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

• US 9,839,614 B2
• Filed: 12/22/2015
• Issued: 12/12/2017
• Est. Priority Date: 06/17/2009
• Status: Active Grant

• Current Assignee: NanoPharmaceuticals LLC
• Original Assignee: NanoPharmaceuticals LLC
• Inventors: Mousa, Shaker, Davis, Paul
• Primary Examiner(s): Richter, Johann R
• Assistant Examiner(s): Alley, Genevieve S
• Application Number:
  US14/977,776
• Publication Number:
  US 20160199309A1
• Time in Patent Office: 721 Days
• 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 conjugated anti-angiogenic thyroid hormone comprising:

a diamino-TETRAC derivative with a chemical structure

2. A composition comprising the conjugated anti-angiogenic thyroid hormone of claim 1, wherein the polylactide-co-glycolide conjugated to the diamino tetrac derivative is prepared into a nanoparticle.

3. The conjugated anti-angiogenic thyroid hormone of claim 2, further comprising a chemotherapeutic agent encapsulated within the nanoparticle.

4. The conjugated anti-angiogenic thyroid hormone of claim 3, wherein the chemotherapeutic agent is selected from a group consisting of doxorubicin, etoposide, cyclophosphamide, 5-fluorouracil, cisplatin, trichostatin A, paclitaxel, gemcitabine, temozolomide, taxotere, cisplatinum, carboplatinum, irinotecan, topotecan, adriamycin, bortezomib, and atoposide.

5. A method for making the conjugated anti-angiogenic thyroid hormone of claim 1, the method comprising the steps of:

preparing a dichloro-TETRAC derivative;

converting the dichloro-TETRAC derivative to a chloro-TETRAC derivative;

converting the chloro-TETRAC derivative to an iodo-TETRAC derivative;

converting the iodo-TETRAC derivative to the diamino-TETRAC derivative;

preparing polylactide-co-glycolide-N-hydroxysuccinimide(PLGA-NHS); and

stirring together the diamino-TETRAC derivative and PLGA-NHS, producing a PLGA-amino-TETRAC conjugate with the final chemical structure;

6. The method of claim 5, wherein the step of preparing the dichloro-TETRAC derivative includes combining potassium carbonate, TETRAC and 1-bromo-3-chloropropane in acetone.

7. The method of claim 5, wherein the step of converting the dichloro-TETRAC derivative to the chloro-TETRAC derivative includes mixing a solution of potassium hydroxide in ethanol with a mixture of dichloro-TETRAC in ethanol.

8. The method of claim 5, wherein the step of converting the chloro-TETRAC derivative to the iodo-TETRAC derivative includes preparing a solution of the chloro-TETRAC derivative in acetone and adding the solution to a second solution comprising sodium iodide and acetone.

9. The method of claim 5, wherein the step of converting the iodo-TETRAC derivative to the diamino-TETRAC derivative includes adding the iodo-TETRAC derivative to 1,3-diaminopropane to form a clear reaction mixture followed by adding a solution of sodium hydroxide and stirring in to the mixture a second mixture comprising ethanol and CH₂Cl₂.

10. The method of claim 5, wherein the step of preparing the PLGA-NHS includes dissolving PLGA in a CHCl₃, N-hydroxysuccinimide, 1-ethyl-3-(3-dimethyaminopropyl)carbodiimide (EDC) and HCl.

11. The method of claim 5, wherein the step of stirring together the diamino-TETRAC derivative and PLGA-NHS include dissolving the PLGA-NHS in DMSO until the PLGA-NHS and DMSO is a homogenous mixture;

stirring together the homogenous mixture and the diamino-TETRAC derivative into a heterogeneous mixture;

pouring methanol into the heterogeneous mixture, producing a precipitate; and

decanting the methanol from the precipitate.

12. The method of claim 5, wherein the PLGA-amino-TETRAC conjugate is prepared into the nanoparticle of claim 3 by dissolving the PLGA-amino-TETRAC conjugate in an organic solvent;

dispersing the PLGA-amino-TETRAC conjugate and the organic solvent in an aqueous phase of polyvinyl alcohol, forming a primary emulsion;

passing the primary emulsion through a homogenizer to produce a nanoemulsion;

transferring the nanoemulsion into water; and

extracting the organic solvent from the nanoemulsion to precipitate the nanoparticle.

13. The method of claim 12 further comprising the step of concentrating the nanoparticle using tangential flow filtration.