ZINC-[Gamma]-PGA COMPOSITIONS AND METHODS FOR TREATING CANCER

A composition and drug technology, applied in the field of anti-tumor reagents for treating patients with cancer

Active Publication Date: 2018-05-11
XYLONIX IP HLDG PTE LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, for the ability to act on many cancer types, even cancers with drug-resistant phenotypes (eg, dysfunctional p53 (dysfunctional p53), MDR1 overexpression, MRP1 overexpression), without toxic consequences, for There is an unmet need for clinically active and safe zinc compositions for the treatment of cancer

Method used

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  • ZINC-[Gamma]-PGA COMPOSITIONS AND METHODS FOR TREATING CANCER
  • ZINC-[Gamma]-PGA COMPOSITIONS AND METHODS FOR TREATING CANCER
  • ZINC-[Gamma]-PGA COMPOSITIONS AND METHODS FOR TREATING CANCER

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Example 1: Preparation and Characterization of ZnPGA at pH 7.0 Using Phosphate-Precipitation to Remove Unbound Excess Zinc

[0126] To prepare ZnPGA, 55 mg PGA (50,000 Da molecular weight) was dissolved at room temperature in pH 7.0 containing 10 mM ZnSO 4 5 mL of 10 mM MES buffer and sonicated for 10 min on ice. Then, 0.5 mL of 200 mM phosphate buffer at pH 7.0 was added to the solution to precipitate free zinc ions, and the mixture was filtered through a 0.2 μm syringe sterile filter. Zinc content was measured using ICP-MS and by 4-(2-pyridylazo)-resorcinol analysis. The final stock ZnPGA contained 1% (wt / vol) PGA and 400 μg / ml bound zinc ions. Stock ZnPGA solutions were prepared fresh at the time of daily administration.

Embodiment 2

[0127] Example 2: Preparation and Characterization of ZnPGA at pH 7.0 Using Dialysis to Remove Unbound Excess Zinc

[0128] To prepare ZnPGA, 55 mg PGA (50,000 Da molecular weight) was dissolved at room temperature in pH 7.0 containing 10 mM ZnSO 4 5 mL of 10 mM MES buffer and sonicated for 10 min on ice. The solution was then dialyzed on ice against 1 L of 10 mM MES, pH 7.0, for 2 hours three consecutive times for a total of 3 dialyzed volumes for 6 hours. The recovered solution was filtered through a 0.2 μm syringe sterile filter. Zinc content was measured using ICP-MS and by 4-(2-pyridylazo)-resorcinol analysis. The final stock ZnPGA contained 0.9% (wt / vol) PGA and 380 μg / ml bound zinc ions. Stock ZnPGA solutions were prepared fresh at the time of daily administration.

Embodiment 3

[0129] Example 3: In vitro flow cytometry analysis (FACS) of ZnPGA-induced cell death in human cancer cells with different drug-resistant genotypes

[0130] The mode of ZnPGA-induced cell death, either apoptosis or necrosis, was examined in three human cancer cells with different drug resistance genotypes: H460 lung cancer (WT p53 cell apoptosis gene, no reported drug resistance ), T98G neuroblastoma (mutated p53 and multidrug resistance protein 1 "MRP1" expression), and MES-SA Dx5 sarcoma (WT p53 and P-glycoprotein "PgP" multidrug resistance protein expression). Briefly, each cell line was prepared as 10,000 attached monolayers in late exponential growth phase according to ATCC recommended methods and media (RPMI-1640, F-12K, McCoy's 5A, EMEM, DMEM, etc.), supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin in CO 2 Incubator at 37°C and 5% CO 2 Next, use a 96-well plate with a medium volume of 200 μL per reaction well. Cells prepared on 96-well pl...

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Abstract

The present invention relates to a zinc-[Gamma]-PGA composition and a method for treating a cancer. The invention relates to pharmaceutical compositions comprising a zinc2+ salt and a [Gamma]-polyglutamic acid carrier, and optionally, an NF-kB inhibitor as a tumor-sensitizing agent, and methods for using such compositions to treat tumors in patients. The method comprises the steps of: administering a liquid dosage form or a solid dosage form of a therapeutically effective amount of a Zn(ll) salt and a [Gamma]-polyglutamic acid carrier to a patient in need thereof. The method of treating a broad spectrum of human tumors, including tumors with a drug-resistant phenotype, using the disclosed compositions are provided. Tumors that respond to the pharmaceutical compositions disclosed herein include neuroendocrine (neuroblastoma), gastric, uterine, and lung tumors.

Description

technical field [0001] The present invention relates to compositions comprising a gamma-polyglutamic acid (γ-PGA) carrier and a zinc salt, and optionally an NF-κB inhibitor, pharmaceutical formulations thereof, and the use of any of said compositions and formulations as A method of treating cancer in a patient with an antineoplastic agent. Background technique [0002] Intrinsic and acquired drug resistance to cancer drugs is a major cause of cancer treatment failure. Common mechanisms of resistance include dysfunction of the p53 apoptotic protein and / or overexpression of energy-dependent drug ejection pumps encoded by the MDR1 or MRP1 genes. One tumor-destroying strategy to overcome the problem of drug resistance is to correct the dysfunctional p53 apoptotic function alone, or to inhibit the drug ejection pump. An alternative approach is to exploit the PARP1-mediated energy depletion-induced necrotic cell death mechanism ("PARP1-mediated necrosis"), which completely bypas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K33/30A61K9/00A61K47/34A61P35/00
CPCA61K9/0019A61K9/0053A61K33/30A61K47/34A61K47/645A61K47/542A61K47/62A61P35/00A61K47/551A61K45/06A61K2300/00A61K38/02
Inventor 郑振赫
Owner XYLONIX IP HLDG PTE LTD
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