HIGH-Z NANOPARTICLES AND THE USE THEREOF IN RADIATION THERAPY

• US 20180250404A1
• Filed: 09/15/2016
• Published: 09/06/2018
• Est. Priority Date: 09/18/2015
• Status: Active Application

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: KRISHNAN, Sunil, SINGH, Pankaj
• Application Number:
  US15/758,437
• Publication Number:
  US 20180250404A1
• Time in Patent Office: Days
• 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 31/365 Lactones
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/4706 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
• CPC Class Codes: A61K 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61K 33/242 Gold; Compounds thereof
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 33/244 Lanthanides; Compounds thereof medicinal preparations containing radioactive lanthanides for use in therapy or testing in vivo A61K51/00
• 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 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6883 Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy
• CPC Class Codes: A61K 47/6929 the form being a nanoparticle, e.g. an immuno-nanoparticle
• CPC Class Codes: A61N 2005/1087 Ions; Protons
• CPC Class Codes: A61N 2005/1098 Enhancing the effect of the particle by an injected agent or implanted device
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/30 : from tumour cells
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/77 : Internalization into the cell

Abstract

Methods for sensitizing target cells to ionizing radiation are provided comprising the administration of high-Z particles (e.g., gold nanoparticles) in conjunction with a de-aggregation agent. In some aspects, particles comprise a targeting molecule to enable cellular uptake by the target cells. Pharmaceutical compositions comprising high-Z particles and de-aggregation agents are also provided.

Claims

1. A method sensitizing target cells in a subject to a radiation therapy comprising:

administering to the subject a effective amount of high-Z particles, said high-Z particles comprising a targeting molecule that binds to target cells and a high-Z element; and

administering to the subject an effective amount of a de-aggregation agent that reduces intracellular aggregation of said high-Z particles.

2. The method of claim 1, wherein the de-aggregation agent is selected from the groups consisting of a lysosomotropic agent, an endosome acidification inhibitor, a vacuolar proton-adenosine triphosphate inhibitor, a proteasome inhibitor, a cathepsin A inhibitor, an intralysosomal proteolysis inhibitor, an intracellular vesicular swelling promoter and an inhibitor of late endosome lysosome fusion.

3. The method of claim 1, further comprising irradiating the target cells with ionizing radiation.

4. The method of claim 3, wherein ionizing radiation is delivered as a plurality of doses over a period of time.

5. The method of claim 1, wherein the targeting molecule mediates internalization of the high-Z particles upon binding with the targeted cells.

6. The method of claim 1, wherein the high-Z particles are administered to the subject two or more times.

7. The method of claim 1, wherein the target cells are irradiated within the subject.

8. The method of claim 1, wherein the target cells are circulating cells.

9. The method of claim 1, wherein the target cells are endothelial cells or stromal cells.

10. The method of claim 1, wherein the target cells comprises cancer cells.

11. The method of claim 10, wherein the cancer cells are primary cancer cells.

12. The method of claim 10, wherein the cancer cells are metastatic cancer cells.

13. The method of claim 10, wherein the cancer cells are selected from the group consisting of brain, lung, liver, spleen, kidney, lymph node, small intestine, pancreas, blood, colon, stomach, breast, endometrium, prostate, testicle, ovary, skin, head and neck, esophagus, lymphatic, bone marrow and bone cancer cells.

14. The method of claim 1, wherein the target cells are irradiated extracorporeally.

15. The method of claim 1, wherein the high-Z element is gold, silver, iodine, gallium, barium, iron, gadolinium, platinum, hafnium or combinations thereof.

16. The method of claim 1, wherein the high-Z particles comprises nanorods, nanoshells, colloids, nanocages, or nanoprisms.

17. The method of claim 1, wherein the high-Z particles have an average size of between about 1 nm and 200 nm.

18. The method of claim 1, wherein the targeting molecule has an affinity for a receptor expressed in cancer cells.

19. The method of claim 1, wherein the targeting molecule binds to human epidermal growth factor receptor, human epidermal growth factor receptor 2, human epidermal growth factor receptor 3, human epidermal growth factor receptor 4, vascular endothelial growth factor receptor, folic acid receptor, melanocyte stimulating hormone receptor, integrin avb3, integrin avb5, transferrin receptor, interleukin receptors, lectins, insulin-like growth factor receptor, hepatocyte growth factor receptor or basic fibroblast growth factor receptor.

