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Endoplasmic Reticulum-Targeting Nanovehicles and Methods for Use Thereof

An endoplasmic reticulum, targeting technology, which can be used in medical preparations without active ingredients, medical preparations containing active ingredients, and pharmaceutical formulas, and can solve problems such as cell apoptosis and cytotoxic side effects.

Inactive Publication Date: 2019-10-25
NAT CHENG KUNG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, curcumin has cytotoxic side effects including ER stress and apoptosis

Method used

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  • Endoplasmic Reticulum-Targeting Nanovehicles and Methods for Use Thereof
  • Endoplasmic Reticulum-Targeting Nanovehicles and Methods for Use Thereof
  • Endoplasmic Reticulum-Targeting Nanovehicles and Methods for Use Thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: Generation of CGD transgenic mice

[0040] The H338Y mutant gp91 was established under the background of Cybb gene knockout as follows phox Transgenic mouse model of induced chronic granulomatous disease (CGD). A bacterial artificial chromosome (BAC) containing the murine Cybb gene (clone number RP23-210P9) was obtained from the BACPAC Resource Center at Children's Hospital Oakland Research Institute (Oakland, CA USA). Using the Counter Selection BAC Modification Kit (Counter Selection BAC Modification Kit) (Gene Bridges Co., Ltd.), the BAC was modified to contain the mutant Cybb C1024T . Using standard techniques the resulting Cybb C1024T The BAC transgene was introduced via prokaryotic injection into mutant B6.129S-Cybb targeting Cybb tm1Din / J mice (Jackson Labs (Jackson Labs) catalog number 002365) isolated eggs. Primary and progeny carrying the BAC transgene were identified by PCR from tail DNA and by direct DNA sequencing. Confirmation of full-le...

Embodiment 2

[0042] Example 2: Analysis of CGD transgenic mice

[0043] Use anti-gp91 phox Antibodies were checked by SDS-PAGE and Western blot from Cybb C1024T Transgenic Cybb - / - H338Y-gp91 in mouse neutrophils phox protein expression. To isolate neutrophils, mice were injected intraperitoneally with 3 ml of 3% thioglycollate to elicit peritoneal neutrophils. Four hours later, mice were sacrificed, and the peritoneal cavity was washed twice with 5 ml of Hanks buffered salt solution (HBSS) with 2 mM ethylene glycol tetraacetic acid to collect elicited peritoneal neutrophils. The peritoneal neutrophils were then washed with PBS before use.

[0044] The results show that from Cybb C1024T Transgenic Cybb - / - Mouse isolated neutrophils produce H338Y-gp91 phox The underglycosylated form of . Compared with wild-type mice, Cybb C1024T Genetically modified Cybb - / - H338Y-gp91 in mice phox The level of the glycosylated form of the protein was significantly lower. As expected, Cybb - / ...

Embodiment 3

[0045] Example 3: Production of Curcumin-loaded Nanoparticles

[0046] Curcumin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles were prepared using a modified double emulsification method (W1 / O / W2 emulsion; see Zhong et al. 2010, J. Nanobiotechnology 8:6). Briefly, curcumin was dissolved in 500 μL of alcohol (W1), while PLGA (PLA:PGA = 50:50, MW = 60,000) was dispersed in dichloromethane (O). W1 was added to O and mixed with a probe-type ultrasonic vibrator to form the first emulsion. The first emulsion, W1 / O, was added to 1% polyvinyl alcohol (PVA) aqueous solution (W2) and stirred to form a second emulsion (W1 / O / W2) containing PLGA nanoparticles. The second emulsion was then degassed under vacuum to remove the organic solvent, and any free curcumin and remaining PVA were removed by centrifugation. By using the NanoDrop 1000 TM (U.S. NanoDrop Technologies Co., Ltd.) measured the optical density at 435nm to analyze the average loading of PLGA nanoparticles.

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Abstract

A method for treating a disease caused by protein retention in the endoplasmic reticulum (ER) with a sarcoplasmic / endoplasmic reticulum calcium ATPase pump inhibitor encapsulated in a polymer nanoparticle. The polymer nanoparticle is surface modified such that it is targeted to the ER. The inhibitor reduces protein retention in the ER and the encapsulation lowers side effects of the inhibitor, e.g., cytotoxicity, as compared to administering the inhibitor without encapsulation. Also disclosed is a pharmaceutical composition that can be used for carrying out the method. Further provided is a transgenic mouse carrying in its genome a heterologous nucleic acid that encodes an H338Y mutant gp9lphx protein. The transgenic mouse can serve as a model for human chronic granulomatous disease.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 652,502, filed April 4, 2018. Background technique [0003] Chronic granulomatous disease (CGD) is a primary immunodeficiency disease caused by a defect in nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) in leukocytes. See, eg, Holland 2013, Hematol. Oncol. Clin. North Am. 27:89-99; O'Neill et al. 2015, Redox Biol. 6:135-156; and Roos 2016, Br. Med. Bull. 118:50 -63 (Roos). NOX2 is regulated by the membrane-bound subunit gp91 phox and p22 phox , and the cytosolic component p40 phox , p47 phox , p67 phox and the small GTPase Rac1 / 2. See Roos. CGD patients carrying a mutation in the gene encoding one of the NOX2 component proteins are susceptible to different infections and certain autoimmune diseases due to the lack of NOX2-mediated reactive oxygen species (ROS) produced by activated leukocytes. See Huang et al. 2016, Infl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K47/34A61K47/36A61K47/24A61K47/42A61K47/32A61P7/00A61P11/00A61P17/00A61P27/02A61P7/10A61P35/00A61P25/28A61P3/10A61P7/12A61P3/06A61P19/08A61P1/00A61P1/16A61P7/06A61P5/14A61P5/06A61P9/00A61P7/04A61P9/10A61P21/00A61P25/00A61P9/14A61P43/00A01K67/027
CPCA61K45/00A61K47/34A61K47/36A61K47/24A61K47/42A61K47/32A61P7/00A61P11/00A61P17/00A61P27/02A61P7/10A61P35/00A61P25/28A61P3/10A61P7/12A61P3/06A61P19/08A61P1/00A61P1/16A61P7/06A61P5/14A61P5/06A61P9/00A61P7/04A61P9/10A61P21/00A61P25/00A61P9/14A61P43/00A01K67/0278A01K2227/105A01K2267/0306A01K2207/15A61K31/05A61K31/12A61K31/365A61K31/407A61K31/55A61K31/58A61K31/7048A61K45/06A01K2217/072A01K2267/0387A61K9/5153A61K47/64A61K31/122A61P29/00A61P37/02A01K67/0276A01K2217/075A01K2267/0331A61K47/593A61K47/6925A61P37/00A01K2217/206A61K9/0056A61K36/06A61K36/22A61K36/23A61K36/9062A61K36/9066A01K67/0275
Inventor 谢奇璋颜嘉良谢达斌蒋思澈
Owner NAT CHENG KUNG UNIV
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