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

• US 9,220,788 B2
• Filed: 06/15/2010
• Issued: 12/29/2015
• Est. Priority Date: 06/17/2009
• Status: Active Grant

• Current Assignee: NanoPharmaceuticals LLC
• Original Assignee: NanoPharmaceuticals LLC
• Inventors: Davis, Paul J., Davis, Faith B., Mousa, Shaker A., Hercbergs, Aleck, Glinksy, Gennadi V.
• Primary Examiner(s): Richter, Johann R
• Assistant Examiner(s): Alley, Genevieve S
• Application Number:
  US12/816,287
• Publication Number:
  US 20110052715A1
• Time in Patent Office: 2,023 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 41/0038 Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy radiotherapy per se A61N5/10
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/593 Polyesters, e.g. PLGA or polylactide-co-glycolide
• 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 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/643 Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61K 47/6455 Polycationic oligopeptides, polypeptides or polyamino acids, e.g. for complexing nucleic acids
• CPC Class Codes: A61K 47/6937 the polymer being PLGA, PLA or polyglycolic acid
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

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. Nanoparticle forms of thyroid hormone or thyroid hormone analogs as well as uses thereof are also disclosed.

Claims

1. A composition comprising a thyroid hormone or thyroid hormone analog wherein the thyroid hormone or thyroid hormone analog is conjugated to a polymer via a linker, wherein said conjugated polymer is a nanoparticle, wherein said nanoparticle is less than 250 nanometers in size, and wherein said thyroid hormone or thyroid hormone analog binds exclusively to a cell surface receptor for thyroid hormone on integrin α

vβ

3 at a cell membrane level, wherein at least one chemotherapeutic drug is encapsulated in the nanoparticle.

2. The composition of claim 1, wherein the linker is between 4 and 15 atoms long.

3. The composition of claim 1, wherein the polymer is selected from the group consisting of polyvinyl alcohol (PVA), acrylic acid ethylene co-polymer, polyethylene glycol (PEG), methoxypolyethylene glycol-poly(lactide-co-glycolide), polyacrylic acid, polylactic acid, agarose, PEO, m-PEG, 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, polylactic acid pectin/chitosan, chitosan, dextran, collagen, polyamine, poly aniline, poly alanine, polytrytophan, poly tyrosine, polylactide-co-glycolide, poly(lactic-co-glycolic acid) (PLGA), polylysylglycolide, polyglycolide, and co-polymers thereof.

4. The composition of claim 3, wherein the polymer is selected from the group consisting of polyglycolide, polylactide, and co-polymers thereof.

5. The composition of claim 1, wherein the amount of thyroid hormone or thyroid hormone analog in the nanoparticle is between 0.1 and 25%.

6. The composition of claim 1 wherein the composition further comprises one or more pharmaceutically acceptable carriers.

7. The composition of claim 1 wherein the composition further comprises one or more biologically active substances.

8. The composition of claim 7 wherein the biologically active substances are selected from the group consisting of TGF-beta, basic fibroblast growth factor (FGF2), epithelial growth factor (EGF), transforming growth factors alpha and beta (TGF-a and TGF-b), nerve growth factor (NGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), anti-virals, anti-bacterials, anti-inflammatory, immuno-suppressants, analgesics, vascularizing agents, and cell adhesion molecules.

9. The composition of claim 1, wherein the thyroid hormone analog is selected from the group consisting of tetraiodothyroacetic acid (TETRAC), triiodothyroacetic acid (TRIAC) and a combination thereof.

10. The composition of claim 1, wherein the thyroid hormone analog is TETRAC bound to an OTIPS protecting group.

11. The composition of claim 1, wherein the nanoparticle co-encapsulates two or more chemotherapeutic agents.

12. The composition of claim 1, wherein the at least one chemotherapeutic drug is selected from the group consisting of doxorubicin, atoposide, etoposide, cyclophosphamide, 5-fluorouracil, cisplatin, trichostatin A, paclitaxel, gemcitabine, taxotere, cisplatinum, carboplatinum, irinotecan, topotecan, adriamycin, bortezomib and combinations thereof.

13. A method of producing the composition of claim 1, the method comprising conjugating the thyroid hormone or thyroid hormone analog to the polymer via the linker after forming the nanoparticle.

14. The method of claim 13, wherein the thyroid hormone or thyroid hormone analog is selected from the group consisting of T4, T3, T4 or T3 N-Methyl, T4 or T3 N-Ethyl, T4 or T3 N-Triphenyl, T4 or T3 N-Propyl, T4 or T3 N-Isopropyl, T4 or T3-N-Tertiary butyl, GC-1, DIPTA, Tetrac and Triac.