20. The method of claim 1, wherein the targeting molecule comprises an antibody, a polypeptide, a dendrimer, an aptamer, an oligomer or a small molecule.

21. The method of claim 1, wherein the targeting molecule is selected from the group consisting of:

cetuximab, an EGFr-binding polypeptide, trastuzumab, folic acid, melanocyte stimulating hormone, a transferrin receptor targeted polypeptide, a transferrin receptor targeted antibody and cyclic-RGD.

22. The method of claim 3, wherein the ionizing radiation is delivered continuously through an implant of a radiation-emitting substance near the target cells.

23. The method of claim 3, wherein the irradiation is a heavy ion therapy.

24. The method of claim 23, wherein the irradiation is a proton therapy.

25. The method of claim 2, wherein the endosome acidification inhibitor comprises tamoxifen.

26. The method of claim 2, wherein the inhibitor of vacuolar-type proton-adenosine triphosphate is selected from the group consisting of bafilomycin A, concanamycin A, concanamycin B and bafilomycin B1.

27. The method of claim 2, wherein the proteasome inhibitor and cathepsin inhibitor are selected from the group consisting of lactacystin, chymostatin, clasto-Lactacystin β

-lactone and MG-132.

28. The method of claim 2, wherein the inhibitor of late endosome lysosome fusion is selected from the group consisting of phosphatidylinositol 3-phosphate kinase inhibitors, Rab-GDP-dissociation inhibitor (Rab-GDI), chloroquine, and primaquine.

29. The method of claim 2, wherein the lysosomotropic agent is selected from the group consisting of acetaminophen, diclofenac, rosuvastatin, amiodarone, chloroquine, amantadine, ammonium chloride, monensin and nigericin.

30. The method of claim 1, wherein the de-aggregation agent is not acetaminophen.

31. The method of claim 1, wherein the de-aggregation agent is not chloroquine.

32. The method of claim 2, wherein the intralysosomal proteolysis inhibitor is selected from the group consisting of suramin, phosphoramidon, leupeptin, E64, pepstatin, a cystatin or a bestatin.

33. The method of claim 2, wherein the intracellular vesicular swelling inducer is selected from the group consisting of polyvinylpyrrolidone and dextran.

34. The method of claim 1, wherein the high-Z particles are administered before or essentially simultaneously with the de-aggregation agent.

35. The method of claim 34, wherein the high-Z particles and the de-aggregation agent are comprised in the same composition.

36. The method of claim 35, wherein the high-Z particles comprise the de-aggregation agent.

37. The method of claim 1, wherein the high-Z particles are administered after the de-aggregation agent.

38. The method of claim 1, further comprising imaging the high-Z particles and the target cells.

39. The method of claim 1, further comprising administering a further anti-cancer therapy to the subject.

40. The method of claim 39, wherein the further anti-cancer therapy is a chemotherapy.

41. The method of claim 1, wherein the high-Z particle further comprises a chemotherapeutic agent.

42. A method sensitizing tumor cells in a subject to a radiation therapy comprising:

administering to the subject a effective amount of high-Z particles; and

administering to the subject an effective amount of a de-aggregation agent that reduces intracellular aggregation of said high-Z particles.

43. A method sensitizing target cells in a subject to a radiation therapy comprising:

administering to the subject a effective amount of high-Z particles, said high-Z particles comprising a targeting molecule that binds to target cells and a high-Z element;

administering to the subject an effective amount of a de-aggregation agent that reduces intracellular aggregation of said high-Z particles; and

irradiating the target cells with ionizing radiation.

44. A pharmaceutical composition comprising (i) high-Z particles, said high-Z particles comprising a targeting molecule that can bind to cells and a high-Z element;

and (ii) a de-aggregation agent.

45. A composition for use in sensitizing target cells in a subject to a radiation therapy, the composition comprising (i) high-Z particles, said high-Z particles comprising a targeting molecule that binds to the target cells and a high-Z element;

and (ii) a de-aggregation agent.

46. A composition for use in treating a subject who has previously been administered high-Z particles, the composition comprising a de-aggregation agent.

47. A composition for use in treating a subject who has previously been administered de-aggregation agent, the composition comprising an effective amount of high-Z particles, comprising a targeting molecule that can bind to cells and a high-Z element.