Targeting intracellular copper ions for inhibiting angiogenesis using nanoparticles of ternary inorganic metal sulfide m1m2s4 (m1, independently, is mg, ca, mn, fe, or zn; m2=mo or w) compounds to treat metastatic cancer

A nanoparticle, independent technology, applied in the field of new covalent network ternary inorganic metal sulfides, which can solve the problem of increased side effects of copper

Inactive Publication Date: 2017-09-22
KENT STATE UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In conclusion, depletion of systemic copper ions rather than specific tissue or organ copper ions increases the tendency to cause copper deficiency-related side effects in patients

Method used

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  • Targeting intracellular copper ions for inhibiting angiogenesis using nanoparticles of ternary inorganic metal sulfide m1m2s4 (m1, independently, is mg, ca, mn, fe, or zn; m2=mo or w) compounds to treat metastatic cancer
  • Targeting intracellular copper ions for inhibiting angiogenesis using nanoparticles of ternary inorganic metal sulfide m1m2s4 (m1, independently, is mg, ca, mn, fe, or zn; m2=mo or w) compounds to treat metastatic cancer
  • Targeting intracellular copper ions for inhibiting angiogenesis using nanoparticles of ternary inorganic metal sulfide m1m2s4 (m1, independently, is mg, ca, mn, fe, or zn; m2=mo or w) compounds to treat metastatic cancer

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preparation example Construction

[0029] The preparation of nanoparticles of the present invention can be carried out in the following manner.

[0030] A main objective of the present invention is to provide novel nanoparticles suitable for intracellular depletion of copper to inhibit angiogenesis. A typical preparation can be carried out as follows: about 0.1 mL to about 300 mL, ideally about 1 mL to about 100 mL, preferably about 25 mL, of 1 to about 50 total carbon atoms, ideally 1 to about 12 carbon atoms Mercapto alkylacid, preferably 3-mercaptopropionic, is added to about 1 mL to about 200 mL, ideally about 2 mL to about 100 mL, preferably 10 mL of about 0.01 N to about 18 N, ideally 0.1 N to about 10N, preferably 1N NH 4 in OH solution. Other suitable hydroxides include NaOH, KOH, Ca(OH) 2 or Na 2 CO 3 . Then an effective amount of M 1 Salt is added to the water. Applicable M 1 Salts include zinc acetate, zinc chloride, zinc sulfate, zinc perchlorate, zinc nitrate, and non-zinc salts such as ma...

Embodiment 1

[0041] Cell viability assays were performed using the MTT method. HuVEC cells were seeded in 96-well plates at a density of 1×10 per well 4 cells in a well containing endothelial cell basal growth medium-2 (EBM-2) containing 10% FBS (fetal bovine serum) and 1% penicillin-streptomycin, at 37°C, 5% CO 2 and 95% air for 5 hours to attach to the surface. Cells in each well were then incubated with 100 μL of fresh medium containing various concentrations of nanoparticles for 24 h and 48 h. Control wells contained the same medium but no nanoparticles. Each concentration was tested in triplicate. At the end of the above incubation period, 10 μL of 5 mg / mL 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide (3-(4,5-dimethylthiazol-2 -yl)-2,5-diphenyltetrazolium bromide (MTT)) was added to each well and incubated for an additional 3 hours. Then, 100 μL of detergent was added to each well and incubation was continued for an additional 4 hours at 37°C. Finally, the absorbance...

Embodiment 2

[0044] m 1 MoS 4 and M 1 m 2 S 4 (M 1 independently Mg, Ca, Mn or Fe; M 2 Mo or W) compounds prevent endothelial cell tube formation in an in vitro model of angiogenesis. All of these compounds were able to reduce the copper concentration in the endothelial cells used in this model study as well as the copper concentration in the culture medium via ion exchange with divalent ions in the ternary compound by the following reactions:

[0045] Cu n+ (n=1 or 2)+M 1 m 2 S 4 → CuM 2 S 4 +M 1 2+ .

[0046] Angiogenesis is inhibited because copper is a required cofactor for many angiogenic factors (including VEGF, bFGF, angiopoietin) during tube formation in endothelial cells.

[0047] Other tests are performed as follows:

[0048] The tube formation assay is an in vitro model of angiogenesis commonly used to measure the ability of endothelial cells to form "tubes," ie, three-dimensional structures resembling blood vessel walls. Tube formation experiments were performe...

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Abstract

This invention describes a new type of covalent-network ternary inorganic metal sulfide compounds M1M2S4 (M1, independently, is, Mg, Ca, Mn, Fe, or Zn; M2=Mo or W) and a process for preparing the biocompatible nanoparticles of such compounds. The nanoparticles are surface-modified with a capping agent and / or a biocompatible polymer and have the size from a few nanometers to several thousand nanometers. These nanoparticles are nontoxic and can be internalized by cells to deplete copper ions via a highly selective ion-exchange reaction between the intracellular copper ions and the divalent ion bound in the nanoparticles for the application of inhibiting angiogenesis in cancer and other diseases.

Description

technical field [0001] The present invention generally relates to novel covalent network ternary inorganic metal sulfides comprising a divalent metal such as Mg, Ca, Mn, Fe or Zn and a hexavalent metal such as molybdenum or tungsten, and Sulfur, its use in inhibiting angiogenesis in cancer and other diseases can be used to reduce intracellular copper concentrations. Background technique [0002] Angiogenesis is the process of new blood vessel formation, also known as neovascularization, which is the process of new blood vessel formation. In healthy adults, this process is tightly regulated and orchestrated into balance by various angiogenic factors and inhibitors. In contrast, angiogenesis is a rate-limiting event in tumorigenesis and thus a hallmark of tumor growth and metastasis. This concept has inspired researchers over the past three decades to find inhibitors of angiogenesis for cancer therapy. Currently, there are more than 50 anti-angiogenic drugs for cancer treat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/51A61K31/28A61P35/04A61P35/00C01B17/42C01G39/06C01G41/00C01G45/00C01G49/12A61K33/24A61K33/26A61K33/32
CPCA61K9/5138A61K31/28A61K33/24A61K33/26A61K33/32C01B17/42C01G39/06C01G41/006C01G45/006C01G49/12A61K9/19A61P35/00A61K9/51
Inventor 松平·D·黄盖尔·C·弗雷泽温迪亚·S·佩雷亚
Owner KENT STATE UNIV
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