, paclitaxel, gemcitabine, taxotere, carboplatinum, irinotecan, topotecan, bortezomib, temozolomide and trichostatin A.

6. The method of claim 1, wherein the polymer is a nanoparticle with a particle size between 10 and 1000 nm, wherein the tetrac particles are bound to the nanoparticle by an ether (—

O—

) or sulfur (—

S—

) linkage bridging an alcohol moiety of the tetrac, triac and analogs thereof and the polymer.

7. The method of claim 1, wherein the analogs thereof include a protecting group at an NH2 moiety of the anti-angiogenic agent.

8. The method of claim 7, wherein the protecting group is selected from the group consisting of N-Methyl, N-Ethyl, N-Triphenyl, N-Propyl, N-Isopropyl, N-tertiary butyl, and other functional groups.

9. The method of claim 6, wherein the nanoparticle contains between 1 and 100 anti-angiogenic agent molecules per nanoparticle.

10. The method of claim 9, wherein the nanoparticle contains between 15 and 30 anti-angiogenic agent molecules per nanoparticle.

11. The method of claim 9, wherein the nanoparticle contains between 3 and 15 anti-angiogenic molecules per nanoparticle.

12. The method of claim 1, further comprising the step of formulating the conjugated anti-angiogenic agent into a pharmaceutical formulation comprising a pharmaceutically acceptable carrier.

13. The method of claim 12, wherein the pharmaceutical formulation further comprises one or more pharmaceutically acceptable excipients.

14. The method of claim 13, wherein the pharmaceutical formulation is suitable for a parenteral, oral, rectal, or topical mode of administration, or combinations thereof.

17. The method of claim 1, wherein the polymer selected from the group consisting of:

polyvinyl alcohol, acrylic acid ethylene co-polymer, polyethyleneglycol (PEG), polyacetic acid, polyglycolide, polylactide, agarose, PEO, m-PEG, PVA, PLLA, PGA, Poly L-Lysine, Human Serum Albumin, Cellulose Derivative, Hyaluronic Acid, Folate Linked Cyclodextrin, folate linked Dextran, Alginate, Carrageenan, Pectin, Chitosan, Dextran, Collagen, Poly amine, Poly aniline, Poly alanine, Polytryptophan, poly(lactic-co-glycolic acid) (PLGA), and Polytryrosine.

18. The method of claim 1 wherein the conjugated anti-angiogenic agent is unable to enter the cell.

19. The method of claim 1 wherein conjugating the anti-angogenic agent to the polymer occurs by a covalent bond.

20. The method of claim 1 wherein conjugating the anti-angogenic agent to the polymer occurs by a non-covalent bond.

15. A method of increasing the chemosensitivity of cancer cells comprising the steps of:

conjugating to a polymer, an anti-angiogenic agent selected from at least one of tetrac, triac and analogs thereof, forming a conjugated anti-angiogenic agent;

encapsulating within the polymer of the conjugated anti-angiogenic agent, at least one chemotherapeutic agent;

administering to the cancer cells the conjugated anti-angiogenic agent in an amount sufficient to perform at least one function selected from enhancing the uptake of chemotherapeutic agents into the cancer cells, and inhibiting export mechanisms for chemotherapeutic agents from the cancer cells.

16. A method of treating a patient suffering from the presence of a tumor, comprising administering to said patient an anti-angiogenic agent of tetrac, tetrac analogs, or nanoparticles thereof in an amount effective for enhancing the chemosensitivity of cancer cells, wherein said anti-angiogenic agent is conjugated to a polymer and wherein said anti-angiogenic agent binds to integrin α

vβ

3 receptor, inhibiting angiogenesis.