Methods of treatment using ultrasmall nanoparticles to induce cell death of nutrient-deprived cancer cells via ferroptosis

Patent metadata

Field	Value
Publication number	US-11246946-B2
Application number	US-202016902577-A
Country	US
Kind code	B2
Filing date	Jun 16, 2020
Priority date	May 29, 2015
Publication date	Feb 15, 2022
Grant date	Feb 15, 2022

Abstract

Described herein is a method of induced cell death via ferroptosis by nanoparticle ingestion. Moreover, the present disclosure describes the administration of high concentrations of ultrasmall nanoparticles at multiple times over the course of treatment in combination with a nutrient-depleted environment, thereby modulating cellular metabolic pathways to induce cell death by the mechanism ferroptosis. Ferroptosis involves iron, reactive oxygen species, and a synchronous mode of cell death execution.

First claim

What is claimed is:

1. A method of treatment of a subject, the method comprising:
administering nanoparticles at an administered concentration greater than 1 μM to tumor tissue to induce ferroptosis of the tumor tissue, characterized by an increased intracellular concentration of iron in the tumor tissue as compared to non-treated cells, and
wherein the administered nanoparticles have an average diameter no greater than 15 nm, and
wherein the administered nanoparticles comprise a core comprising silica and a silica shell surrounding at least a portion of the core.

2. The method of claim 1 , wherein the tissue is amino acid deprived.

3. A method of combinational treatment of a subject, the method comprising:
depriving a tumor tissue of hormones; and
administering nanoparticles at an administered concentration greater than 1 μM to tumor tissue to induce ferroptosis of the tumor tissue, characterized by an increased intracellular concentration of iron in the tumor tissue as compared to non-treated cells,
wherein the administered nanoparticles have an average diameter no greater than 15 nm, and
wherein the administered nanoparticles comprise a core comprising silica and a silica shell surrounding at least a portion of the core.

4. The method of claim 3 , wherein the tumor tissue is deprived of hormones via castration.

5. The method of claim 3 , wherein the tissue is amino acid deprived.

6. The method of claim 1 , wherein the tissue comprises tumor tissue, and wherein the tumor tissue is selected from the group consisting of renal, prostate, melanoma, pancreatic, lung, fibrosarcoma, breast, brain, ovarian, and colon tumor tissue.

7. The method of claim 6 , wherein the tumor pancreatic tissue comprises BxPC3 cells.

8. The method of claim 6 , wherein the tumor lung tissue comprises H1650 cells.

9. The method of claim 1 , wherein the nanoparticles have an average diameter no greater than 10 nm.

10. The method of claim 1 , wherein the nanoparticles have an average diameter from about 5 nm to about 7 nm.

11. The method of claim 1 , wherein the nanoparticles comprise from 1 to 20 targeting moieties, wherein the targeting moieties bind to receptors on cells.

12. The method of claim 1 , wherein the nanoparticles comprise from 1 to 20 targeting moieties, wherein the 1 to 20 targeting moieties comprises alpha-melanocyte-stimulating hormone (αMSH).

13. The method of claim 1 , wherein the nanoparticles comprise a targeting moiety.

14. The method of claim 1 , wherein the nanoparticles are administered multiple times over the course of treatment.

15. The method of claim 1 , further comprising administering the nanoparticles every 3 or 4 days over the course of treatment.

16. The method of claim 1 , wherein the treatment combines with native immunomodulation properties of the administered nanoparticles to increase the therapeutic potential of the nanoparticles in cancer treatment and/or tissue repair processes.

17. The method of claim 1 , wherein the tissue comprises amino acid-deprived tissue or tumor tissue.

18. The method of claim 1 , wherein the increased intracellular concentration of iron is 8.3 parts per billion (ppb) or higher.

19. The method of claim 1 , wherein the increased intracellular concentration of iron is 144.7 parts per billion (ppb) or higher.

20. The method of claim 1 , wherein the increased intracellular concentration of iron is 2.58 μM or higher.

Assignees

• Memorial Sloan Kettering Cancer Center
• Univ Cornell

Inventors

• Bradbury Michelle S
• Wiesner Ulrich
• Overholtzer Michael
• Scher Howard
• Ma Kai

Classifications

• A61K47/6923

  the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb · CPC title

• A61K47/6929 Primary

  the form being a nanoparticle, e.g. an immuno-nanoparticle · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K38/22

  Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35) · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title