Method for terminating cancer cells with an azole-based compound

Patent metadata

Field	Value
Publication number	US-11738091-B2
Application number	US-202218056310-A
Country	US
Kind code	B2
Filing date	Nov 17, 2022
Priority date	Apr 10, 2019
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

A combination therapy involving different therapeutic molecules can enhance and improve the therapeutic potentials. An effective therapeutic strategy conjugates silica (SiO2) nanoparticles with, e.g., 3-glycidyloxypropyl, trimethoxysilane and azoles, e.g., 1,2,4-triazole (Tri), 3-aminotriazole (ATri), 5-aminetetrazole (Atet), imidazole (Imi). These exemplary materials—classified as SiO2-3GPS-Tri (Conj. 1), SiO2-3GPS-Atri (Conj. 2), SiO2-3GPS-Atet (Conj. 3), SiO2-3GPS-Btri (Conj. 4), and SiO2-3GPS-Imi (Conj. 5)—can amplify targeting of therepeutics for human colorectal carcinoma cells (HCT-116), enhancing anti-cancer effects.

First claim

The invention claimed is:

1. A method of bringing about human colorectal cancer cell death, the method comprising:
exposing cancer cells to a 1 to 10 mg/mL solution of a conjugate compound for a period of no more than 96 hours, thereby reducing a cancer cell survival rate to no more than 50% the amount of a control.
wherein the conjugate compound comprises, in reacted form:
a silicon dioxide nanoparticle having a surface modified with a linker of Formula (1)
(C 1-5 O—) 3 -Si-C 2-10 -O-C 1-10 -oxirane   (1a),

and an azole,
wherein the nanoparticle comprises at least 85 wt. % silica, based on total nanoparticle weight,
wherein, in the reacted form, the silicon of the linker forms a covalent bond to at least one of the oxygen atoms of the silicon dioxide of the nanoparticle,
wherein the azole, in the reacted form, is covalently bonded with a carbon atom of the oxirane via ring-opening of the oxirane of the linker with the azole, as an optionally substituted hydroxymethine-methylene-azole unit, and
wherein the azole of the conjugate compound is 1,2,4-triazole, 3-amino-1,2,4-triazole, 5-aminotetrazole, 1H-benzotriazole, or imidazole.

2. The method of claim 1 , wherein the silicon dioxide nanoparticle of the conjugate compound is non-magnetic.

3. The method of claim 1 , wherein the silicon dioxide nanoparticle of the conjugate compound comprises at least 97.5 wt. % silica, relative to the total nanoparticle weight.

4. The method of claim 1 , wherein the cancer cells comprise HCT-116 cells.

5. The method of claim 1 , wherein the linker of Formula (1) of the conjugate compound has Formula (1a):
(C 1-30 O—) 3 -Si-C 2-5 -O-C 1-3 -oxirane   (1a).

6. The method of claim 1 , wherein the linker of the conjugate compound comprises, in reacted form, (3-glycidyloxypropyl)-trimethoxysilane and/or (3-glycidyloxypropyl)-triethoxysilane.

7. The method of claim 1 , wherein the silicon dioxide nanoparticle of the conjugate compound has a bulk density in a range of from 0.008 to 0.015 g/mL.

8. The method of claim 1 , wherein the conjugate compound enhances cell death of cancer cells exposed to the conjugate compound, at least 50% more relative to cell death of cancer cells exposed to a placebo within 48 hours of exposure.

9. The method of claim 1 , wherein the cell death arises from nuclear condensation, nuclear augmentation, and/or cell membrane disruption.

10. A method of treating a colorectal cancer, comprising:
administering to a patient in need thereof an effective amount of a conjugate compound,
wherein the conjugate compound comprises, in reacted form:
a silicon dioxide nanoparticle having a surface modified with a linker of Formula (1):
(C 1-5 O—) 3 -Si-C 2-10 -O-C 1-10 -oxirane   (1)

and an azole,
wherein the nanoparticle comprises at least 85 wt. % silica, based on total nanoparticle weight,
wherein, in the reacted form, the silicon of the linker forms a covalent bond to at least one of the oxygen atoms of the silicon dioxide of the nanoparticle,
wherein the azole, in the reacted form, is covalently bonded with a carbon atom of the oxirane, via ring-opening of the oxirane of the linker with the azole, as an optionally substituted hydroxymethine-methylene-azole unit, and wherein the azole of the conjugate compound is 1,2,4-triazole, 3-amino-1,2,4-triazole, 5-aminotetrazole, 1H-benzotriazole, or imidazole.

11. A method of bringing about cancer cell death of human colorectal cancer cells, the method comprising:
contacting the human colorectal cancer cells with a conjugate compound;
wherein the conjugate compound comprises, in reacted form:
a silicon dioxide nanoparticle having a surface modified with a linker of Formula (1):
(C 1-5 O—) 3 -Si-C 2-10 -O-C 1-10 -oxirane   (1),

and an azole,
wherein the nanoparticle comprises at least 85 wt. % silica, based on total nanoparticle weight,
wherein, in the reacted form, the silicon of the linker forms a covalent bond to at least one of the oxygen atoms of the silicon dioxide of the nanoparticle,
wherein the azole, in the reacted form, is covalently bonded with a carbon atom of the oxirane of the linker, via ring-opening of the oxirane with the azole, as an optionally substituted hydroxymethine-methylene-azole unit, and
wherein the azole is 1,2,4-triazole, 3-amino-1,2,4-triazole, 5-aminotetrazole, 1H -benzotriazole, or imidazole.

Assignees

• Univ Imam Abdulrahman Bin Faisal

Inventors

• Asiri Sarah Mousa
• Khan Firdos Alam
• Bozkurt Ayhan

Classifications

• A61K47/6923 Primary

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

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• A61K47/6935

  the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• B82Y5/00

  Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery · CPC title