15. The method of claim 13, wherein the linker is between 4 and 15 atoms long.

16. The method of claim 13 wherein the polymer is selected from the group consisting of polyvinyl alcohol (PVA), acrylic acid ethylene co-polymer, polyethylene glycol (PEG), methoxypolyethylene glycol-poly(lactide-co-glycolide), polyacrylic acid, polylactic acid, agarose, PEO, m-PEG, PLLA, PGA, poly-L-lysine, Human Serum Albumin, cellulose derivatives, carbomethoxy/ethylhydroxypropyl, hyaluronic acid, folate linked cyclodextrinldextran, 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, poly(lactide co-glycolic acid) (PLGA), polylysyl glycolide, polyglycolide, polylactide, and co-polymers thereof.

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

18. The method of claim 13, wherein the thyroid hormone or analogs thereof have a protecting group at the NH2 moiety or at the carboxyl moiety.

19. The method of claim 18, 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.

20. A method of producing the composition of claim 1, the method comprising conjugating the thyroid hormone or thyroid hormone analog to the polymer via the linker prior to forming the nanoparticle.

21. The method of claim 20, wherein the thyroid hormone or thyroid hormone analog is selected from the group consisting of T4, T3, T4 or T3 N-Methyl, T4 or T3 N-Ethyl, T4 or T3 N-Triphenyl, T4 or T3 N-Propyl, T4 or T3 N-Isopropyl, T4 or T3-N-Tertiary butyl, GC-1, DIPTA, Tetrac and Triac.

22. The method of claim 20, wherein the linker is between 4 and 15 atoms long.

23. The method of claim 20 wherein the polymer is selected from the group consisting of polyvinyl alcohol (PVA), acrylic acid ethylene co-polymer, polyethylene glycol (PEG), methoxypolyethylene glycol-poly(lactide-co-glycolide), polyacrylic acid, polylactic acid, agarose, PEO, m-PEG, PLLA, PGA, poly-L-Iysine, Human Serum Albumin, cellulose derivatives, carbomethoxy/ethyl/hydroxypropyl, hyaluronic acid, folate linked cyclodextrin dextran, sarcosine/amino acid spaced polymer, alginate, carrageenan, poly lactic acid pectin/chitosan, chitosan, dextran, collagen, polyamine, poly aniline, poly alanine, polytrytophan, poly tyrosine, polylactide-co-glycolide, poly(lactide co-glycolic acid) (PLGA), polylysyl glycolide, polyglycolide, polylactide, or co-polymers thereof.

24. The method of claim 20 wherein the amount of thyroid hormone or thyroid hormone analog in the nanoparticle is between 0.1 and 25%.

25. The method of claim 20, wherein the thyroid hormone or analogs thereof have a protecting group at the NH2 moiety or at the carboxyl moiety.

26. The method of claim 25, 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.

27. A pro-angiogenic formulation comprising the composition of claim 1 and a pharmaceutically acceptable carrier, wherein the thyroid hormone or thyroid hormone analog is selected from the group consisting ofT4, T3, T4 or T3 N-Methyl, T4 or T3 N-Ethyl, T4 or T3 N-Triphenyl, T4 or T3 N-Propyl, T4 or T3 N-Isopropyl, T4 or T3 N-Tertiary butyl, GC-1, and DIPTA.

28. The formulation of claim 27, further comprising one or more biologically active substances selected from the group consisting of TGF-beta, basic fibroblast growth factor (FGF2), epithelial growth factor (EGF), insulin-like growth factor-1 (IGF-1), transforming growth factors alpha and beta (TGF-α

and β

), nerve growth factor (NGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), anti-virals, anti-bacterials, antiinflammatory, immuno-suppressants, analgesics, vascularizing agents, and cell adhesion molecules.

29. An anti-angiogenic formulation comprising the composition of claim 1 and a pharmaceutically acceptable carrier, wherein the thyroid hormone analog is selected from the group consisting of Tetrac and Triac.

30. The formulation of claim 29, further comprising one or more chemotherapeutic drugs selected from a group consisting of doxorubicin, etoposide, cyclophosphamide, 5-fluorouracil, cisplatin, trichostatin A, paclitaxel, gemcitabine, taxotere, cisplatinum, carboplatinum, irinotecan, topotecan, adriamycin, bortezomib, and atoposide.

31. A combination therapy comprising the steps of:

administering the composition of claim 1 and at least one compound selected from the group consisting of thyrotropin (TSH), recombinant human TSH and radioiodine.